This application claims priority over US Provisional Patent Application No. 63/221,871, filed July 14, 2021, which is incorporated herein by reference in its entirety. This application is also a continuation-in-part of US Patent Application Ser. No. 17/148,427, filed January 13, 2021, which claims priority over US Provisional Patent Application No. No. 62/960,564, filed January 13, 2020, which is a continuation-in-part of US Patent Application 17/138,703, filed December 30, 2020, which is a continuation of the Treaty Application Cooperation Agreement No. PCT/US2019/040429, filed July 2, 2019, claiming benefit under 35 U.S.C. § 119(e) as a non-provisional application of US Provisional Patent Application 62/692,858, filed July 2, 2018, and US Provisional Patent Application no. 62/822,881, filed March 24, 2019, each of the above applications are incorporated herein by reference in their entirety.
Neuromas are benign tumors that arise from neural tissue and are composed of abnormally sprouting axons, Schwann cells, and connective tissue. Although neuromas can appear after various types of injuries, some of the most common and difficult to treat are those resulting from trauma or surgical procedures in which neural tissue has been damaged or sectioned. Amputation surgeries require the section of one or more sensory or mixed nerves. Chronic neuropathic pain, attributed to neuroma formation, develops in up to 30% of patients after surgery and results in subsequent challenges with prosthesis use and poor quality of life. In addition to amputation-related and traumatic neuromas, neuromas form in various clinical indications, including general surgery (hernia repair, mastectomy, laparoscopic cholecystectomy), gynecologic surgery (cesarean section, hysterectomy), and orthopedics (arthroscopy, amputation, bone replacement). knee). .
Neuromas develop as part of a normal repair process after peripheral nerve injury. They form when nerve recovery to the distal end of the nerve or target organ fails and nerve fibers regenerate inappropriately and irregularly in the surrounding scar tissue. Neuromas include a disturbed architecture of tangled axons, Schwann cells, endoneurial cells, and perineural cells in a dense collagenous matrix with surrounding fibroblasts (Mackinnon S E et al. 1985. Altering neuroma formation by manipulation of its microenvironment. Plast Reconstr Surg. 76 :345-53). Upregulation of certain channels and receptors during neuroma development can also cause abnormal sensitivity and spontaneous activity of injured axons (Curtin C and Carroll I. 2009. Cutaneous Neuroma Physiology and Its Relation to Chronic Pain. J. Hand Surg Am 34:1334-6). Randomly arranged nerve fibers are known to produce abnormal activity that stimulates central neurons (Wall P D and Gutnick M. 1974. Continuous Activity in Peripheral Nerves; Physiology and Pharmacology of Impulses Arising from Neuroma. Exp Neurol. 43:580-593 ). This ongoing abnormal activity can be increased by mechanical stimulation, for example, of the constantly rebuilding scar at the lesion site (Nordin M et al. 1984. Ectopic Sensory Discharges and Paraesthesia inpatients with Disorders of the Peripheral Nerves, Dorsal Roots , and Dorsal Columns Pain 20:231-245 Scadding J W 1981. Development of continuous activity, mechanosensitivity, and adrenaline sensitivity in severed peripheral nerve axons Exp Neurol 73:345-364).
Nerve stump neuromas, or continuum neuromas, are inevitable consequences of nerve damage when the nerve is unrepaired or unrepairable and can cause debilitating pain. It is estimated that approximately 30% of neuromas become painful and troublesome. This is particularly likely if the neuroma is present on or near the surface of the skin, since physical stimulation induces signaling in the nerve, resulting in a sensation of pain.
The number of amputees in the world has increased significantly in recent years, with war injuries and disvascular diseases such as diabetes accounting for approximately 90% of all amputee cases. Currently, approximately 1.7 million amputees live in the United States alone, and more than 230,000 new amputees are discharged from hospitals annually. Furthermore, it is estimated that there will be a 20% increase in the number of new amputees per year by 2050.
Unfortunately, due to persistent pain in the remaining limbs, around 25% of amputees are unable to begin rehabilitation, let alone resume normal daily activities. The cause of this pain could be a neuroma. A recent study reported that 78% of amputees experienced mild to severe pain as a consequence of neuroma formation during the 25-year study period, of whom 63% described the pain as constant pain. Pain is also often described as sharp, sharp, or phantom electrical sensations that persist for years after surgical amputation. In addition, patients present with tenderness of the skin overlying the neuroma, spontaneous burning pain, allodynia, and hyperalgesia.
Although various methods have been used to prevent, minimize, or protect neuromas in an attempt to minimize neuropathic pain, the current clinical "gold standard" for the treatment of neuromas is traction neurectomy, in which the nerve is it pulls forward under traction and is severed as far as possible. back as possible. possible in the hope that if a neuroma forms, it will be located deep in the tissue. Another well recognized approach is to bury the proximal end of the nerve (which will form the neuroma) in the muscle or in a hole made in the bone. The nerve is then sutured to the muscle or periosteum of the bone to maintain its position. The reason for this is that the surrounding tissue cushions and insulates the neuroma to inhibit stimulation and the resulting painful sensations. However, this procedure can greatly complicate surgery, as significant additional dissection of healthy tissue is required to position the nerve stump. This, along with the poor and variable efficacy, the lack of appropriate/available tissue, and the additional time required for the procedure, results in a procedure that is rarely performed to prevent neuroma formation.
Another method is to cut the nerve stump back to leave a protruding segment or cuff of epineurium. This crest can be ligated to cover the face of the nerve stump. Alternatively, a segment of epineurium can be acquired from other nerve tissue or a corresponding nerve stump can be cut to create an epineurium sleeve that can be used to connect and cover the other nerve stump.
Yet another commonly used method is suture ligation, where a loop of suture is placed around the end of the nerve and tightened. This pressure is thought to mechanically block the exit of the axons and cause the terminal end to eventually form scar tissue over the site. However, clinical and preclinical evidence has shown that this procedure can lead to the formation of a painful neuroma behind the ligation. Also, the ligated nerve is usually not placed to minimize mechanical stimulation of the neuroma, as the scar tissue is expected to provide sufficient protection for the nerve end.
Other methods used clinically include placing the nerve stump inside a solid biodegradable polymer or silicone implantable tube with an open or, more recently, sealed end (eg, Polyganics NEUROCAP) or a closed tube with a shelf ( eg, AXOGEN Nerve Cap®); wrapping the proximal end of the nerve with a harvested vein or fat graft, again with the goal of providing a physical barrier to aberrant nerve regeneration. The use of biomaterial devices and implantation methods requires insertion followed by fixation of the nerve with sutures at the opening of the device, which can be difficult and further damage the nerve end. For example, the current procedure to secure the NEUROCAP requires a suture to be placed at the epineurium of the nerve and through the wall of the tube, then the nerve is pulled and inserted into the lumen of the tube using the suture and multiple sutures are placed. to retain the nerve in the device. These methods and devices can also cause mechanical stimulation of neuroma tissue due to 1) mismatch between tissue flexibility and canal stiffness and 2) the inability of the cap to prevent neuroma formation within the cap due to potential space, with the consequent sensation of pain. Although these nerve capsules degrade over a period of 3 to 24 months, substantial degradation-mediated mass loss occurs within the first 3 to 6 months, resulting in exposure of a temporarily protected neuroma to the surrounding environment. and fragments that stimulate fibroblast infiltration and scar formation around the healing nerve. As a result, the effectiveness of these preformed implantable caps is limited by the cap's ability to conform to the proximal end of the nerve to prevent neuroma formation and, secondarily, its subsequent degradation to expose the neuroma to the surrounding environment and products. an adverse inflammatory response. Finally, as these methods require suturing with fine threads (9-0 or 8-0 nylon), the procedure time and skill required to secure these implants with surgical magnification (loupes) or an operating microscope prevent surgeons from more widely adopting these methods. procedures.
Unfortunately, current methods of addressing the formation and pain caused by neuromas have not been widely adopted. Therefore, there remains a need for an effective technology or therapy to control or inhibit neuroma formation after planned or inadvertent surgical or traumatic nerve injury, in addition to reducing scarring.
A variety of biomaterial conduits have been explored preclinically to attempt to prevent neuroma formation, including other solid implantable biodegradable polymeric conduits based on polylactide/polycaprolactone sciatic nerve, J Neurosurg. P. 1-9; Yan et al (2014) Mechanisms of Nerve Sparing Technique to Prevent Formation of Painful Neuromas, PLOS One, 9(4) p. 1-11; Yi et al (2018) Prevention of painful terminal neuroma by plugging the PGRD/PDLLA duct in rat sciatic nerves Adv. Sci, 1-11), atelocollagen (Sakai et al (2005) Prevention and treatment of amputation neuroma using an atelocollagen tube in rat sciatic nerves. J Biomed Mater Res Part B: Appl Biomater 73B: 355-360) or submucosa from porcine small intestine (Tork et al (2018), ePoster: Preventing Neuromas with a Porcine SIS Nerve Cap: Histopathological Evaluation, http://meeting.handsurgety.org/files/2018/ePosters/HSEP106.pdf) or microcrystalline chitosan (Marcol et al (2011) Reduction of post-traumatic neuroma and epineural scar formation in rat sciatic nerve by application of microcrystalline chitosan, Microsurgery, 31: 642-649). To date, these approaches have not been successful in preventing neuroma formation because, again, solid implants do not form in situ and create a potential space to allow for nerve growth and varying degrees of neuroma formation or, most importantly, because the in vivo persistence of the materials was not sufficient to prevent neuroma formation.
Other technological applications aimed at nerve involvement or coaptation to prevent aberrant growth of axons and stimulate nerve regeneration are also described. In particular, methods of protecting nerves by wrapping them in in situ-forming hydrogels administered within a form of temporary wrap or methods of aiding nerve regeneration using permissive/growth-supporting solutions or gels, rapidly resorbable thin-film wraps in combination with In situ formation inhibitory hydrogels are described.
There is provided, in accordance with one aspect of the present invention, a method of forming a conformable nerve sheath in situ to inhibit neuroma formation in a severed nerve ending. The method comprises the steps of identifying a severed end of a nerve; placing the cut end in a cavity defined by a shape; insert media into the form to surround the cut end; and allowing the medium to undergo a transformation from a relatively fluid first state to a relatively non-fluid second state to form a conformal protective barrier surrounding the severed end. The method may further comprise the step of removing the former to leave a formed biocompatible protective nerve sheath in situ.
Identification of a severed end of a nerve passage may comprise identification of a severed nerve, for example by cutting or ablation or traumatically severed. The former may comprise a nerve guide and the positioning step may comprise positioning the nerve such that the nerve guide keeps the cut end within the cavity away from a side wall of the pin. The tip of the cut end can be positioned at least about 0.1 mm or 2 mm from the sidewall or, more preferably, about 1 mm prior to delivery of the moldable cap. In some embodiments, the shape itself serves as a conformable cap and is placed directly over the end of the severed nerve ending or at 0mm distance. Preferably, the form is bioabsorbable or composed of a non-degradable flexible material that can be easily removed from the surgical site after forming the nerve sheath in situ.
The transformation from the fluid to the non-fluid state can occur within approximately 1 minute, or within approximately 30 seconds, or within approximately 10 seconds from the introduction step. The method may further comprise the step of removing a volume of axoplasm from the severed nerve prior to the introduction step. The method may alternatively comprise the step of performing axon fusion using a "PEG fusion" protocol, described below, prior to placing the nerve within the nerve shape.
In one implementation of the invention, the shape may comprise a first configuration in which the cavity is exposed and a second configuration in which the cavity is partially or completely covered; and further comprising the step of advancing the shape from the first pattern to the second pattern after introducing a nerve pitch. Alternatively, the step of advancing the shape from the first configuration to the second configuration may occur before the rib or media introduction steps. The shape may alternatively comprise an open celled foam, and the cavity comprises a tortuous and interconnected interstitial volume within the foam. In the latter embodiment, the form would remain in place in situ after integration and formation of the rib cap. Alternatively, the form may comprise a porous lyophilized biomaterial that dissolves within minutes to hours after being exposed to physiological fluid. In some cases, the form may comprise a dry preformed cross-linked hydrogel that is hydrated in saline immediately prior to use. The hydrogel can equilibrate and expand in size for 10 minutes to its original size, preferably within 5 minutes, prior to placement in situ. In some embodiments, the hydrogel is a crosslinked hydrogel template that has been dried (eg, lyophilized) and stored in a well in the PETG tray. Saline or other physiological solution is then added to the hydrogel to rehydrate the hydrogel and return it to its original hydrated size. The preformed hydrogel can then be placed in situ under and/or around the nerve prior to administration of the growth inhibitory and/or permissive gel. Such hydrogel molds can be made by crosslinking the tube-shaped hydrogel precursor solutions and then cutting the hydrogel tube longitudinally along the length of the tube to form a half-tube mold.
Identification of a severed nerve step may include the step of cutting a target nerve, such as with scissors, a blade (eg, No.10o no11) or a razor blade. The step may further comprise cutting the rib cleanly at an oblique angle before placing the rib into the shape. Alternatively, the ribs can be severed with a rib cutting or cutting device.
The transformation step may comprise a cross-linking reaction (physical, chemical, self-assembly) or polymerization and may use an in situ-forming hydrogel that may intersperse with interstices in the host tissue to form an adhesion or bond between the hydrogel and the fabric In the preferred embodiment, the hydrogel is a neutral or negatively charged material with submicron or smaller pores that allow nutrient and protein exchange, but not cellular infiltration. In one implementation, the transformation produces a protective barrier of synthetic cross-linked hydrogel through which nerves cannot regenerate around the end of an amputated nerve stump. By crisscrossing the hydrogel at the distal tip of the severed nerve containing the severed axons, the hydrogel provides a physical block to nerve regeneration or neuroma formation and, as it absorbs fluid and equilibrates, draws fluid out of the axoplasm and cellular/cytoplasmic debris. of the severed nerve, thus improving the self-sealing capacity of the axonal membranes.
In accordance with another aspect of the present invention, there is provided a method of forming an implant around a nerve (severed, compressed, intact, repaired) in situ with quick release from a mold. The method comprises the steps of identifying a nerve; placing the nerve in a cavity defined by a shape; introducing means into the cavity to surround the nerve; and allowing the medium to undergo a transformation from a relatively fluid first state to a relatively non-fluid second state to form a protective barrier surrounding the nerve; wherein a hydrophilic feature of the medium cooperates with a hydrophobic feature of the socket to facilitate rapid release of the implant from the socket after transformation.
The positioning step may comprise placing a rib into the socket and allowing the medium to undergo transformation to form a protective barrier surrounding the severed end of the rib. The implant can be removed from the socket by a pulling force of no more than about 10 N, applied for no more than about 5 seconds. In some implementations, the implant can be withdrawn from the socket by a pulling force of no more than about 5 N or a pulling force of no more than about 2 N applied for no more than about 2 seconds. In general, the implant can be removed from the socket in 10 seconds, preferably in 5 seconds, preferably in about 2 seconds, without disrupting the fixation between the implant and the nerve.
The media input step may include input of a first media volume and, after transforming the first volume, input of a second media volume. In one embodiment, the first layer is administered first to position the nerve and a subsequent second layer is administered to completely cover the nerve. In some embodiments, multiple layers are successively distributed as needed, eg, three or more layers. In some cases, focal drops or boluses of hydrogel may be administered to specific locations within the form. For example, a bolus of hydrogel may be administered around the nerve ending and additional "layers" may include filling in the remainder of the form. With less viscous solutions, the liquid can flow to fill the bottom of the mold before crosslinking. In some cases, the form can be tilted intraoperatively or the form can be designed at an angle that causes the solution to flow and fill the bottom of the form. In some cases, the surface (hydrophobicity, wettability, surface roughness/smoothness) can be designed so that the hydrophilic solution pools and forms a dome in the shape of the surface of the material. With more viscous solutions, the liquid may remain at one end or region of the shape due to reduced fluidity, surface tension, and/or convexity/concavity of the shape. In some cases, a bolus of the hydrogel may be administered under the nerve at one or more locations, as dictated by the length of the form. The hydrogel cake is then crisscrossed and stays in place and the nerve is placed on top of the hydrogel away from the casing wall. After this step, the form is filled with hydrogel to complete coverage of the nerve and ensure that the nerve is at least 0.1 mm from the side wall of the form.
Another method of in situ formation of an implant comprises the steps of identifying an implant formation site; positioning a shape that has an implant socket in place; introducing media into the cavity to form an implant precursor; and allowing the medium to undergo a transformation from a relatively fluid first state to a relatively non-fluid second state to form the implant; wherein a hydrophilic feature of the medium cooperates with a hydrophobic feature of the socket to facilitate rapid release of the implant from the socket after transformation.
The implant may be a nerve sheath to inhibit the formation of a neuroma around a severed nerve ending, a sheath to protect the nerve from inflammation and scarring, or it may be a nerve conduit to guide nerve growth. The implant can cover 180 degrees of the circumference of the nerve, or between 180 degrees and 360 degrees (full circumferential coverage). In some embodiments, the gel forms on only one side of the nerve, providing sufficient force to keep the severed nerves in alignment until sufficient wound healing has occurred. Alternatively, the implant may be a tissue augmentation implant or a vascular occlusion device. Alternatively, the implant can serve as a tendon protector or facilitate tendon repair.
A method for forming a nerve sheath in situ may comprise the steps of identifying a severed end of a nerve; placing the cut end in a cavity defined by a shape; inserting media into the cavity to surround the cut end; and allowing the medium to undergo a transformation from a relatively fluid first state to a relatively non-fluid second state to form a protective barrier surrounding the severed nerve end; wherein a hydrophilic feature of the medium cooperates with a hydrophobic feature of the socket to facilitate rapid release of the nerve sheath from the socket after transformation.
The method may further comprise the step of removing the form. The identification step may comprise identifying a surgically severed nerve.
The former may comprise a nerve guide and said positioning step may comprise positioning the nerve such that the nerve guide keeps the cut end within the cavity away from a side wall of the anterior. The cut end can be placed at least about 1 mm from the side wall. The nerve can be covered circumferentially with a layer of at least 0.05mm, preferably at least 0.5mm hydrogel, more preferably at least 1mm hydrogel, although greater thicknesses of hydrogel are also acceptable, with sufficient clearance.
The transformation can take place within approximately 30 seconds after the introduction step, preferably within approximately 10 seconds after the introduction step, preferably within approximately 5 seconds after the introduction step. The method may further comprise the step of removing a volume of axoplasm from the severed nerve prior to the introduction step.
The form may comprise a first configuration in which the cavity is exposed and a second configuration in which the cavity is covered. The method may further comprise the step of advancing the form from the first configuration to the second configuration after the media input step. In another embodiment, the nerve is placed within the cavity of the first configuration, the first is moved to a second configuration in which the nerve is enclosed in the first and the medium is subsequently delivered through a port in the first. The form may have a cup-shaped lid and may have an entry region to retain the nerve and prevent premature leakage of PEG from the form. The shape may comprise an open cell foam and the cavity may comprise an interstitial volume within the foam. The step of identifying a severed nerve includes the step of cutting a target nerve.
The transformation may comprise crosslinking or polymerization. The transformation can produce a protective barrier of cross-linked hydrogel (synthetic, natural). For the prevention of neuroma formation, the protective barrier may have an in vivo persistence of at least about two months or at least about three months, more preferably 6 months or longer. The transformation can cause the medium to increase in volume as it equilibrates with the surrounding tissue in the range of about 2% to about 60% volumetrically or in the range of about 5% to about 30%, preferably from 10 to 30%. .
The method may further comprise the step of placing a shape at a treatment site prior to placing the final cutting step. The method may further comprise the step of forming the shape in situ prior to positioning the final cutting step. The method may further comprise distributing the medium around the nerve in two successive steps. The steps of cutting a target nerve and placing a shape at a treatment site can be accomplished using a single instrument.
The viscosity of the fluid medium may be less than 70,000 cps, preferably less than 10,000 cps, more preferably less than 500 cps. In one embodiment, the viscosity of the fluid medium is similar to that of water (~1 cps). The density of the fluid medium can be less than 1.1 g/cm3. The shape may comprise a biocompatible silicone. The form may contain one or more integral silicone pins to seat the rib. The form may contain a biodegradable polymer post for seating the nerve which remains in situ after formation of the hydrogel. In one embodiment, the polymer post is lyophilized in place and in another embodiment, the polymer post is adhered to the form with a biocompatible adhesive. In one embodiment, the biodegradable polymer post remains in situ with the hydrogel cap and separates from the silicone liner when the silicone liner is removed. In another embodiment, the complete shape may comprise PEG, with or without an integral PEG post to seat the nerve. In the latter embodiment, the form will remain in situ and will degrade within the degradation time frame of the hydrogel. In some embodiments, the publication is a layer or shelf at one or more locations within the form. Longer forms may require more posts to lift the rib away from the form wall. The post, pad, or cap may be preformed, as described above, or may be formed intraoperatively prior to placing the nerve in the form.
Applications to support nerve survival or regeneration. In some modalities, such as situations where a nerve is in continuity and needs protection during healing after trauma or compression, a hydrogel that forms in situ with different characteristics than the hydrogel designed to prevent neuroma formation is desired. In situations where it is desirable to protect a nerve from scar tissue and abnormal growth of damaged nerves, such as after nerve neurolysis, separating a nerve from surrounding tissue, a hydrogel with a shorter in vivo degradation time is preferred. . Instead of the degradation profile described above, without significant degradation at 3 months to avoid neuroma formation during the regenerative period, nerve protection can be performed in a shorter period of time: hydrogels with 3-month degradation profiles , preferably substantially degraded within 6 weeks, most preferably it is desirable to substantially degrade within 4 weeks. Furthermore, unlike hydrogels designed to prevent a neuroma, the balanced swelling of protective hydrogels should be sufficient to accommodate edema in the pinched nerve, increasing volumetrically by 5-100%, preferably 20-60%. , more preferably between 25 and 40%. volumetrically. Since these hydrogels are delivered circumferentially around the nerves, the hydrogels must be designed to swell in a radial outward direction, expanding the lumen around the nerve to accommodate any neural edema or swelling that occurs after nerve damage. As these hydrogels are delivered around a nerve continuum or a repaired or decompressed nerve, the cavity in which they are formed has an inlet and outlet, allowing the nerve to be placed through the continuum atraumatically. In still other embodiments, after partial or complete section of the nerve where the nerve fibers are not in continuity, disclosed herein is a dual component that forms an in situ biomaterial composition comprising a component that allows for nerve regeneration and a component It inhibits nerve growth. In some embodiments, the growth-enabling gel is composed of natural polymers to form a viscous solution, either as a result of the solid content of the biomaterial or of physical crosslinks or physical associations that result in the formation of a homogeneous viscous solution. In some embodiments, the growth-enabling component comprises a heat-sensitive hydrogel that forms in situ and the growth-inhibiting component comprises a chemically crosslinked hydrogel that forms in situ. In other embodiments, the growth-enabling component comprises a physically crosslinked hydrogel or a viscous solution. Examples of matrices that allow growth are provided in Pabari et al 2011. Recent advances in artificial nerve conduit design: strategies for applying luminal fillers. J. Controlled Release, 156, 2-10, incorporated herein by reference. The in vivo persistence of the growth inhibitory component around partially or completely severed nerves is longer than that of hydrogel administered around continuous nerves, as the growth inhibitory component must support the nerve load until the proximal stump of the nerve The regenerating nerve crosses the distal stump and can begin to take some of the load/tension on the nerve again. Preferably, the hydrogel "wrap" around the nerve will transport load circumferentially and prevent immune infiltration until the nerve regenerates and then degrades to transfer the natural tension of the nerve to the regenerated native tissue. In yet other embodiments, the hydrogels can be adapted for use to support regeneration and recovery of function after allograft and conduit implantation. In one embodiment, the hydrogel is distributed around the allograft to improve manageability and aid in coaptation with the severed nerve. For example, after selecting the autograft threads to match the length and diameter of the transected nerve, the threads can be attached using the hydrogel that forms in situ as an artificial epineurium. This can be accomplished by temporarily positioning the leads and delivering the hydrogel focally at one or more points along the bundles. The hydrogel can also improve the cutability and overall handling of the graft tissue. In a similar approach, the hydrogel formed in situ can be routed around a canal (solid, porous grid/strut) to adhere the canal to the sectioned proximal and distal stump with or without sutures.
Hydrogel formed in situ with grooves on the outer surface. In some embodiments, the hydrogel is dispensed in a form having a series of parallel raised protrusions on the interior surface (wall) of the form. In this way, a corresponding series of channels will be formed on the outer surface of the hydrogel formed in situ. These channels are designed to guide and align scar tissue formation around the nerve to better align any tissue responses. These channels can be from 10 to 500 microns wide, more preferably 100 to 200 microns deep, and will align fibrin and other extracellular fibers longitudinally around the shape, thus preventing circumferential compression of the formed hydrogel and instead they will align the tension longitudinally as clinically relevant to the nerve.
In some embodiments, the hydrogel is administered in situ around a fluted sheet that has been previously placed around the severed nerve endings. Since hydrogel precursors are low in viscosity, the solution will flow into the grooves prior to gel formation, leaving grooves on the inside of the hydrogel shell or conduit after crosslinking. These formed-in-situ internal ridges are designed to guide nerve regeneration through the gel sheath or conduit. Extending Schwann cells and then axons will find their way into these cristae and help guide subsequent regenerating fibers through the gap. The ribbed sheet can be rapidly dissolved and dissipated from the site or dissolved in the growth-enabling solution within an hour, several hours, or several days after placement in vivo. The dissipation will put the nerves in direct contact with the hydrogel to help guide regeneration. In some cases, the lamina striatum can remain in place for a month or more and provide the surface on which nerves regenerate. The ribbed lamina can provide adequate or improved attachment of the hydrogel to the lamina and adjacent neural tissue.
In some applications, the technology can provide a temporary nerve sheath or wrap a nerve until nerve damage occurs or until another surgeon can definitively address the nerve damage through their preferred method of nerve repair. These situations can occur clinically when a patient presents with trauma to an emergency room. In these circumstances, the surgeon focuses on repair of the primary trauma and stabilization of the patient and may not focus on nerve repair. As a result, a second surgery can be performed a week to several months after the initial injury to repair the nerves. In these circumstances, surgeons are often faced with extensive post-procedure scar tissue formation, both around the nerve and at the tip of the severed nerve. The nerve tip may also have some early evidence of neuroma formation. To prevent this, hydrogels that are formed in situ can be administered as a cap (around the end of a severed nerve) or as a wrap (around a nerve to prevent scar tissue from forming around the nerve) to provide an environment protector around the nerve. nerve until it can be repaired. At the time of secondary surgery, the hydrogel formed in situ can be removed around the nerve with forceps and discarded. The purpose of this is to reduce the distance a nerve is cut to healthy tissue. These smaller spaces and the closer apposition between the nerves may lead to better results. In some situations, the hydrogel prevents scar tissue around the nerve and maintains the health of the nerve until it can be repaired. Additionally, the hydrogel can be applied around the proximal and distal nerve stump to prevent nerve retraction that normally occurs after nerve section. By preventing nerve retraction and the gap between severed nerve endings, the rate of nerve recovery will be higher because the length of the gap is directly related to successful nerve repair outcomes.
In some embodiments, the nerve growth enabling component is administered first and the nerve growth inhibitory component is administered second. The nerve growth permissive component has sufficient mechanical integrity to prevent the growth inhibitory component from entering the desired regenerative growth zone.
In some embodiments, the nerve ingrowth components conform to the nerve and facilitate nerve ingrowth into, through, and through the ingrowth-enhancing biomaterial in the distal stump. In some embodiments, the nerve ingrowth component is injected between the proximal and distal ends of the severed nerve. In other embodiments, the permissive component of nerve growth is distributed around the nerve circumferentially at the site of compression, crush, partial cross section, full cross section with no gap, or full cross section with gap. In one embodiment, the growth-enhancing component is a flowable composition and can be spread in the area between damaged or cut fibers. In some embodiments, the growth-enhancing biomaterial is a temporary filler that prevents the growth-inhibiting biomaterial from accessing damaged nerves and inhibiting regeneration.
In some embodiments, the nerve growth inhibitory components prevent nerve growth in the material. Preferably, the nerve growth inhibitory component covers the distal and proximal nerve growth-enabling material and stumps for a distance of at least 2 mm in each direction, more preferably a distance of 10 mm. In this way, the infiltration of immune cells into the regenerating nerve fibers is limited and the typical contraction of the regenerating nerve cable is avoided.
In some embodiments, the nerve growth inhibitory components act as a guide on or along which nerve regeneration can occur.
In yet another embodiment, the nerve growth inhibitory components are formed or drawn into fibers or rods and are provided in the nerve repair kit. These fibers or rods are then deposited within the permissive region of growth that runs in the same axis as the nerves to help guide regenerating axons. These fibers can be between 1 micron and 500 microns in diameter, preferably 10 microns and 50 microns in diameter, which makes it possible to discover the path of the nerve through a structure. These fibers are present long enough to allow nerve regeneration and then degrade to allow future regeneration along the tracts created by the first wave of neural regeneration. The fibers can be made and loaded into the lumen of the syringe. At the time of use, the hydrogel is aspirated into the lumen of the syringe, infiltrating and incorporating into the fibers. The delivery system then delivers the hydrogel and encapsulated fibers into the space between the proximal and distal nerve.
In one embodiment, the growth-enhancing biomaterial is temporarily placed as a barrier to the growth-inhibiting biomaterial and discarded after in situ formation of the growth-inhibiting hydrogel has occurred. Removal of the growth-enabling biomaterial can occur within 1 hour to 3 months after delivery of the growth inhibitory material, preferably 1 hour to 2 months, more preferably 1 hour to 3 days. In the latter case, the rapid dissolution of the growth-enabled biomaterial removes any physical barrier to neuron regeneration in the case of close apposition between two nerves (proximal and distal tips), either by suture or sutureless placement.
In some embodiments, the components of the biomaterial comprise crosslinked gel formed in situ, thermosensitive hydrogel formed in situ, thermoreversible hydrogel formed in situ, viscous solutions of synthetic or natural polymers, microparticles, nanoparticles, foam, paste of hydrogel microparticles, or micelles.
In some embodiments, both the growth-enhancing and growth-inhibiting components contain polyethylene glycol (PEG).
In some embodiments, the PEG is a multi-armed PEG. In some embodiments, the PEG is a linear PEG. In some embodiments, the growth inhibitory PEG comprises a multi-armed PEG and the regenerative growth PEG comprises a linear PEG.
In some embodiments, the PEG comprises a urethane or amide linkage.
In some embodiments, the PEG comprises an ester and/or amine linkage.
In some embodiments, the PEG further comprises a straight-ended PEG of 5000 Daltons or less, such as PEG 3350.
In some embodiments, the crosslinking is between a PEG-NHS ester and a PEG-amine or a trilysine.
In some embodiments, the growth-enabling gel contains pores that are 1 µm in size or larger.
In some embodiments, the growth-enabling gel contains rods or filaments.
In some embodiments, the growth-enabling component contains chitosan, collagen, laminin, fibrin, fibronectin, gelatin, alginate, hyaluronic acid, HPMC, CMC, other natural material, or combinations thereof. In some embodiments, the growth-enabling component contains a synthetic material, such as polyethylene glycol or pluronic (eg, F127). In other embodiments, these components or regions of these components are covalently conjugated to each other. In another embodiment, these components are physically mixed.
In some embodiments, the growth-promoting component contains polylysine, preferably between 0.001 and 10% by weight, more preferably between 0.01 and 0.1% by weight.
In some embodiments, the nerve-enhancing components contain between 0.001 and 20% collagen, preferably between 3 and 6% by weight.
In some embodiments, the component that enables nerve growth contains fibronectin.
In some embodiments, the growth-enabling component contains poly-L-ornithine.
In some embodiments, the growth-enhancing component includes laminin, preferably between 0 and 5% by weight, more preferably between 0 and 0.5%.
In some embodiments, the swelling of the growth-enabling component is less than 20%, preferably between 0 and 20%. In some embodiments, the viscosity of the growth-enabling component is greater than 5,000 Cps, preferably between 7,500 and 150,000 Cps, more preferably between 10,000 and 20,000. In some embodiments, the Young's modulus of the growth-promoting component is less than 2 kPa, preferably less than 1 kPa, most preferably less than 600 Pa. In one embodiment, the growth-promoting component is a soft gel with a Young's modulus between 100 and 300 Pa. In some embodiments, the osmolarity of the gel that allows growth is between 275 and 320 mOsm, preferably between 280 and 320 mOsm.
In some embodiments, the swelling of the growth inhibitory component is less than 50%, preferably between 0 and 30%, more preferably between 5 and 20%. In yet another embodiment, the swelling of the growth-enabling component is the same as that of the growth-inhibiting component.
In some embodiments, the swelling of the growth-promoting component is less than or equal to the swelling of the growth-inhibiting component.
In some embodiments, the compression modulus of the growth inhibitory component is greater than 50 kPa, preferably >10 kPa, more preferably >20 kPa.
In some embodiments, the growth-enabling component and the growth-inhibiting component are different colors.
In some embodiments, the growth-enabling region comprises agents that promote nerve survival, growth, and regeneration.
In some embodiments, the permissive region of growth allows infiltration of Schwann or other supporting cells. In some embodiments, the region that allows for growth can be loaded with cells prior to placement in situ. The growth inhibitory region can prevent these cells from migrating out of the implantation site. In some embodiments, the system contains support cells, such as glial cells, including Schwann cells, oligodendrocytes, or progenitor cells, such as stem cells.
In some embodiments, a composition includes agents that may comprise one or more growth factors, anti-inhibitory peptides or antibodies, and/or axon guidance signals.
In some embodiments, the region that allows growth can be administered with a precision syringe, preferably with an 18 gauge or larger needle in volumes of 10 microliters to 5 milliliters. Smaller volumes of less than 100 microliters can be delivered to smaller nerves or partially severed nerves, and larger volumes can be delivered to partial or complete lesions in larger nerves.
In some embodiments, the system distributes to peripheral nerves, ventral or dorsal roots, sympathetic ganglia, cauda equina, spinal cord, brachial plexus, tarsal tunnel, or brain. In yet other embodiments, the system can be distributed around a peripheral neurovascular bundle or tendon. In some embodiments, the patch is delivered to the nerves without using the form, although use of the form is preferred. In some embodiments, the hydrogel is delivered on a silicone sheet that is in the shape of a "sign" to prevent spread of the hydrogel off-target.
In some embodiments, the growth inhibitory and growth permissive region includes a P2XR receptor antagonist.
In some embodiments, the P2XR receptor antagonist is a P2X7 receptor antagonist, including Brilliant Blue FCF (BB FCF) or Brilliant Blue G (BBG). In some embodiments, the P2XR antagonist is a P2X3 receptor antagonist, such as AF-219 or gefapixant. In some embodiments, the concentration of the P2XR antagonist is between 0.001 and 0.55% of the hydrogel.
In some embodiments, the hydrogel is administered circumferentially around a nerve. In yet other embodiments, the hydrogel is distributed only partially over the nerve surface, eg, 25-85%, preferably 50-80% of the nerve circumference. In yet other embodiments, multiple wraps are administered in sequence to cover longer lengths of nerve. For example, in some modalities between one and four hydrogel wraps are placed around the nerve in situations such as after ulnar nerve transposition when a large portion of the nerve has been released and moved. In yet other embodiments, if a nerve needs protection but is a vascular nerve or bifurcates in the region where sheathing is desired, the sheath can be cut with surgical scissors intraoperatively to allow room for the bifurcated nerve to exit the sheath outside of the sheath. the wrapping region. available output of the Wrap form.
In some embodiments, the length of the cap shape or the wrapper shape is between 10mm and 60mm, depending on the length of the rib. For smaller ribs less than 4mm in diameter (small rib array), preferably the cap-shaped or shell-shaped cavities are between 11mm and 40mm in length, preferably 15mm to 20mm in length . For the cap shape, preferably at least 5mm in length of the nerve should be covered with hydrogel to entrap the nerve in the hydrogel, more preferably at least 10mm in length of the nerve. As a result, to preferably secure 1 mm of hydrogel around the nerve tip, the length of the cap-shaped cavity should be approximately 11 mm in length, preferably 15 mm in length for small nerve coverage. For the cap shape and the wraparound shape, the longer sockets are preferred for the larger ribs due to the longer length of these ribs being exposed and therefore the sockets are on the order of 15mm to 60mm in length. mm, more preferably from 20 mm to 50 mm. the length of the cavity.
In some embodiments, a kit is disclosed that includes two or more hydrogels formed in situ. The kit includes a dual applicator system clearly marked as a growth permitting applicator and a dual applicator system clearly marked as a growth inhibiting applicator. Each component can be clearly color coded and includes a vial of powder, diluting/reconstitution solution, and accelerator solution for use in the dual applicator system. The kit may also include one or more shapes: one shape to receive the growth-inhibiting hydrogel, the other for the growth-enabling hydrogel. The kit may include a bioabsorbable form to receive the growth-enabling biomaterial, followed by a temporarily non-degradable form to subsequently receive the growth-inhibiting hydrogel. In yet another embodiment, a kit is described that includes a hydrogel formed in situ and a low viscosity gel solution (viscosity between 5,000 and 30,000 Cps with a modulus less than 1 kPa). The kit includes a dual applicator system clearly marked with indices as a growth inhibitor applicator and a syringe/applicator system clearly marked as a growth permitting applicator. The kit may also include one or more forms: a form for receiving the growth-enabling gel solution that is biodegradable and a form for receiving the growth-inhibiting hydrogel that is degradable. In one embodiment, the biodegradable form for receiving the growth-enabling gel solution is a biodegradable cling sheet that adheres to the nerve when wet and resorbs several days after application. In another embodiment, the biodegradable form degrades in one to two months and becomes positively charged to facilitate the spread of neuritis.
In some embodiments, a method of delivering dual gels including a formed-in-situ hydrogel and a low-viscosity gel to treat conditions affecting nerves is described herein. Nerves may need repair, such as end-to-end anastomosis, coaptation, allograft or autograft, or conduit or sheath repair, or gap repair. The dual gel system can be applied around the site of anastomoses between the proximal nerve and distal nerve stump, the proximal nerve and allograft nerve or lead(s), or as a connector-assisted coaptation where the connector is delivered by hydrogel formation in situ. The dual gel system can be provided as an adjunct to suture repair or, preferably, without suturing the nerve tissue.
In some embodiments, a region that allows for growth is distributed between the proximal and distal nerve stumps, between the end-to-end anastomosis sites, between the proximal stump and the allograft/autograft, and between the allograft/autograft and the distal stump. . .
In some embodiments, a region that allows growth is injected between the proximal and graft and/or the graft and distal stumps, with or without the aid of a mold. The growth allowing solution may comprise a volume of about 5 µl to 3 ml, more preferably 10 µl to 1 cc. Sufficient volume should be provided to fill the space between the nerve and also cover 1 mm or more of the length of the proximal and distal nerves, preferably 2 to 5 mm of the length of the proximal and distal nerves.
In some embodiments, the growth-enabling region is delivered within a conduit or enclosure. In some embodiments, the growth-permitting region is distributed within a lyophilized PEG conduit or shell. The lyophilized PEG may comprise a cross-linked multi-arm PEG, a multi-arm PEG, a linear PEG solution, or a combination thereof that provides sufficient structural support during the procedure as a temporary way to prevent off-target spread of the material. growth permit. After the procedure, the form is removed from the site in 3-5 days, preferably less than 1-2 days.
In some embodiments, a regrowth-permitting region is administered in a form that allows the regrowth-permitting gel to adhere to the nerves, but not to form. In yet another embodiment, the regrowth-enabling region is supplied in a porous form that allows the regrowth-enabling gel to adhere to both the nerve and the form. The growth-permitting region is sandwiched into the pores of the bioabsorbable form to provide good adhesion to the form.
In some embodiments, a growth inhibitory region is distributed after the growth permissive region. In some embodiments, a growth-inhibiting region is distributed around the growth-permitting region, completely covering the growth-permitting material. In another embodiment, a growth inhibitory region layer is first distributed in the manner followed by rib placement, growth inhibitory region distribution, and subsequent growth inhibitory region final layer distribution.
In some embodiments, a region that inhibits growth covers the proximal and distal nerves and the region that allows growth. In some embodiments, the growth inhibitory region extends across the proximal and distal nerves of the anastomosis view at least 2 cm in each direction, preferably 1 cm in each direction, preferably providing 5 mm of coverage of each nerve stump.
In some embodiments, a kit can include a hydrogel that forms in situ. The kit includes a dual applicator system and a vial of powder, diluting/reconstitution solution, and accelerator solution for use in the dual applicator system. The dual applicator system is connected to an application tip, which consists of a static mixer and a blunt needle. The mixer allows the two-component hydrogel to be mixed before it flows through the needle and is distributed around the nerve. The kit may also include a selection of molds in a variety of sizes and lengths to receive the hydrogel.
In some embodiments, a growth inhibitory region covers the junction of the anastomoses or the site of direct nerve coaptation.
In some embodiments, a growth inhibitory region is deployed to cover the junction(s) between the nerve and the conduit or sheath.
In some embodiments, a growth inhibitory region covers a healthy, pinched, or bruised nerve.
In some modalities, the shape has a natural curve to a specific location, following the natural path of the nerves that pass through the tissue (ulnar nerve in the cubital tunnel or tibial nerve in the tarsal tunnel).
In some embodiments, disclosed herein is a formed-in-situ nerve regeneration construct, comprising: a growth-enabling hydrogel bridge having first and second ends and configured to span a space between two nerve endings and facilitate nerve growth across the bridge; and a growth inhibitory hydrogel sheath encapsulating the growth enabling hydrogel bridge and configured to extend beyond the first and second ends to directly contact and adhere to the two nerve endings. In some embodiments, the adhesion of the growth inhibitory hydrogel to the nerves provides sufficient strength to hold the nerves together and support nerve regeneration without the need for sutures. In some embodiments, the nerves can be placed within the biomaterials at an angle or flex over the nerves to relieve the load on the nerve endings and enhance nerve repair.
In some embodiments, a method of stimulating nerve growth between a first nerve end and a second nerve end is described herein, comprising: placing the first nerve end and the second nerve end in a shaped cavity; introducing a growth-enabling medium into the cavity and bringing the first nerve ending and the second nerve ending into contact to form a junction; placing the gasket in a second cavity shape; and introducing growth inhibitory medium into the second well to encapsulate the ligation. In some embodiments, a method of supporting regeneration between a first nerve ending and a second nerve ending is described herein, comprising: placing the first nerve ending and the second nerve ending in a bioresorbable nerve socket and introducing a medium that allows growth in the cavity and in contact with the first nerve end and the second nerve end to form a junction. The bioresorbable medium that allows nerve growth/cavity (eg, sheath or conduit) can be manipulated with forceps as a unit and then transferred to a second cavity shape into which the growth inhibitory medium is administered.
In some embodiments, described herein, a dual component form is used to complete the administration of growth inhibitory and permissive biomaterial without the need for unnecessary nerve manipulation or movement. For example, the form contains a bioabsorbable inner form (eg, chitosan film, HPMC, CMC) that sits within the non-resorbable outer form (eg, silicone). Growth-enabling material is distributed directly in the bioresorbable form and growth-inhibiting biomaterial is distributed between the bioresorbable and non-resorbable forms. In one embodiment, the bioabsorbable form is a thin sheet that, when wet, becomes tacky and sticky. Hydration of the biocompatible biodegradable sheet, which can occur through interaction with naturally moist neural fluids and/or surrounding tissues or through direct application of an aqueous solution, can cross-link in situ to adhere to tissue through physical intercalation. with the tissue surface. After the formation of the hydrogel, the non-resorbable form is removed.
Applications to prevent neuronal regeneration and the formation of neuromas. In some embodiments, described herein is a way of creating a nerve sheath in situ to inhibit neuroma formation, comprising: a concave wall defining a cavity, the wall having a top opening for access to the cavity, the top opening located in a foreground and having an area that is less than the area of a background in accordance with the internal dimensions of the cavity and spacing in the cavity and parallel to the foreground; and a concave nerve guide that passes through the wall and provides lateral access to the cavity.
Applications for nerve protection and regeneration. In some embodiments, described herein is a way of creating an in-situ wrap around a nerve-to-rib junction, comprising: a concave wall defining a cavity, the wall having a top opening for access to the cavity, the top opening lies in a foreground and has an area that is less than the area of a background according to the internal dimensions of the cavity and spaced apart in the cavity and parallel to the foreground; a first concave nerve guide carried through the wall and providing a first lateral access for placing a first nerve end in the cavity; and a second concave nerve guide carried through the wall and providing a second lateral access for placing a second nerve end into the cavity.
In some embodiments, disclosed herein is a composition for a growth inhibitory hydrogel that forms in situ having: compressive strength greater than 10 kDa for greater than 3 months, persistence in vivo for at least 3 months comprising less than 15 % mass loss and/or swelling of less than 30% for more than 3 months. In some embodiments, disclosed herein is a composition for an in situ growth inhibitory hydrogel having: a compressive strength greater than 20 kDa for greater than 6 months, persistence in vivo for at least 6 months comprising less than 15% of in vitro mass loss and/or swelling of less than 20% for more than 6 months. In a preferred embodiment, the growth inhibitory hydrogel to prevent neuroma formation has a compressive strength greater than 30 kDa, an in vivo persistence for more than 4 months comprising a weight loss of less than 15% and/or a less than 20% swelling for more than 4 months. In the preferred embodiment, the growth inhibitory hydrogel bulges radially outward as it degrades, avoiding compression of the nerve. Thus, swelling of the hydrogel occurs along with the loss of tensile strength of the hydrogel, preventing compression of the encapsulated nerve and adjacent structures. In some embodiments, described herein is a Wrap composition for a growth inhibitory hydrogel that forms in situ with a compressive strength greater than 10 kDa for more than 2 weeks, with in vivo persistence of at least 4 weeks and/or swelling. less than 60% in 3 months. In this modality, at least 10% swelling is desirable to accommodate any post-trauma nerve swelling. In a preferred embodiment, the hydrogel swells by at least 20% after equilibration, more preferably by more than 30%, but at no time by more than 60% before removal. In this embodiment, the hydrogel swells enough to allow any inflammation of the nerve and then remains in the nerve to prevent immune cell infiltration and secondarily as degradation and loss of resistance to traction, additional swelling occurs in the external radial direction. slide into the hydrogel. In yet another embodiment, bandages with an even shorter breakdown time are desired to avoid the occurrence of nerve compression in the first postoperative week. These Wrap hydrogels remain in situ for at least 2 weeks in vivo, but are rapidly cleared from the site and are substantially cleared from the site by 4 weeks. These more rapidly degrading Wrap hydrogels allow for slippage during the hydrogel degradation phase, during which the hydrogel forms a viscous solution around the nerve through which the nerve can move freely.
The surface of the gels (lid, shell, conduit) have a surface roughness of less than 0.40mm in certain embodiments, in other embodiments less than 0.15mm. In certain embodiments, the roughness of the outer surface may be between 0.05 and 0.10mm and in certain embodiments between 0.012 and 0.40mm. In certain embodiments, the smooth outer surface of the lid/housing/duct is formed by placing the gel in the shape of the lid/housing/duct. In embodiments where the shape comprises medical grade silicone, the surface of the shape (and therefore of the hydrogel) is determined by the surface of the tool (aluminum, steel) into which the silicone is injected and cured. In certain embodiments, the tools are polished with #15 diamond polisher and/or 600 grit sandpaper to create a smooth surface (SPIA3-B1 or RMA F-2 standard). In certain embodiments, the internal surface of the cover/housing/conduit is finished to SPI SP1 A1, A2, A3, B1, B2, B3 and/or C1 standards.
In some embodiments, the composition includes one or more of: poly(ethylene glycol) succinimidyl carbonate, a P2XR receptor antagonist, such as a P2X7 receptor antagonist.
In some embodiments, a P2X7 receptor antagonist is Brilliant Blue FCF (BB FCF) or Brilliant Blue G (BBG).
In some embodiments, a method of forming a nerve sheath in situ, comprising identifying a section of a nerve; placing the nerve in a cavity defined by a shape; inserting means into the cavity of the form to surround the rib; and allowing the medium to undergo a transformation from a relatively fluid first state to a relatively non-fluid second state to form a protective barrier around the nerve.
In some modalities, the nerve is healthy, compressed, bruised, partially or completely severed. In some modalities, the nerve is transected during the procedure, and in other modalities, nerve damage, such as neuroma formation, occurred between 3 months and approximately 10 years earlier and is excised prior to hydrogel application. In other modalities, the nerve is repaired between minutes and three months after injury, usually between one and 14 days after injury. In other modalities, such as after trauma, when the extent of nerve damage or the ability of the nerve to regenerate is unclear and the surgeon prefers to assess whether nerve function can be recovered without surgical intervention, the surgeon may choose not to do so. perform the procedure within two months to 6 months after the initial nerve trauma.
In some modalities, the nerve is first repaired via direct anastomoses, allograft or autograft repair, or conduit repair prior to administration of the permissive and growth-inhibiting biomaterials.
In some embodiments, the method includes removing the form.
In some embodiments, the shape comprises a nerve guide and the positioning comprises positioning the rib such that the nerve guide keeps the nerve away from a side wall of the shape. In one embodiment, the hydrogel is formed around a nerve placed in a cylindrical tube which is subsequently removed after which the nerve hydrogel is rotated and placed in a second cylindrical tube and a second application of the growth inhibitory hydrogel is applied. By properly positioning the tubes of increasing diameter, the nerve can be delivered into the center of the formed hydrogel. This same approach can be used for permissive or growth inhibitory gel applications.
In some embodiments, a method of forming a nerve sheath in situ includes the nerve being covered circumferentially with a thickness of biomaterial around the nerve of at least 0.1mm of a protective barrier, preferably 0.5mm to 10mm, more preferably from 0.5 to 10 mm. 5mm thick, most preferably 0.2 to 1mm thick.
In some in situ forming hydrogel delivery embodiments in the form of a cap or shell, transformation occurs within about 10 seconds of the introduction step, preferably less than 5 seconds of the introduction step. In some wrap/cap hydrogel delivery modalities, transformation preferably occurs within 15 seconds of the introduction step, or longer as necessary to wrap longer sections of nerve. To accommodate different volumes or gel times, the kits will be designated for small nerves (nerves less than 4mm) and large nerves (nerves greater than 4mm). Kits may also contain different needle gauges to accommodate delivery of different volumes and times of gel to the nerve sheath/wrap. For example, a small nerve kit may contain a 22 gauge needle and a large nerve kit may contain a 20 or 18 gauge needle.
In some embodiments, the transformation comprises crosslinking or polymerization. In some embodiments, the transformation comprises gelling after a temperature change from room temperature to body temperature.
In some embodiments, the transformation produces a synthetic cross-linked hydrogel protective barrier. In some embodiments, the transformation produces a natural protective barrier of cross-linked hydrogel, such as can be achieved with a fibrin sealant (Tisseel, Baxter).
In some embodiments, the protective barrier has an in vivo persistence of at least about two months.
In some embodiments, the protective barrier has an in vivo persistence of at least about three months.
In some embodiments, the protective barrier has an in vivo persistence of at least about 6 months.
In some embodiments, the protective barrier is not degraded in vivo.
In some embodiments, the transformation causes the medium to swell in volume in the range of about 5% to about 100%.
In some embodiments, the transformation causes the medium to swell in volume in the range of about 20% to 60%.
In some embodiments, the method includes forming a shape in situ before placing the cut end; and/or deliver the medium around the nerve in two successive steps.
In some modalities, one-step cutting of the target nerve and one-step one-way positioning of the treatment site are performed with a single instrument.
In some embodiments, the viscosity of the fluid hydrogel precursor medium is less than 70,000 cps, preferably less than 10,000 cps.
In some embodiments, the density of the fluid medium is less than about 1.2 g/cm3, or approximately that of water at 1 g/cm3.
In some embodiments, the shape is comprised of biocompatible medical grade silicone.
In some embodiments, the shape contains integral posts to accommodate longer rib lengths.
In some embodiments, the cap or wrapper form is comprised of PEG.
In some embodiments, the form has a clamshell lid and a separate port or inlet for delivery of the hydrogel.
In some embodiments, the growth inhibitory and permissive region contains a P2XR receptor antagonist.
In some embodiments, the P2XR receptor antagonist is a P2X7 receptor antagonist, including Brilliant Blue FCF or Brilliant Blue G (BBG). In some embodiments, the concentration of the P2XR antagonist is between 0.001 and 0.55% in the hydrogel.
In other embodiments, the growth-permissive and/or growth-inhibiting region contains the antioxidant methylene blue. In other embodiments, the growth permissive and/or growth inhibitor contains FD&C No. 1 alone or in combination with FD&C No. 5 to create blue, turquoise/teal, and various shades of green hydrogels. In other embodiments, the growth-enabling and/or growth-inhibiting region contains straight-ended PEGs (3.35 kDa or 5 kDa or mixtures thereof) with a solids content of 1% to 50% by weight, more preferably 10 to 20% by weight. weight.
In some embodiments, hydrogels formed in situ as a cap are described herein. In some embodiments, the rib cap is not preformed.
Some embodiments, as described herein, include hydrogel scaffolds formed in situ or those that can be formed/wrapped in situ around a nerve. In some embodiments, these hydrogels are delivered without a pre-formed shell or conduit, for example, in a natural wall created by tissue. An example of this is Morton's neuroma, where the nerve can be decompressed or severed between two bones in the foot and the surrounding tissue naturally retains the hydrogel around the nerve. In one embodiment, the hydrogel is then released from the surrounding tissue with forceps and allowed to move within the fascial plane.
In some embodiments, the nerve is prevented from forming a neuroma by administering a "bridge to nowhere" conduit that forms in situ in the form of an in situ formed hydrogel with open lumens that allow regeneration of the nerves along the nerve. and in the hydrogel until its ability to regenerate was aborted. In some embodiments, the channel within the hydrogel is 1 cm or more in length, preferably 2 cm or more in length. In some embodiments, the channel is composed of a rapidly resorbable biomaterial, such as low molecular weight PEG, collagen, hyaluronic acid, or hydroxymethylcellulose, or combinations thereof. The hydrogel is formed around the nerve and canal of rapidly absorbed biomaterial. The biomaterial cast retains its three-dimensional structure long enough to provide a scaffold upon which the growth inhibitory cast can be formed. To achieve this configuration, the nerve is placed in the form of a bioresorbable wrap and the form is filled with the rapidly resorbable material. The Wrap form is wrapped circumferentially around the nerve and the rapidly resorbable biomaterial, after which the growth inhibitory hydrogel is applied around the nerve and wrapped in a second, larger Wrap form. The larger Wrap form can be a biodegradable or non-degradable removable form.
In some embodiments, the hydrogel provides a means of securing the nerve in place with an autologous nerve or an allograft, with or without the use of sutures. In certain embodiments, the need to secure/secure devices is eliminated, preventing suture granuloma or other damage resulting from the use of non-degradable sutures/staples.
In some embodiments, the device adheres solely to neural tissue and does not adhere to adjacent fascia, muscle, bone, tendon, or other non-nerve tissue. This ensures that the device can slide into the space.
In some embodiments, a method of enhancing nerve regeneration results in providing protective compression, i.e., dd
In some embodiments, systems and methods for delivering the hydrogel circumferentially around the nerve in appropriately designed ways are described herein. In some embodiments, the systems and methods may include the use of a specific shape or design of the PEG hydrogel to prevent neuroma formation, such as circumferential delivery and nerve tip coverage, sufficient in vivo persistence beyond time during which the nerves can regenerate (3 months or more), minimal swelling to prevent nerve compression or loss of adhesion between the nerve and the hydrogel, sufficient tensile strength to prevent nerve growth into the hydrogel and deliver them in a removable form.
Provided, in accordance with another aspect of the invention, is a kit for forming in situ an implant for guiding nerve regeneration between two nerve endings. The kit includes first components to produce a first hydrogel that allows growth; second components for making a second growth inhibitory hydrogel; at least one shape that has a concavity; a first applicator to administer the hydrogel that allows growth in the cavity; and a second applicator for delivering the growth inhibitory hydrogel into the cavity.
The first components may include a hydrogel precursor that enables powder growth, a reconstitution solution, and an accelerator solution. The powdery growth-enabling hydrogel precursor may contain an agent for stimulating nerve regeneration. The second components may include a powdered growth inhibitory hydrogel precursor, a reconstitution solution, and an accelerator solution. The first components include a powdery growth-enabling gel precursor and a reconstitution solution. The second components may include a pre-filled syringe containing the growth-enabling gel.
The kit may further include a first shape having a first configuration to receive the growth-inhibiting hydrogel and a second shape having a different second configuration to receive the growth-enabling hydrogel. The concavity may have a surface with a hydrophobic characteristic. At least one of the growth-permitting and growth-inhibiting hydrogels may have a hydrophilic characteristic.
The second form may comprise a biocompatible biodegradable sheet, which may have a thickness of less than about 200 microns, preferably about 60 microns or less, more preferably less than about 40 microns.
A kit for in situ formation of a hydrogel nerve sheath is also provided. The kit may include a dual applicator system; a vial of powdered hydrogel precursor; a reconstitution solution; an accelerator solution; and at least one form of nerve sheath.
A site-formed nerve regeneration construct is also provided. The construct comprises a regrowth-enabling hydrogel bridge having first and second ends and configured to span a space between two nerve endings and stimulate regrowth of the nerve across the bridge; and a growth inhibitory hydrogel sheath encapsulating the growth enabling hydrogel bridge and configured to extend beyond the first and second ends to directly contact the two nerve endings.
Also provided is a way to create a nerve sheath in situ to inhibit neuroma formation. The shape comprises a concave wall defining a cavity, the wall having an upper opening for access to the cavity, the upper opening located in a first plane and having an area smaller than the area of a second plane according to the internal dimensions of the cavity and spaced in cavity and parallel to foreground; and a concave nerve guide that passes through the wall and provides lateral access to the cavity; wherein the concave wall has a hydrophobic characteristic.
The shape is configured to receive a second biodegradable shape that contains the nerve endings to be repaired. The shape may facilitate nerve growth through a nerve-to-nerve junction. The shape may facilitate the formation of a hydrogel to prevent compression of the nerve and the formation of scar tissue around the nerve.
Also provided is a way to create a nerve conduit in situ to facilitate growth through a nerve-to-nerve junction. The shape comprises a concave wall defining a cavity, the wall having an upper opening for access to the cavity, the upper opening located in a first plane and having an area smaller than the area of a second plane according to the internal dimensions of the cavity and spaced in cavity and parallel to foreground; a first concave nerve guide carried through the wall and providing a first lateral access for placing a first nerve end in the cavity; and a second concave nerve guide carried through the wall and providing a second lateral access for placing a second nerve end into the cavity.
Also provided is a composition for an in situ formation growth inhibitory hydrogel. The hydrogel has a compressive strength greater than 10 kDa for more than 3 months; in vivo persistence for at least 3 months comprising less than 15% weight loss and less than 30% swelling for more than 3 months. Degradation of the hydrogel can result in external radial swelling of the hydrogel.
The composition may comprise one or more of an amide-linked biodegradable urethane or polyethylene glycol; a poly(ethylene glycol) succinimidyl carbonate; a P2XR receptor antagonist; a P2X7 receptor antagonist. The P2X7 receptor antagonist can be Brilliant Blue FCF (BB FCF) or Brilliant Blue G (BBG).
The composition may also contain one or more than one polyethylene glycol with a biodegradable ester linkage; a poly(ethylene glycol) succinimidyl adipate; a multi-arm PEG with individual arm lengths between 1 and 10 kDa; preferably greater than 2 kDa, most preferably at least one multi-armed PEG with an arm length of 5 kDa. The total molecular weight of the PEGs is preferably between 10 kDa and 100 kDa, preferably between 10 and 40 kDa.
Also provided is a composition for an in situ formation growth inhibitory hydrogel. The composition comprises a hydrogel having a compressive strength greater than about 10 kPa; In vivo persistence for at least 2 weeks; and initial swelling greater than 20% but less than 100%
Degradation of the hydrogel can result in external radial swelling of the hydrogel with a volumetric swelling of less than about 160%. Hydrogel degradation can occur in as little as 16 weeks. The growth-inhibiting hydrogel can be configured to encapsulate a growth-enabling gel having a Young's modulus of less than about 10 kPa and a viscosity greater than about 5000 cP.
The composition may include one or more of a polyethylene glycol with a biodegradable ester linkage; a poly(ethylene glycol) succinimidyl adipate; a multi-arm PEG with arm lengths between 1 and 10 kDa; or at least one multi-armed PEG with an arm length of 5 kDa.
Also provided is a formed-in-situ absorbable electrode anchor, comprising a volume of hydrogel polymerized in situ around an electrode and configured to maintain the electrode in electrical communication with a nerve. The hydrogel may be electrically conductive.
Also provided is an implant formed in situ comprising a volume of hydrogel which is brought into contact with a form from a relatively fluid state to a relatively non-flowable state and is removed from the form by a tensile force of no more than about 5 N. , in which removal was facilitated by a hydrophilic feature of the hydrogel and a hydrophobic feature of the shape. The formed in situ implant may comprise a nerve sheath, a nerve conduit to guide the regeneration of a nerve, or a nerve sheath to prevent scarring and entrapment of a nerve.
Some modalities, as described here, have been shown to prevent neuroma formation preclinically and 1) eliminate the need to suture, drag, or stuff the nerve into a canal, 2) fit the end of the nerve stump to the provide a physical barrier to the nerve. regeneration, and 3) provide mechanical resistance to prevent nerve regeneration for a period of two months, preferably three months or longer, as needed to prevent nerve growth during the regenerative phase of growth after nerve injury. The form-in-situ implants described in this document can conform to surrounding tissue, adhere to but not compress underlying nerve tissue, are flexible so that they can move over regions of tissue surrounding joints or where nerves glide across tissues. and avoid scar tissue around the nerves and potentially constricting or compressing the nerve. Finally, some of these in situ training implants can be placed without advanced surgical training. In other situations, there remains a need for technology that prevents nerve ingrowth into surrounding tissue and directs regrowth of a severed or pinched nerve to the distal nerve stump or allograft/autograft. Thus, in some respects, a sutureless technology that can direct nerve regeneration from a proximal nerve stump either directly (via direct coaptation/anastomosis with distal nerve stump) or indirectly (via a nerve conduit, canal). guidewire, allograft, autograft), or through a matrix that allows growth into the distal nerve stump. In addition, in some aspects, a technology is disclosed that allows the anastomosis site to be loosened to promote better nerve regeneration. By administering the hydrogel circumferentially around the nerve, stress can be distributed circumferentially and over a distance over the nerve to distribute stress evenly across the nerve surface. In doing so, the stress is transferred to the hydrogel and does not arise at the focal points of the three or four sutures at the anastomotic sites. As is done within the canals, by creating a space in the nerves (positioning them with a curve) prior to administration of the growth inhibitory hydrogel, additional slack can be achieved so that tension at the anastomotic site is minimal. Finally, in some respects, a versatile technology that can be rapidly and widely applied to nerves is desirable to prevent inadvertent damage to adjacent nerves during a variety of surgical procedures.
Also provided is a kit for in situ formation of an implant to guide nerve regeneration between two nerve stumps. The kit includes first components to produce a first hydrogel that allows growth; second components for making a second growth inhibitory hydrogel; at least one shape that has a concavity; a first applicator to administer the hydrogel that allows growth in the cavity; and a second applicator for delivering the growth inhibitory hydrogel into the cavity.
The first components may include a hydrogel precursor that enables powder growth, a reconstitution solution, and an accelerator solution. The second components may include a powdered growth inhibitory hydrogel precursor, a reconstitution solution, and an accelerator solution. A first shape with a first configuration to receive the growth-inhibiting hydrogel and a second shape with a different second configuration to receive the growth-enabling hydrogel may also be provided. The concavity may have a surface with a hydrophobic characteristic. At least the hydrogel that allows growth can have a hydrophilic character.
A kit for in situ formation of a hydrogel nerve sheath is also provided. The kit consists of a double applicator system; a vial of powdered hydrogel precursor; a reconstitution solution; an accelerator solution; and at least one form of nerve sheath.
Also provided is a formed-in-situ nerve regeneration construct comprising a growth-enabling hydrogel bridge having first and second ends and configured to span a space between two nerve endings and stimulate nerve growth across the bridge; and a growth inhibitory hydrogel sheath encapsulating the growth enabling hydrogel bridge and configured to extend beyond the first and second ends to directly contact the two nerve endings.
Also provided is a way of creating a nerve sheath in situ to inhibit neuroma formation, comprising a concave wall defining a cavity, the wall having a top opening for access to the cavity, the top opening being in the foreground. and has an area that is less than the area of a second plane conforming to the internal dimensions of the cavity and spacing in the cavity and parallel to the first plane; and a concave nerve guide that passes through the wall and provides lateral access to the cavity. At least the surface of the concave wall can have a hydrophobic character.
Also provided is a way of creating a nerve conduit in situ to facilitate growth through a nerve-to-nerve junction, comprising a concave wall defining a cavity, the wall having a top opening for access to the cavity, the wall being top opening in close-up. and having an area that is less than the area of a second plane conforming to the internal dimensions of the cavity and spacing in the cavity and parallel to the first plane; a first concave nerve guide carried through the wall and providing a first lateral access for placing a first nerve end in the cavity; and a second concave nerve guide carried through the wall and providing a second lateral access for placing a second nerve end into the cavity.
Also provided is a composition for an in situ formed growth inhibitory hydrogel having a compressive strength greater than 10 kDa for greater than 3 months; an in vivo persistence for at least 3 months comprising less than 15% mass loss; and swelling of less than 30% for more than 3 months. The composition may comprise polyethylene glycol succinimidyl carbonate. The hydrogel may contain a P2XR receptor antagonist and/or a P2X7 receptor antagonist. The P2X7 receptor antagonist can be Brilliant Blue FCF (BB FCF) or Brilliant Blue G (BBG).
Also provided is a formed-in-situ absorbable electrode anchor, comprising a volume of hydrogel polymerized in situ around an electrode and configured to maintain the electrode in electrical communication with a nerve. The hydrogel may be electrically conductive.
Also provided is an implant formed in situ comprising a volume of hydrogel transformed within a cavity shaped from a relatively fluid to a relatively non-fluid state and withdrawn from the cavity by a tensile force of not more than about 5 N, in that extraction was facilitated by a hydrophilic characteristic of the hydrogel and a hydrophobic characteristic of the cavity. The implant may be a nerve cap or a nerve conduit to guide the regeneration of a nerve.
Some modalities, as described here, have been shown to prevent neuroma formation preclinically and 1) eliminate the need to suture, drag, or stuff the nerve into a canal, 2) fit the end of the nerve stump to the provide a physical barrier to the nerve. regeneration, and 3) provide mechanical resistance to prevent nerve regeneration for a period of two months, preferably three months or longer, as needed to prevent nerve growth during the regenerative phase of growth after nerve injury. The form-in-situ implants described herein can conform to surrounding tissue, adhere to but not compress underlying nerve tissue, are flexible so they can move over regions of tissue surrounding joints or where nerves glide past each other, and prevent scar formation. tissue formation around nerves. Finally, some of these in situ training implants can be placed without advanced surgical training. In other situations, there remains a need for technology that prevents nerve ingrowth into surrounding tissue and directs regrowth of a severed or pinched nerve to the distal nerve stump or allograft/autograft. Thus, in some respects, a sutureless technology that can direct nerve regeneration from a proximal nerve stump either directly (via direct coaptation/anastomosis with distal nerve stump) or indirectly (via a nerve conduit, canal). guidewire, allograft, autograft), or through a matrix that allows growth into the distal nerve stump. In addition, in some aspects, a technology is disclosed that allows the anastomosis site to be loosened to promote better nerve regeneration. By administering the hydrogel circumferentially around the nerve, stress can be distributed circumferentially and over a distance over the nerve to distribute stress evenly across the nerve surface. In doing so, the stress is transferred to the hydrogel and does not arise at the focal points of the three or four sutures at the anastomotic sites. As is done within the canals, by creating a space in the nerves (positioning them with a curve) prior to administration of the growth inhibitory hydrogel, additional slack can be achieved so that tension at the anastomotic site is minimal. Finally, in some respects, a versatile technology that can be rapidly and widely applied to nerves is desirable to prevent inadvertent damage to adjacent nerves during a variety of surgical procedures.
FIGO.1A is a schematic perspective view of a nerve end placed within a molded socket. An entry region that allows the nerve to be guided into shape. The length of the shape provides a sufficient surface area on which the hydrogel forms and adheres to nerve tissue.
FIGO.1B is a side elevational cross section through the construction of FIG.1AND.
FIGO.1C is a view from above of the construction of fig.1AND.
FIGO.1D is an end view of the construction of fig.1AND.
FIGO.1Y is a sectional view taken along the line1MI-1by fig.1B.
FIGO.1F is a top view of another embodiment of the construction of fig.1AND.
FIGO.2is a schematic illustration of a barrier formed in accordance with some embodiments of the present invention.
FIGO.3A is a perspective view of a shape having a stabilizing feature.
FIGO.3B is a perspective view of one way of creating a wrap around a nerve or a region that allows growth in a space between the ends of the nerve. Thus, depending on the application, the casing form may contain a growth-inhibiting or permissive hydrogel.
FIGO.4A shows electrical stimulation of nerve endings through growth-enabling means in an open surgical procedure.
FIGO.4B shows the anchoring of an electrode adjacent to a nerve to provide stimulation for pain control in a percutaneous procedure.
FIGURES.5AND-5M illustrates a series of steps for one embodiment of creating a growth-enabling hydrogel junction encapsulated by a growth-inhibiting hydrogel barrier.
FIGO.5N is a perspective view of one way of creating a wrap around a nerve or a region that allows growth in a space between the ends of the nerve. Thus, depending on the application, the casing form may contain a growth-inhibiting or permissive hydrogel.
FIGO.5He illustrates a series of steps for one embodiment of creating a growth-enabling hydrogel junction encapsulated by a growth-inhibiting hydrogel barrier.
FIGO.5P illustrates a series of steps for one embodiment of creating a growth-enabling hydrogel junction encapsulated by a growth-inhibiting hydrogel barrier.
FIGO.6It is a perspective view of a shell shape.
FIGURES.7-10C illustrates embodiments of tools for severing nerves and/or creating a hydrogel junction.
FIGURES.11AND-11And they illustrate visions of a form and methods of use.
FIGO.12It is a perspective view of a formwork with a stabilizing rod.
FIGURES.13AND-13D are perspective views of a cap shape with a partial overlap and an internal bar to support the rib.
FIGURES.14AND-14C are perspective views of a cap shape with a partial cover.
FIGURES.15AND-15C are perspective views of a rupturable form of nerve sheath.
FIGURES.sixteenAND-sixteenAnd they illustrate perspective views and photographs of in situ formed hydrogels (growth inhibitory and growth permissive) around nerves, in both cap and sheath forms.
FIGURES.17AND-17B illustrates preclinical data demonstrating neuroma formation after administration of hydrogels with adequate initial mechanical strength but inadequate in vivo persistence relative to hydrogels with longer-term mechanical strength and persistence.
FIGURES.18AND-18B illustrates a mixing element design to improve hydrogel consistency by delivering low volumes of precursor solution.
FIGURES.18C e18D illustrates the distal mix tip configurations.
FIGO.18E is a cross section taken along the lines18MI-18Y of fig.18D.
FIGO.19schematically illustrates a dual chamber syringe system.
FIGO.20schematically illustrates a dual chamber syringe and mixing system.
FIGO.21illustrates one embodiment of a slotted shape.
FIGURES.22AND-22E illustrates one embodiment of a nerve coaptation method.
FIGURES.23AND-23C illustrates another embodiment of a nerve coaptation method.
FIGO.24illustrates one embodiment of a nerve repair method.
FIGO.25illustrates another embodiment of a nerve repair method.
FIGO.26illustrates one embodiment of a leaf vein repair method.
FIGURES.27AND-27F illustrates various embodiments of a system and methods for nerve stimulation.
Some aspects of the present invention involve the in situ formation of a protective barrier around a nerve end using surgically introduced or injectable media, which may be a gel/hydrogel or gel precursors to block nerve regeneration and/or formation. and inflammation of neuromas and scar formation, etc. around/in contact with the nerves. Access can be through an open surgical approach or a percutaneous (needle, endovascular/transvascular) approach. The nerve end or stump can be formed by transection (cutting), traumatic injury, or ablation through a variety of modalities, including radio frequency (RF), cryotherapy, ultrasound, chemical, thermal, microwave, or others known in the art. technique.
Hydrogels can "stick" to nerve endings, providing a conformable, comfortable cushioning barrier around a nerve ending, as opposed to a cap with a vacuum (inflammatory cells/fluid cysts present support neuroma formation) . The hydrogels are clear to the eye, swell low, conform, and are administered in a form to generate hydrogel capsules with volumes of 0.05 to 10 mL, preferably 0.1 to 5 mL, more preferably 0.1 to 2.8 ml. The barrier can inhibit neuroma formation simply by mechanically blocking nerve growth. The means can further comprise any of a variety of drugs, such as to inhibit nerve regrowth, as described in more detail herein.
Target ribs can vary widely in diameter with a spherical or non-spherical external configuration, and the angle of cut or spacing and precision can also vary. While it can be appreciated that all nerves would benefit from this hydrogel technology, nerves from approximately 0.2mm to 15mm, preferably 1mm to 5mm, more preferably 1mm to 2mm can be treated with this focus. In accordance with some embodiments of the present invention, coating is best accomplished by forming a soft, cushioning, conformable protective barrier in situ. A fluid medium or medium precursor(s) may be introduced to surround and conform to the configuration of the nerve end and then transformed into a non-fluid state to form a protective plug that closely fits and bonds to the nerve end. To contain the media before and during transformation (eg, crosslinking), the media can be introduced in a form in which the rib end has already been or will be placed. Filling the media into a shape allows the media to wrap around the nerve end and transform into a solid state while contained in a predetermined volume and configuration to consistently produce a conformable and protective nerve sheath, regardless of diameter and configuration. of the stump . The shape prevents the medium from contacting the surgical site and creates a smooth shape around the nerve, allowing the nerve and shape to glide into the surrounding tissue.
With reference to Figs.1through1D, the shape of a nerve sheath is illustrated.10. Form10extends between a proximal end12, a distal end14and includes a side wallsixteenspreading there between. side wallsixteenis concave to produce a cavity of the form18there inside the cavity of the form18is exposed to the outside of the form through a window20.
the proximal end12Shape10supplied with a nerve guide22to facilitate the passage of the nerve24place the nerve ending26inside the cavity of the form18. the nerve guide22may comprise a window or opening in the wall of the proximal end12Shape10, and is configured to support the rib at a level that positions the end of the rib26inside the cavity of the form18. In the illustrated embodiment, the nerve guide22includes a support surface28in an upwardly concave casing to produce a nerve guide channel30. Ver FIG.1D.
FIGO.1Y is a sectional view taken along the line1MI-1by fig.1B. The width of the window20in a circumferential direction is less than the inner diameter of the cavity. This results in a reentrant wall segment29on both sides of the window20, which has an edge that lies in a plane33which is parallel to a central vertical (not shown) through the center of the window20. the edge plane33is parallel and off tangent31to the inner surface of the side wallsixteen. The distance between the plane of the edge33and the tangent31it is within the range of about 2% to about 30%, generally within the range of about 5% to about 20% of the inside diameter of the cavity.
With reference to Figs.1Banda1C, nerve ending26it is placed so that at least 1 mm and preferably 2 mm or more in any direction separates the end of the nerve26of the inner surface of the side wall of the formwork10. This allows the media27to flow into the cavity of the form and surround the end of the nerve26to provide a protective barrier in all directions.
In general, a sufficient volume of hydrogel precursor will be introduced into the cavity to produce a continuous protective coating around the nerve end and at least about 1mm or 2mm or 5mm or more of the nerve leading to the end. In some embodiments, the axial length of the cavity will be up to 10mm or 12mm to about 2cm or less, and the width of the ID may be less than about 2.5mm or 2mm or less. The volume of the fluid precursor is generally at least about 100 microliters or 200 microliters or more, but not more than about 500 microliters for small nerves (eg, nerves up to about 4 mm in diameter). Shaped cavities intended for larger ribs (eg, ribs with diameters from about 4 mm to about 10 mm) may receive at least about 1 ml or 1.5 ml, but usually less than about 4 ml or 3 ml of precursor. fluid. As discussed elsewhere herein, the precursor can be introduced into the cavity as two or three or more separate layers that adhere together to form the end cap. For example, a first base layer can be introduced into the cavity before or after placing the rib in the cavity. During or after the transformation of the first layer, a second layer can be introduced to join the first layer and encapsulate the nerve and form the protective nerve sheath. The first layer will preferably contact at least the lower surface of the rib and may partially surround the rib, with at least an upper portion of the rib surface exposed. Within approximately 5 minutes, preferably within approximately 1 minute or within approximately 30 seconds after completion of administration of the first layer, the second top layer is applied in contact with the exposed portion of the nerve and the exposed surface of the top layer. to encircle the rib and form the final construction of the cap. In another preferred embodiment, the nerve is totally or partially immersed in the precursor solution until it forms a gel. The needle/blunt mixer is removed from the applicator tip and a new needle/blunt mixer is placed so that additional material can be delivered in a second layer to cover the nerve.
With reference to fig.1F, the inner surface of the cavity may be provided with one or more surface structures35to facilitate mixing and/or filling of cavities. In the illustrated embodiment, the surface structure35it comprises a flow guide in the form of a radially inwardly extending projection to facilitate flow, like a helical wire. The pitch and depth of the wire can be optimized with the viscosity of the fluid medium to facilitate filling and complete circumferential coverage of the nerve root as the fluid hydrogel precursor medium is injected into the cavity.
After the transformation of the medium from a relatively fluid state to a relatively non-fluid state, the shape10can be left in place or removed to leave behind a formed barrier60plug-shaped, as schematically illustrated in fig.2.
To stabilize the shape10after laying and during the filling and processing phases, at least one stabilizing feature32It can be added. See figure.3A. The stabilizing function32maybe at least one or two or four or more grooves, tabs or feet that provide a transverse bearing surface34to contact the adjacent tissue and stabilize the shape against movement. cross support surface34may extend along or be parallel to a tangent to the side wall of the form10.
In one implementation of the invention, a dual hydrogel construct is provided with connectivity across the junction between two nerve endings achieved by creating a hydrogel junction that allows growth between the two opposing nerve endings, then encapsulating this junction with a growth inhibitory hydrogel capsule. The use of an in situ cross-linking hydrogel for the permissive growth medium produces a junction with sufficient mechanical integrity and adhesiveness that it can be taken as a unit as if it were an intact nerve and then placed in a second shape to form the hydrogel capsule. external growth inhibitor.
In another implementation, a thermosensitive hydrogel that forms in situ (such as a PEG-PCL-PEG triblock copolymer) is selected as a growth-enabling hydrogel. The hydrogel formed at the junction is soft enough so that the nerves can grow through the hydrogel without hindrance, but viscous enough to prevent the inhibitory hydrogel from seeping into the junction between the two nerves. In another implementation, the growth-permitting biomaterial provides a temporary barrier to exit from the growth-inhibiting hydrogel, for example through the use of a viscous solution of hyaluronic, pluronic, PEG, fibrin, or collagen.
In another implementation, the injectable growth-enabling biomaterial is delivered in the form of a bioabsorbable wrapper, which wrapper is comprised of PEG-based dry sheet, pullulan, pullulan-collagen, or HPMC. These films can be formed into a lid or wrapper and solvent pour-dried with organic or aqueous solvents and the films dried by evaporation at room temperature or in a lyophilizer. For example, these materials can be molded into cap shapes similar to the Capsugel Plantcaps manufacturing process, in which the biomaterial is melted, compressed, and shaped into the desired shape. Plasticizers include sorbitol and glycerin. General instructions on forming soft gelatin capsules can be found on the SaintyCo website (https://www.saintytec.com/soft-gelatin-capsules-manufacturing-process/) using small or small automated encapsulation equipment. large scale with forms adapted to be of the appropriate size and shape for use as covers and wraps around ribs.
Other sheets of interest include sheets of fibrinogen and thrombin (US Patent No. 10,485,894), hydroxypropylcellulose (JP2009/183649A), or hydrophobic polymers (US2012/0095418). The films are thick enough to support delivery of the hydrogel precursor solution and are ideally 10 to 100 microns, preferably 50 to 200 microns, most preferably 10 to 150 microns thick. The films preferably swell minimally, less than 50% in thickness, after hydration. In one embodiment, the thin film biodegradable cap and wrap forms dissolve after 5 minutes into molecules or polymers that allow growth. In another embodiment, the films remain in place and are cleaned within one day to 6 months, preferably one day to three months.
In another embodiment, the injectable growth-enabling biomaterial is provided in a more traditional wraparound sheet form, similar in size and shape to that available commercially (Axoguard Nerve Protector), approximately 1 to 4 cm in length and 0.5 cm to 4 cm. wide (similar in thickness and size to Listerine POCKETPAK oral sheets). When wound around two ribs and the growth-permissive biomaterial, these form casings of approximately 2 mm in diameter by 40 mm of compression (2 mm, 3.5 mm, 5 mm, 7 mm, 10 mm and 20 mm to 40 mm long). The shell shapes or conduit shapes containing a biocompatible biodegradable material may or may not be pre-assembled in the second larger shell shape. If this is the case, after the growth-enabling biomaterial is placed as a wrap around a nerve or nerve stump, for example, it is not necessary to manipulate the biomaterial from the wrap and the physician can directly apply the biomaterial that inhibits growth around it. permissive growth material. By delivering the growth-enabled biomaterial in a biocompatible and biodegradable shell, softer or low-viscosity solutions, gels or pastes can be delivered in close juxtaposition to the nerve without oozing from the site. Finally, the growth inhibitory biomaterial is administered in the second wrapper shape with a larger diameter around the nerve (usually 1 to 4 mm in diameter greater than the diameter of the wrapper shape and, if the second wrapper shape does not it is biodegradable, it can be disposed of and discarded.
With reference to fig.3B, a shape10includes a curved side wall66define a shape cavity68. A first nervous guide70and a second nerve guide72are in communication with the cavity68and sized and oriented to allow placement of the first and second nerve endings in the cavity68in a position where they will face each other and be surrounded by fluid media introduced into the cavity68.
With reference to Figs.5AND-5And a sequence of steps for forming a double hydrogel conductive nerve junction between two nerve endings is illustrated. a first form50it comprises an elongated side wall curved to form a hollow such as in the shape of a half cylinder, having an internal diameter greater than the diameter of a target rib. The shape50has a first end52, a second end54and an elongated channel56spreading there between. The first nerve ending58is placed inside the channel56from the first ending52. A second nerve ending60extends to channel56from the second end54. The result is a cavity of the form62formed between the first and second nerve endings and the lateral wall of the form50.
A transformable growth permissive hydrogel precursor is introduced into the mold cavity.62adhere to nerve endings and polymerize in situ to form a conductive bridge64between the first nerve ending58and second nerve ending60as shown in fig.5B. After transformation of the gel to a less fluid state, the form50it is removed as shown leaving a junction comprising the nerve endings connected by a conductive bridge64polymerized growth permissive gel62. Ver FIG.5C.
The polymerized joint is then placed into a second form.66have a central chamber68separating the supports of the first and second nerve70,72, such as or illustrated in FIG.3B. A second growth inhibitory hydrogel precursor is introduced into the central chamber68to surround and form the conductive bridge64and nerve endings to produce a final construct into which the first growth-enabling polymeric bridge is placed.62is encapsulated by a second growth-inhibiting polymer capsule70. Ver FIG.5MI.
FIGURES.5F-5M illustrates a series of steps for one embodiment of creating a growth-enabling hydrogel junction encapsulated by a growth-inhibiting hydrogel barrier.
With reference to fig.5no one way10′ includes a curved side wall66' at least partially defining a cavity of the form68'. the cavity of the form68' is configured to receive one or more nerve endings within the shape10′. Form10' may also include one or more nerve guides70′ that at least partially define the cavity of the shape68′ and/or are placed inside the cavity of the form68'. In some embodiments, the10' may include at least two or more nerve guides70′ inside the cavity of the shape68′.
One or more nerve guides70', in some cases, it may extend from an inner surface of the lateral wall66′ and towards a central longitudinal axis of the shape10'. One or more nerve guides70are configured to receive and provide support for at least one rib end that is positioned at least partially within the shape10'. One or more nerve guides70it can comprise any shape configured to receive at least one nerve ending. For example, as illustrated in FIG.5N, or one or more nerve guides70' can comprise a cylindrical body and at least one central cavity71′ extending through the body. the central cavity71it may be of the size and shape necessary to receive at least a part of a nerve ending through it. Consequently, one or more nerve guides70' can advantageously allow a healthcare professional to size the form to the desired length, while also providing support along the entire length of the form10' to one or more nerve endings received through them. For example, the shape10it may comprise being shaped to be long enough in length that it can be shortened to the desired length by a healthcare professional once the necessary parameters for the procedure are determined. In some cases, the shape10′ may have two or more nerve guides70′ positioned along the length of the shape10' so that when a health professional shortens the length of the form10′ to the desired dimension, the guide never70′ are still positioned throughout the form10′ to provide support for one or more nerve endings to be placed within the cavity of the form68′.
In some embodiments, one or more nerve guides70′ advantageously elevates and/or positions a nerve end so that the nerve end rests in the nerve guide70′ in a position away from the side wall66'. In this manner, a healthcare professional can easily administer any desired compound, agent, or medium at a location between the nerve end and the lateral wall.66' without requiring the healthcare professional to physically grasp or hold the nerve end in a detached position during administration of the agent or medium.
With reference to fig.5Illustrated is a sequence of steps to form a double hydrogel conductive nerve junction between two nerve endings. a first form50it comprises an elongated side wall curved to form a concavity, as in the shape of a half cylinder, having an internal diameter greater than the diameter of a target nerve. the first way50' You may use any structure or function described in connection with any form here, such as form10and/or shape10'. For example, although not illustrated in FIG.5the shape50' may comprise one or more nerve guides70′ to facilitate management and support of one or both nerve endings58′,60′. Form50′ has a first full stop52', a second ending54’, and an elongated channel56′ spreading there between. The first nerve ending58′ is placed inside the channel56′ of the first ending52'. A second nerve ending60′ extends to channel56′ of the second extreme54'. The result is a cavity of the form62’ formed between the first and second nerve endings58′,60′ and the side wall of the form50′.
Any desired compound, agent or medium described herein, as a transformable growth-permissive hydrogel precursor, is introduced into the cavity of the form.62adhere to nerve endings and polymerize in situ to form a conductive bridge64′ between the first nerve ending58' and the second nerve ending60as shown in fig.5The shape50' is removed as shown leaving a junction comprising the nerve endings58′,60′ connected by a conducting jumper64′ polymerized growth permissive gel62′.
After that, the board is placed inside a second form.66′ which has a central chamber68'. In some embodiments, the second form66′ can be the same or similar in structure to the first form50', except that the second form66′ comprises a larger central chamber68′ than the channel56′ in the first way. the second way66' You may use any structure or function described in connection with any form here, such as form10and/or shape10'. For example, although not illustrated in FIG.5the shape66' may comprise one or more nerve guides70′ to facilitate management and support of one or both nerve endings58′,60′.
Any desired compound, agent or medium described herein, as a second growth inhibitory hydrogel precursor, is introduced into the central chamber.68′ to surround and form the conducting bridge64' and nerve endings to produce a final construct in which the first compound, agent or medium is encapsulated by the second compound, agent or medium. In some cases, the first and second agents interact to form a unique construction around the mold cavity.62between nerve endings58′,60′.
With reference to fig.5P, Another embodiment of a sequence of steps for forming a double hydrogel conductive nerve junction between two nerve endings is illustrated. The sequence of steps illustrated in5P can comprise any structure, feature, step, or combination thereof as described herein in connection with FIG.5Or, unless otherwise stated. In some cases, two forms of different sizes are not necessary.
In some cases, although not illustrated, the sequence of steps illustrated in FIGS.5The I5P can be made and/or used along a single nerve. One or more of the steps, in some embodiments, may be performed in an elongated nerve body and not include two or more nerve endings.
In some embodiments, the shape can be configured to have an adjustable length. For example, the shape may comprise two cylindrical body portions configured to move relative to each other while defining an internal cavity configured to receive one or more nerve endings. A first body part may reside at least partially against an internal side wall of a second body part, such that the first body part is configured to enter and/or exit the second body part to adjust for an overall length.
The forms of nerve protection or nerve regeneration of some embodiments of the present invention may be provided in a shell configuration as illustrated in FIG.6. a first shell80defines a first cavity82and a second shell84defines a second complementary cavity86. The first and second layers are joined by a hinge.88like a flexible living hinge made of a thin polymeric membrane. The first and second layer80,84they can be rotated towards each other on the hinge88to form a closed chamber shape.
FIGO.7illustrates a perspective view of a fixing tool700configured to cut nerve tissue, as well as to accommodate a shape for forming a hydrogel nerve junction, as described elsewhere herein, eg, after nerve transection. The tool700may include a plurality of proximal movable jaws702, each connected to the axes706attached to pivot704, and can have an unlocked configuration as shown, movable to a locked configuration using a locking mechanism705, like a series of interlocking teeth. the distal ends707of axes706may include end effectors708which may include side walls710which can have a curved geometry as shown, and complementary cutting elements712operatively connected to the curved side walls. In some embodiments, a10can be attached to the side wall710after cutting the nerve. In other embodiments, a shape may include an integrally formed cutting element. In some embodiments, the cutting element can be detached or removed after cutting, leaving the shape in place.
FIGO.8is a close up view of an end effector708of fig.7, also illustrating that the end effector708you can also take a form10. FIGO.9is a close-up side view of the distal end of one embodiment of the tool, illustrating that each of the end effectors may include cutting elements and/or shapes.
FIGURES.10AND-10C illustrates various steps in a method of transecting a nerve while removing the axoplasm from the nerve tip to improve close apposition between the nerve tip and the hydrogel. In some embodiments, the opposing end effectors708may include blades712, which can be of the same or different length. blades712in each end effector708they may be generally opposite but offset from each other, as shown in some embodiments. Activation of end effectors708can result in the blades cutting the nerve24creating a nerve ending26. The blades may have the shape described above. an absorbent material780how can a cotton swab be attached to one or more end effectors708(such as within a shape, for example) and being close, such as directly adjacent to one or more of the blades712, in order to absorb any axoplasm after nerve section. The tip of the swab can be, for example, less than 5mm, more preferably less than 2mm, to fit snugly into the mold and retain the nerve while the hydrogel is applied.
With reference to Figs.11AND-11And, in some embodiments, a delivery needle1102progress in an opening1104in the form of a cap1100to deliver the hydrogel precursor into and around the nerve1124. Opening1104can communicate with cavity18through the side wall approximately at the level of the support surface28or below, to facilitate the insertion of the medium below the nerve to form a first layer at the bottom and partially encapsulate the nerve. The nerve guide is also shown.1122which may be as described elsewhere here. See figure.11AND.
The hydrogel can be administered in two or more successive applications to partially (eg, half) fill the shape and form a hydrogel layer.1150as shown in fig.11B. A second volume of precursor can then be introduced to completely fill the form as shown in FIG.11C and forms a hydrogel layer surrounding the nerve end, after which the form is removed. The hydrogel can be administered as a small bolus.1152to wrap the nerve tip as shown in FIG.11D and then the remainder of the cap is subsequently filled to form a hydrogel cap as shown in FIG.11And after which the form is deleted. Thus, a multilayer (two or three or four or more) hydrogel shell can be formed to encapsulate the nerve ending.
With reference to fig.12, in some embodiments, a support bar1215is placed next to and in contact with a section of nerve1224. to haste1215provides additional strength to the nerve1224and naturally adheres to the nerve1224such that, regardless of the position of the stem, the nerve1224hurry up1215. The hydrogel solution is then administered onto or around the nerve.1224and the biodegradable rod1215to form a reinforced nerve sheath. the bar1215it can be biodegradable.
With reference to Figs.13AND-13D, in some embodiments, one, two, or more openings1310are provided on the side of a cap or wrapper form1300to guide the needle to deliver the precursor solution to the correct location. The hollow1310it can be in one of many locations around the form as needed to provide the precursor solution. a publication1330It can be tucked into the bottom of a cap or wrap to provide additional nerve support. The length of the rib is placed at the top of the post.1330taking care that the tip of the nerve does not come into contact with the pin1330. opposite1330it may be an integral part of the lid or wrapper form and may be removed later when the form is removed. Alternatively, post1330may include a biodegradable post that remains integrated into the hydrogel cap. See FIGS.13Banda13C. Alternatively, a first layer of hydrogel can be formed at the bottom of the socket prior to inserting the nerve end into the socket. The rib end can then be laid on top of the first base layer. The rib wrap precursor can then be introduced and bonded to the first base layer. The first base layer can be formed during the clinical procedure or prior to the point of manufacture of the form.
In some embodiments, a cap shape may include a partial cap1320, shown in fig.13A. The shape is angled so that the precursor material will flow and fill the distal capsule first, encircling the end of the proximal nerve stump, and then filling the remainder of the nerve capsule. As shown in fig.13D, the cap or wrapper shape may also include raised flaps1333to skew the long axis of the shape. By slightly angling the shape of the eyelid, spillage of precursor material from the nerve entry site can be minimized.
FIGURES.14AND-14C illustrates multiple views of one embodiment of a nerve sheath shape.1400similar to that shown in Figs.13AND-13D with a partial cap1420connected through a hinge1428with an insert1440to help center the lid1420above the cap-shaped window1400. The nerve guide is also shown.1405, which may be as described elsewhere in this document.
FIGURES.15AND-15C illustrates various views of a removable lid form1500which may include a detachable hem1560including a side wall1561, in which the nerve is placed (nerve canal1562). The precursor solution is administered into and around a first nerve canal.1562and detachable blade1560later separates from the nerve1524, how to use a tear-off tab1564as shown in fig.15A. The nerve hydrogel1570it is then rotated approximately 90 degrees and placed in a second, larger diameter detachable lid1501. Then the precursor solution is applied to the nerve canal to wrap the nerve and the first layer is formed. The detachable hem is then torn from the second tear-off lid shape.1501. The resulting cylindrical cap shape contains the centered rib. The nerve1524then it can be rotated back to the normal physiological position as shown in FIG.15B. FIG.15C illustrates an alternative peel-off cap shape design that can include a plurality of tabs.
FIGO.sixteenAND-sixteenAnd it is illustrated by filling with hydrogel and surrounding a nerve in the form of a cap. FIG.sixteenB illustrates a photograph of the hydrogel formed within a cap shape. FIG.sixteenC illustrates a high resolution image of a cap. FIG.sixteenD illustrates an example of a cap and wrap around a porcine sciatic nerve. Example of a growth-enabling hydrogel (pink) wrapped around a nerve and subsequently embedded in a second growth-inhibiting hydrogel wrap (blue). See also FIGS.5AND-5E. The hydrogels are cut in cross section to view the growth-enabling hydrogel (pink) embedded in the growth-inhibiting hydrogel (blue) as shown in FIG.sixteenMI.
FIGO.17A illustrates the formation of a neuroma after administration of DuraSeal in a layer around a severed rat sciatic nerve. FIG.17B illustrates the absence of neuroma formation after administration of a formulation of the present invention around a severed rat sciatic nerve. The hydrogel cap maintains mechanical strength and persistence in vivo for at least about 3 months, more preferably about 6 months.
FIGURES.18AND-18B schematically illustrates one embodiment of a mixing element for mixing a two-part hydrogel system. In some embodiments, a static mixer1800delivers the hydrogel precursor solution into a central chamber, allowing for reflux and recirculation of the starting material exiting the mixer. A second static mixer captures the well-mixed solution and delivers it through the needle tip. fluid inlet1802(from a dual-chamber applicator) and fluid outlet1804(to a blunt needle) are also shown.
With reference to Figs.18our18B, a mixer is shown1800to mix the precursor components of two parts of the gel of the present invention. The mixer in1800includes accommodation1802have an influential port1804and an effluent port1806in fluid communication through a flow path1808. the influential port1804and effluent port1806it may comprise luer connectors or other standard connection structures. Media featured through the influential port.1804follow the flow path1808through at least a first static primary mix column1810. the mixing column1810includes a tubular casing1812and an internal column of mixing elements in the form of baffles1814.
Media leaving the first static mix column1810enters a secondary mixing chamber1816. In the illustrated embodiment, the secondary mixing chamber1816causes the media to follow the flow path1808to insert an optional second static mix column1818. Media leaving the second mixing column1818goes to the effluent port1806.
The total volume of mixed media delivered will generally be less than about 5 ml, typically no more than about 2 ml, and in some applications less than 1 ml. The first component to enter the primary mix column1810will normally be the first out of the main mix column1810. The secondary mixing chamber1816functions to perform a different type of collapsible mixing, to mix the effluent from the primary mix column1810with yourself and achieve superior uniformity. Adding a third mixing function by adding the optional second static mixing column1818it also guarantees uniformity in the mixing of the hydrogel components for the first 0.5 ml. o 1 ml of hydrogel to exit the effluent port1806.
the mixing column1810preferably includes at least 4 mixing elements1814and usually includes between 6 and 12 baffles1814and normally no more than about 32 baffles1814. The baffles may have an outside diameter of no more than about ⅛ of an inch and, in some implementations, no more than about 1/16 or 1/32 of an inch. Static Primary Mix Column Length1010it is generally less than about 4 inches and typically less than about 2 inches or less than about 1.5 inches. In one implementation, the length is within the range of about 0.4 to 1.0 inches, more particularly about 0.5 to 0.7 inches.
With reference to Figs.18C-E, Dual-chamber combination dispenser and mixing assembly shown.1830. With reference to fig.18C, the distribution and mixing set1830includes accommodation1832involving a first camera1834and a second camera1836for containing and keeping the first and second components separate. Components begin to mix upon melting1838of the chamber flow paths, as in response to the advancement of emboli (not shown) at the proximal ends of the first and second chambers. Combined media streams advance through a main mix column
In Fig.18D, a dual chamber mixer and dispenser combination1830shown, having a single primary mix column1810and a secondary mixing chamber1816. Media leaving the static mix column1810follow a flow path1808through a secondary mixing chamber1816, and finally through an opening1820and in an exit chamber1822. a deflector1824can be provided to direct the effluent from the static mixing column1810in the secondary mixing chamber1816which will be substantially filled before exiting the opening1820.
With reference to fig.19, a two component syringe for use with the mixer of FIG.18A. The syringe comprises a housing1842involving a first camera1844have a first plunger1846, and a second camera1848involving a second plunger1850. The first and second pistons are connected via a bridge.1852, to avoid distributing one of the cameras in front of the other.
an adapter1854can be provided for removable fixing to the casing1842and for a first camera1858and a second camera1864detachably attached to the adapter1854. The adapter comprises a first connector1856for detachable connection to the first chamber1858containing a first medium1860. a second connector1862can be detachably attached to a second container1864that can contain a second medium1866.
Proximal retraction of the first and second plungers, such as by manual bridge retraction1852we will raffle the first media1860and second half1866in their respective chambers in the syringe. Adapter1854be there after being disconnected from the cabinet1842and then the double chamber syringe is attached to a mixer such as that described herein.
With reference to fig.20, the two-component syringe1840it is illustrated as filled with the first media1860and second half1866. a connector1805can be delivered at a distal end of the syringe1840for connection to the influencing port1804in a blender, like a blender1800. Medium express syringe follows flow path1808as described and finally fully mixed, the first and second media mix can be voiced through a stylus1868in a mold as described elsewhere in this document.
The following table refers to specific, non-limiting modalities and devices for delivering in situ-forming hydrogels.
| form form | |||
| Delivery of on-site training hydrogels to: | Selected | hydrogel | |
| 1) | intact nerves | rice | growth inhibitor |
| 2) | Nerves that have been pinched, | rice | growth inhibitor |
| bruised or twisted | |||
| 3) | Stump neuroma or severed nerve | Cap | growth inhibitor |
| that can't be fixed | |||
| 4) | Nerves that have been partially or | rice | permissive growth |
| completely transverse and | and then Growth | ||
| undergo direct suture repair | inhibitor | ||
| (coaptation, end to end | |||
| anastomosis) | |||
| 5) | sutured nerves | Wrap(s) - protect | permissive growth |
| repair and placement on a nerve | nerve canal | and then Growth | |
| conduit or casing | union | inhibitor | |
| 6) | nerves that suffered | Wrap(s) - protect | permissive growth |
| 'sutureless' assisted connector | nerve canal | and then Growth | |
| neurorrhaphy in which the sutures are | union | Inhibitor or Growth | |
| located between the epineurium and | inhibitor only | ||
| the connector but not each other | |||
| 7) | Nerves that were placed in a | Wrap(s) - protect | permissive growth |
| sutureless connector | anastomosis | and then Growth | |
| Inhibitor or Growth | |||
| inhibitor only | |||
| 8) | Nerves passing through ducts | Wrap(s) - protect | permissive growth |
| stress gap repair | nerve canal | and then Growth | |
| union | Inhibitor or Growth | ||
| inhibitor only | |||
| 9) | Arrested nerves | Wrap(s) - protect | permissive growth |
| allograft interposition with connector | nerve-nerve | and then Growth | |
| suture-assisted repair | anastomosis | Inhibitor or Growth | |
| inhibitor only | |||
| 10) | Arrested nerves | Wrap(s) - protect | permissive growth |
| autologous nerve graft interposition | nerve-nerve | and then Growth | |
| suture repair | inhibitor | ||
| 11) | Nerves that have non-union lacunae | wrappers | permissive growth |
| (for example, it cannot be repaired directly) | and then Growth | ||
| inhibitor | |||
| 12) | Nerves that have been repaired and | Wrap(s) - Protect | permissive growth |
| one or more wraps are placed | nerve sheath | and then Growth | |
| around the anastomosis site | inhibitor | ||
| 13) | Nerves undergoing repair by suture in | Engage - Protect | permissive growth |
| targeted muscle reinnervation | nerve-nerve | and then Growth | |
| Interface | inhibitor | ||
Peripheral Nerve Stimulation (PNS). As neurostimulators have advanced from the spine to the periphery and hardware and batteries have become miniaturized, specially designed peripheral nerve stimulators are being developed and advanced to block pain, stimulate muscle contractions, and stimulate or block nerves. to modulate the disease and/or symptomatology. (eg pain) and stimulate nerve regeneration. As new applications and new neurostimulators have been developed, there has also been an awareness of the need to keep stimulation electrodes and catheters in direct or close apposition to the target nerve, since 1) placing the electrodes close to the nerve during the procedure can be challenging and electrodes can migrate during the procedure even after optimal placement adjacent to a nerve and 2) after placement, electrodes can drift due to patient movement or manipulation as muscles contract or the implant better conforms to the tissue. This can lead to loss of therapy reaching the target nerve and therefore loss of efficacy.
percutaneous delivery. With the advent of higher-resolution portable ultrasound and better training among interventional and orthopedic physicians, percutaneously delivered implantable neurostimulators are increasingly being used as an alternative method of treating chronic pain. In one embodiment, once an electrode has been placed adjacent to a nerve using a percutaneous delivery system, the position of the electrode proximal to the nerve can be maintained by applying approximately 0.1 to 3 cc of an electrically conductive hydrogel to form around the nerve. the electrode and hold it in close apposition to the nerve. In this modality, the electrode is placed in the desired location and then the hydrogel that forms in situ is delivered to anchor its location. The hydrogel medium can be administered through the lumen of the catheter delivery system or the lumen of the lead and will form in situ. In some embodiments, the electrode surface can be designed so that the interface is rougher, allowing for a stronger intercalation between the hydrogel and the electrode to prevent electrode migration. In other embodiments, a coil or other screw-like design is placed at the end of the electrode to provide better contact between the electrode, the hydrogel, and the surrounding tissue. For percutaneous applications, for the treatment of nerve regeneration, more rapidly degradable PEG hydrogels are desirable, maintaining mechanical strength for a week or two before abrading and cleaning the site. While these formed-in-situ hydrogels have sufficient adhesiveness to hold the catheter or wire at the delivery site, if removal of the wire or catheter is necessary, a sharp jerk on the catheter wire will allow percutaneous removal of the delivery site. PEG hydrogels suitable for these applications are based on more rapidly degradable multi-armed PEGS, such as PEG-SS (PEG-succinimidyl succinamate-NHS ester) or PEG-SG (PEG-succinimidyl glutarate-NHS ester). For chronic pain treatment applications where a resident peripheral electrode is desirable, the administration of growth inhibitory hydrogels or hydrogels with medium to long-term mechanical strength, such as multi-arm PEG based on more degradation bonds, is desirable. slow. Generally speaking, it is desirable to maintain mechanical strength to maintain electrode position within the hydrogel until the chronic foreign body response is sufficient to hold the electrode in place. For example, to maintain long-term electrode placement, it is desirable to select crosslinked PEG hydrogels that contain more stable ester, urethane, or amide linkages, such as PEG-SG (PEG-succinimidyl glutarate-NHS ester), PEG-SAP ( PEG-succinimidyl glutaramate-NHS ester), PEG-SAP (PEG-succinimidyl adipate-NHS ester), PEG-SC (succinimidyl carbonate-NHS ester) or PEG-SGA (succinimidyl glutaramide-NHS ester). Preferably, these PEG-NHS esters are mixed and subsequently cross-linked with PEG-amines for greater flexibility in small molecule cross-linking systems such as trilin, for example.
In yet other embodiments, the neurostimulators are injectable wireless implants and take the form of a pellet, rod, bead, wrap, sheet, or sleeve that is held in place by a hydrogel adjacent to a nerve, ganglion, or plexus. In one embodiment, the hydrogel is first administered to the target site and the neurostimulator is administered in a hydrogel paste. In another embodiment, the neurostimulator implant(s) is(are) first delivered, fitted to the desired location, and then hydrogel is wrapped around it to secure it in the desired location. Also, the location of the neurostimulator implant can be adjusted using an external magnet to orient the implant adjacent to or in contact with the nerve or neural tissue. In this embodiment, the gel time can be adjusted to provide sufficient time for proper alignment of the neurostimulator, eg, 15 seconds to one minute of gel. In some embodiments, a plurality of injectable microstimulatory implants are injected into a degradable or non-degradable in situ-forming hydrogel.
In yet another embodiment, microstimulators in the form of micro-or nanorods-are implanted into the growth-enabling hydrogel between the two nerve stumps to promote neurite outgrowth and accelerated regeneration. These microstimulators can generate magnetic, chemical or electrical fields to stimulate nerve regeneration through the gel and potentially throughout the microstimulator implants. In one embodiment, the microstimulators are nanofibers and can be injected through a small-gauge needle or catheter into the nerve.
In another embodiment, the short- or long-acting microstimulators can be administered with an injectable biocompatible biomaterial, such as a hydrogel, to form an anisogel neurostimulator. Microstimulators are magnetic, allowing directional control of the microstimulator implant and, for example, parallel alignment of the microimplants within the hydrogel prior to gel formation from a precursor solution. These hydrogels would be injected around or near nerve bundles or tendrils, and then the microstimulators can physically provide regions through which they can grow and guide themselves, as well as provide chemical, electrical, or magnetic field stimulation to support neurite growth.
With reference to fig.4A, A construct according to the present invention for electrically stimulating new nerve growth is schematically illustrated. A proximal nerve stump100and distal nerve stump102are placed inside a temporary shape104as a silicone cover in a manner described earlier in this document. A gel that allows growth106is inserted into the form, to cover the space between the proximal nerve stump100and distal nerve stump102. A set of electrodes108have a probe or holder110with at least one conductive surface112and, in a bipolar system, a second conductive surface114, is placed inside the temporary form104. An electrically conductive hydrogel116comes in shape104and solidified to support nerve stumps and gel that allows growth and maintains the position of the electrodes108in relation to the growth permissive gel106.
RF stimulation can be performed using any of a variety of microneedle electrodes, such as a stainless steel needle electrode (0.35 mm OD, 12 mm length) connected to the negative lead (cathode) of a stimulator ( Trio300; Ito, Tokyo, Japan). Operating parameters may include low frequency stimulation, generally less than about 200 Hz and preferably in the range of about 2 Hz to about . The current may be in the range of about 1 to about 10 mA or more. The voltage may be about 3 V, with a square waveform of about 0.1 ms pulse. The duration can be from approximately one hour to 2 weeks, depending on the desired clinical performance.
open surgery. For open surgical applications, the hydrogel can also be similarly deposited around the electrode with the electrode in direct contact with and/or adjacent to the nerve under direct visualization. Again, deposition of about 0.1 to 5 cc, preferably 0.2 to 2 cc, most preferably 0.5 to 1 cc of hydrogel is sufficient to maintain electrode position relative to a nerve. In one embodiment, the electrode can be inserted into a silicone-shaped groove adjacent to and with the nerve prior to administration of the hydrogel. Shapes can be provided that have a second entry area for the electrode. In this way, for example, the electrode can be aligned to run parallel to the nerve or in direct apposition to the nerve when the gel is applied. For applications where neurostimulation therapy is only needed for a day or several weeks, pulling the wire will remove it from the hydrogel relatively easily. The use of combinations of growth inhibitory and growth permissive hydrogels described above can be selected depending on the application. For cases where electrodes placed near the nerve only need to remain in place for a few days or weeks, a short-term degradable hydrogel may be employed. This provides enough time for the hydrogel to remain in place while the therapy is delivered and then quickly removed from the tissue. An example of this would be the selection of cross-linked PEG hydrogels containing more reactive ester linkages such as PEG-SS or PEG-SAZ. These hydrogels are electrically conductive and therefore suitable for applications involving neurostimulators. In other embodiments, electrically non-conductive polymers can also be used to isolate the electrical signal from surrounding tissue.
Generally, the selection of the low-swelling formulation is essential to maintain apposition with the electrode; In one embodiment, the swelling of the hydrogel is less than 30%, more preferably less than 20%, to maintain apposition with the nerve and the electrode.
With reference to fig.4B, A hydrogel anchor formed in situ to secure an electrode in electrical communication with a nerve is illustrated. a support110carries conductors in electrical communication with at least one first conductive surface112and preferably at least one second conductive surface114to supply RF energy from an external power source. A second, third, or more pairs of electrically conductive surfaces may be provided. A volume of electrically conductive hydrogel116it can be introduced into a form and solidified in situ in the manner previously discussed. The conductive hydrogel116surrounds the cord and stabilizes it in relation to an adjacent nerve120such that the electrode is in electrical communication with the nerve120through the conductive hydrogel116. Alternatively, the electrode can be fixed between an in situ formed hydrogel anchor and the nerve.120, or forming the conductive hydrogel anchor around the nerve120and the adjacent electrode. The electrode can be configured to be approximately withdrawn from the electrically conductive hydrogel. Alternatively, the electrode can be removed from the patient after the hydrogel has been absorbed. In one embodiment, the electrical conductivity of PEG hydrogels can be increased by incorporating PSS into a PEG hydrogel matrix, resulting in the in situ formation of PEDOT to form a PEDOT:PSS-loaded PEG hydrogel. (Kim et al 2016. Hydrated Conductive PEG for Potential Application in a Tissue Engineering Scaffold Reactive and Functional Polymers, DOI: 10.1016/j.reactfunctpolym.2016.09.003) In another embodiment, the metal nanoparticles and carbon can be delivered in the hydrogel, including gold, silver, platinum, iron oxide, zinc oxide, or polypyrrole (PPy), polyaniline (PANi), polythiophone (PT), PEDOT (above), or poly(p-phenylene vinylene) (PPV) as described describes in Min et al 2018 Incorporation of Conductive Materials into Hydrogels for Tissue Engineering Applications, Polymers, 10, 1078; doi: 10.3390/polym10101078, incorporated here.
In yet another embodiment, the hydrogel that forms in situ can be used to ensure a convectively enhanced delivery system to the site. Like the implantable neurostimulator, a drug delivery catheter can be attached approximately 10 mm proximal to a damaged nerve site with the tip approximately 5 mm from the nerve lesion. Like the implantable neurostimulator, the silicone form can be designed to include an entry zone or cut the top edge of the silicone form to allow the stimulator or catheter wire to rest on the form in preparation for addition of the silicone form. hydrogel. Following delivery of therapy (neurostimulation, convective enhanced drug delivery), the catheter or neurostimulator can be withdrawn from the hydrogel without breaching the protective barrier around the hydrogel. For example, the US patent in the. 9,386,990 teaches the use of DuraSeal to repair nerves with an in vivo persistence of two to four weeks, the hydrogel does not provide the sustained mechanical force necessary to prevent neuroma formation or nerve arrest during regeneration, as in 3 and 4 months after surgery to repair. For example, cross-linked multi-armed PEGs containing rapidly degradable ester linkages, such as PEG-SS or PEG-SG, are suitable for applications to prevent acute and subacute scar-induced nerve-constriction formation around the nerve. For another example, low molecular weight linear PEGs have been shown to act as a fusogen and promote nerve repair and regeneration when injected around injured nerves (but do not provide mechanical strength or persistence to prevent neuroma formation). For example, PEG hydrogels such as PEG tetracrylate hydrogels have been used to bind nerves in preclinical models (Hubbell 2004/0195710).
Generally, PEGs with ester linkages susceptible to hydrolysis do not contain degradable linkages necessary to withstand the necessary mechanical strength or in vivo persistence necessary for applications to prevent aberrant nerve growth and neuroma formation. Commercially available PEG hydrogels, particularly conventional PEGs with a hydrolytic ester linkage, do not have adequate mechanical strength or in vivo persistence to prevent neuroma formation for three to four months until the nerve is repaired or healing is achieved. neuroma prevention. These PEGs and PEG gels may have sufficient mechanical strength initially to help temporarily repair nerves across anastomoses and/or prevent scar formation, but hydrogels do not have sufficient mechanical strength at two months, or more preferably at three months after administration, to prevent the formation of aberrant neuromas. and therefore may not be suitable for a hydrogel cap. FIG.sixteenprovides an example of the lack of durability of DuraSeal hydrogel in preventing neuroma formation in a rat sciatic nerve transection model. Hydrogels containing ester bonds have degraded enough that they no longer provide a barrier to nerve regeneration, fall off the nerve, or are removed entirely. As a result, the initial mechanical barrier was not sufficient to act as a long-term barrier to prevent nerve growth, and a neuroma formed.
In another embodiment, mechanical nerve shock is desirable. By designing the ribs to be covered by at least 8mm, preferably a 10, 15 or 20mm rib length, there is sufficient adhesion force circumferentially so that the stress is partially offloaded into the gel and better distributed. By providing a mechanical shock, the hydrogel can support a regenerating nerve (sheath). Given a nerve stump length of 10mm or more (one or more nerve stumps), the nerve can be embedded in the hydrogel in an 'S' bend or loop, so that stress on nerve anastomoses is minimized. .
Other approaches teach administering a hydrogel that forms in situ around the nerves directly, without protecting the underlying muscle from the scar tissue that forms and ultimately constricts the nerve, or provide a method of systematically circumferentially covering the proximal end of the nerve with hydrogel. Polymer systems that form in situ adhere, albeit to varying degrees, to the surrounding tissues with which they come into contact during crosslinking or polymerization. If non-target tissue (eg, muscle or fascia) is not protected or shielded from the reaction, the hydrogel also adheres to this tissue. Since it is preferable for the nerves to glide freely within a fascial plane, usually between the muscles, it is undesirable to limit their movement and may cause pain and/or loss of efficacy. Some modalities described here provide shapes that separate the in situ-formed hydrogel from the surrounding environment, preventing tethering between the nerve and surrounding tissue and allowing the nerve to glide within the fascial tunnel. Gliding can be achieved through two mechanisms: 1) the lubricity and aerodynamic shape of the hydrogel after formation into a Cap or Wrap shape. The low-friction surface is provided, in part, through the smooth inner surface of the cap or wrapper form, which allows for a low-friction hydrogel surface, or 2) by selecting a formulation with minimal equilibrium swelling during two to three weeks using a PEG of faster hydrogel degradation, hydrogel hydrolysis supports 20-80% swelling, more preferably 20-60% swelling. The second stage of inflammation, degradation inflammation, allows the damaged nerve to glide through the internal lumen of the hydrogel (the lumen expands as the hydrogel swelling translates into external swelling) after inflammation of the hydrogel. negligible balance to avoid the inflammatory response at the time of surgery and in the acute postoperative period. period. In this way, the smooth hydrogel provides a barrier to immune cell infiltration, but provides a viscous solution through which the nerve can slip.
Nerve block. To block nerve regeneration, the biomaterial formed in situ must have the physical properties to prevent nerves from migrating into the biomaterial, including negative or neutral charge, smaller pore size, hydrophilicity, and/or higher crosslink density. Although most studies focus on the materials through which nerves will regenerate, several studies have documented the biomaterials through which nerves will not grow, including polyethylene glycol-based hydrogels, a agarose and alginate base, particularly at higher concentrations of the polymers. Higher concentrations typically have a higher crosslink density and therefore a smaller pore size. These hydrogels can be used for their ability to prevent neurite outgrowth in vitro and in vivo due to their charge, inert surface area, hydrophilicity, and pore size. In one embodiment, agarose, at an exemplary concentration of 1.25% w/vol, may be selected to prevent nerve regeneration. In another example, PEG hydrogels can prevent neuroma formation at 4% w/v and higher, preferably 6 to 9% w/v, more preferably 8% w/v or higher. In other embodiments, even naturally occurring or positively charged in situ formed biomaterials can provide a barrier to nerve regeneration if the solid content and crosslinking density are such that the pores are too small for cell growth.
To prevent neuroma formation, the biomaterial that forms in situ needs to provide the necessary mechanical strength to act as a barrier to nerve regeneration for two months, more preferably three months or more. Many gels that form in situ, including commercial PEG hydrogels that form in situ with biodegradable ester linkages, may have sufficient mechanical strength initially, but hydrolyze at such a rate that their crosslinking density is lost sufficiently that their mechanical resistance is 1 to 2 months is not enough to prevent neuroma formation (see Table 1). In vivo experiments in a rat sciatic nerve model demonstrated the formation of bulbous neuromas between one and three months after administration of these hydrogels around the end of a severed nerve stump, comparable to nerve section alone. Preclinical tests have shown that a mechanical strength of at least 5 kPa, preferably 10 kPa, more preferably 20 kPa or more is required to prevent neuroma formation. By three months, in vivo studies have shown that these hydrogels have completely degraded and either been removed from the site or have lost sufficient mechanical integrity that the nerve has grown into soft gels, collapsed and/or fractured, and formed a neuroma. Therefore, although the prior art teaches the use of PEG hydrogels for nerve repair purposes, not all PEG hydrogels are adequate to support the mechanical strength and long-term persistence requirements necessary to prevent the formation of neuromas and aberrant nerve growth. Preferably, the barrier has an in vivo persistence of at least about two months or at least about three months, preferably four months, more preferably 6 months or to reduce or prevent neuroma formation and reduce chronic neuropathic pain after surgery. The mechanical integrity of hydrogels at various points in vitro and in vivo can be assessed by compression tests, described below.
Persistence. The in vivo persistence of biodegradable hydrogels is related to the crosslinking density and thus to the mechanical integrity of the hydrogel. For applications to prevent the formation of neuromas, the degradation of the hydrogel must be slow enough that the hydrogel does not lose significant structural integrity during the weeks to months during which the nerves attempt to regenerate, which occurs in approximately 3 months and it can last 6 months or longer in humans. Therefore, the persistence of the hydrogel and the persistence of the mechanical integrity of the hydrogel are critical to provide continued protection and filling of neuromas and aberrant nerve growths preferably for 3 months or longer, preferably 4 months or longer. In embodiments using a degradable hydrogel, the mechanical strength must be maintained for more than 2 months, preferably 3 months, and therefore there must be no substantial degradation of the hydrogel during this period of time, preferably 3 months or more. Likewise, the persistence of the mechanical integrity and, in turn, of the hydrogel is critical for the continuous discharge provided by the hydrogel around the nerve-nerve or nerve-graft interface for a period of preferably 2 months, more preferably 3 months. months. as even nerves that were sutured directly together by direct coaptation have not yet regained their original strength (nerves are approximately 60% of their original strength 3 months after a section).
The development of in-situ-forming polymers, and particularly in-situ-forming synthetic hydrogels, including PEG-based hydrogels with higher mechanical strength in vivo and longer persistence profiles beyond 2.5 to 3 months but less than 12 months, it is a challenge. For example, there is a significant gap between the in vivo persistence of PEG hydrogels with biodegradable esters (weeks to less than 3 months) in and around the nerve surgical environment and PEG hydrogels containing biodegradable urethane or amide linkages, with degradation profiles in this subcutaneous. extramuscular location in the order of 9 months to 18 months or more. Some embodiments focus on the in situ formation of polymers, preferably multi-arm PEG, including combinations of PEG-NHS-esters and PEG-amines with biodegradable linkages, with the necessary mechanical strength and persistence to prevent neuroma formation. In particular, the swelling, mechanical strength, and in vivo persistence of PEG hydrogels are described to enable long-term safety and efficacy in applications that require the long-term prevention of aberrant nerve growth and the ability to relax and unload the nerves for a prolonged period. period of months after surgical repair.
To obtain adequate mechanical strength and persistence in vivo, conventional PEG hydrogels containing degradable ester linkers that are widely commercially available as pulmonary and dural sealants are not suitable for applications around nerves, due to loss of mechanical strength and /or debugging within a few months. Degradation simply occurs at a fast enough rate that mechanical integrity cannot be maintained long enough, making these hydrogels suitable for the prevention of non-adhesion, but not for the prevention of ingrowth of adhesions. nerves. In embodiments using a non-degradable PEG hydrogel, the mechanical strength of the hydrogel is based on the initial mechanical strength of the hydrogel, since the crosslinks do not degrade over time. In vitro and in vivo testing of a variety of hydrogels with various molecular weights, degradable bonds, and crosslinking densities demonstrated that only hydrogels with sufficient mechanical strength at 3 months (and therefore in vivo persistence) were able to prevent the neuroma formation. Examples of hydrogels, degradation times and neuroma formation are given in the table below. FIG.sixteenA illustrates the formation of a neuroma after administration of DuraSeal.
| neuroma formation | |||
| Live | in the rat sciatic nerve | ||
| PEG hydrogels | Persistence | Transaction template | |
| PEG-SS (ester link) | 2 | weeks | large bulbous neuroma |
| observed in 1 month | |||
| Duraseal (ester bond) | 2 a 8 | weeks | large bulbous neuroma |
| formation observed in | |||
| 2 and 3 months | |||
| PEG-SG (ester link) | 4 a 8 | weeks | large bulbous neuroma |
| formation observed in | |||
| 3 months | |||
| PEG-SAP (ester bond) | 6 a 8 | weeks | large bulbous neuroma |
| formation observed in | |||
| 2 and 3 months | |||
| PEG-SAZ (ester link) | 2-3 | weeks | large bulbous neuroma |
| at 2 and 3 months | |||
| PEG-SGA (amide bond) | 9 months or more | No neuroma formation | |
| PEG-SC (urethane crosslinker) | 6 months or more | No neuroma formation | |
In vivo persistence refers to the absence of significant uptake of the biomaterial, such as less than 25% reuptake, preferably less than 15% at any given time. Depending on the biomaterial, this can be assessed by loss of mass, loss of crosslinking density, or shape change of the biomaterial. Active bonds that have longer degradation in vivo, such as PEG-ureas (eg, PEG isocyanate, PEG-NCO), PEG-urethanes (PEG-succinimidyl carbonate) (PEG-SC), and PEG-carbamate. Hydrogels composed of polyethylene glycol succinimidyl carbonates (PEG-SC) with more than 2 arms, such as 4-arm, 6-arm, or 8-arm PEG with molecular weights ranging from 1K to 50K, preferably 10K to 20K, such as 10 K, 15K or 20 kDa are preferred for cap or nerve repairs where greater in vivo persistence of the hydrogel is preferred. In some embodiments, 4-arm 10K PEG-SC, 4-arm 20K PEG-SC, 8-arm 10K PEG-SC, 8-arm 15K PEG-SC, or 8-arm 20K PEG-SC are selected. , more preferably 4-arm 10K PEG-SC or 8-arm PEG-SC 20K to mix with 8-arm 20K or 4-arm 10K amine. The following patent is incorporated by reference 20160331738A1. In other modalities, such as nerve wrapping, 8-arm PEG-SG 20K or 8-arm PEG-SAP 15K combined with 8-arm amine 40K or 8-arm 20K amine blends are preferred to provide structural support while the nerve is in place. involved regenerates and/or to prevent nerve compression and scar tissue formation in the acute and subchronic period and their subsequent degradation and removal from the site. For applications to prevent nerve compression or support nerve regeneration after nerve injury, growth inhibitory PEG hydrogels with shorter in vivo degradation profiles are preferred. For these applications, the hydrogel must provide sufficient mechanical strength to prevent aberrant nerve growth and prevent immune infiltration into the healing nerve. suitable pegs for these
compressive strength. The desired compressive strength (elastic modulus, Young's modulus) of the growth-inhibiting hydrogel is greater than 10 kPa, preferably greater than 20 kPa, preferably greater than 30 kPa. In the preferred embodiment, the compressive strength of is greater than 20 kPa after 3 months in vivo, more preferably 40 kPa at 3 months after administration.
Compressive strength was measured on the bench after equilibration in vitro and also after collection of implanted samples from the subcutaneous space in rats, in which hydrogel cylinders (d = 6 mm) were cut to 6 mm in length. , were previously equilibrated (for 12 hours at 37°C) and the compressive strength was evaluated. The compressive properties of the hydrogel formulations were measured at 1 mm/min with the Instron. The modulus was calculated as the tangent slope of the linear region between 0.05 and 0.17 of the stress-strain curve.
Compressive strength of various formulations.
| Compressive | Compressive | |||
| module | module (t = 3 | |||
| Polymer | (t = 0) | months, in vivo) | neuroma formation | |
| Formulation G | 20 kPa | 5 | kPa | neuroma formation |
| Formulation H | 12 kPa | 8 | kPa | neuroma formation |
| Formulation I | 1 kPa | 1 | kPa | neuroma formation |
| Formulation I | 25 kPa | 17 | kPa | sin neuroma |
| training | ||||
| Formulation J | 72 kPa | 55 | kPa | sin neuroma |
| training | ||||
| K formation | 80 kPa | 75 | kPa | sin neuroma |
| training | ||||
Although in vitro mechanical strength and persistence of hydrogels (37°C, PBS) generally do not correlate well with in vivo persistence, maintenance of hydrogels' mechanical strength at 3 months in vitro is a strong indicator of the ability of the hydrogel to provide a sustained mechanical barrier for nerve regeneration in vivo.
In some embodiments, a cleavable carbamate, carbonate, or amide linker in a biodegradable hydrogel allows for a more stable linkage that degrades slowly to maintain the mechanical strength necessary to prevent nerve growth for three months or longer, and thereby persistence. in the future. alive to provide a sustained mechanical barrier for nerve regeneration.
In general, the structure of multi-armed PEGs is
C-[(PEG)norte-M-L-F]metro
Where
C = central structure of the multi-arm PEG
n = PEG repeat units in each arm (25 to 60 units)
M=Modifier
L = cleavable or non-cleavable connector (ester, urethane, amide, urea, carbamate, carbonate, thiourea, thioester, disulfide, hydrazone, oxime, imine, amidine, triazole and thiol/maleimide).
F = reactive functional group for covalent crosslinking, e.g. maleimide, thiol or protected thiol, alcohols, acrylates, acrylamides, amines, protected amines, carboxylic acids or protected carboxylic acids, azides, alkynes, 1,3-dienes, furans, alpha-halocarbonyls, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl esters or carbonates
m = number of PEG arms (for example, 2, 3, 4, 6, 8, 10)
In some embodiments, hydrolysis modifiers (M) may be incorporated into the hydrogel structure to retard the hydrolytic degradation of ester (L) linkages in the hydrogel. This can be accomplished with electron donating groups surrounding the reaction or by increasing the length of the carbon chain adjacent to the ester bond to increase hydrophobicity and protect the bond from hydrolysis. For example, PEG-SAP, PEG-SAZ are examples of PEG-ester linkages with longer carbon chains than PEG-SG. In another embodiment, an aromatic group is placed adjacent to the ester group to provide additional stability of the ester bond against hydrolysis, such as an aromatic carboxylic ester of PEG, including a benzoic acid ester or a substituted benzoic acid ester.
In some embodiments, a more stable or slowly degrading bond, such as a urethane bond or an amide bond, may be selected to provide the necessary mechanical strength and persistence in vivo to prevent neuroma formation.
In other embodiments, hydrolysis modifiers (M) can be designed into the backbone of the hydrogels to enhance the hydrolytic degradation of the urethane in the hydrogel. This can be accomplished by adding electron-withdrawing groups that speed up the reactions.
In one embodiment, the rate of hydrolysis of the carbamate bond can be modulated by adjacent groups, thus modulating the persistence of the hydrogel in vivo. R1 and R3 can be any aliphatic hydrocarbon group (—CH2—, —CHR—, —CRR′—), substituted aliphatic hydrocarbon group, aromatic groups, and substituted aromatic group in any ordered form. The aromatic group includes, but is not limited to, phenyl, biphenyl, polycyclic aryl, and heterocyclic aryl. The substitution moiety of the aliphatic and aromatic group includes, among others, halogen, alkyl, aryl, substituted alkyl, substituted aryl, substituted heteroaryl, alkenylalkyl, alkoxy, hydroxy, amine, phenol ester, amide, carboalkoxy, carboxamide, aldehyde, carboxyl, nitro and cyanide. R2 can be H and any group in R1 and R3. Furthermore, R1 can include isocyanate, aromatic isocyanate, diisocyanate (eg LDI). In one embodiment, R3 can be anilide and in another embodiment, R1 can be phenyl.
In another embodiment, the rate of hydrolysis of the carbamate bond can be modulated by the modulator at the beta position. The modulator can be CF3FSO2—, CIPhSO2—, FSO2-, MimnorteFSO2—, MeOPhSO2—, MeSO2-, OR ALONE2CH2)NSO2-, CN-, (E)2ONE2—. In yet other embodiments, these modifiers can be adapted for use in PEG hydrogels containing amide, carbonate, and urea linkages. Additional Modifiers Affecting ηψδρoλψσξσ ρατε oϕ τηε χαρβαματε λξνκαγε αρε δεσχρξβεδ ξν 7,060,259, incorporated by reference herein. Additional cleavable crosslinking is described in Henise et al (2019) In vitro-in vivo correlation for degradation of Tetra-PEG hydrogel microspheres with adjustable b eliminative crosslinking cleavage rates. International Journal of Polymer Science, incorporated in its entirety. These modifying groups, M, can be on the backbone itself or on a nearby side chain, such as with a beta-eliminative linker, as described by D. V. Santi et al (2012) Predictable and adjustable extension of the half-life of therapeutic agents by control chemical release of macromolecular conjugates. PNAS, 109(6) 6211-6216 and US20170312368A1 incorporated herein by reference. In some embodiments, a mild chain extender is added, such as an ester-linked amino acid peptide-based chain extender. For example, poly(phosphoester urethanes) with chain extenders containing phosphoester linkages. For example, poly(DL, lactide) is a chain extender or poly(caprolactone) to extend the PEG chain and add a soft segment. Preferably, the molecular weight of the chain extender may be 0.5 kDa to 5 kDa, preferably 1 to 2 kDa, most preferably 2 kDa. The soft segments can provide additional properties to improve the physical properties of the hydrogel, including heat sensitivity, crystallinity, the potential to result in both physical and chemical crosslinking. These hydrogels can be composed, for example, of PEGs with molecular weights between 1,000 Da and 50 kDa, including multi-armed PEG succinimidyl carbonate (4 arms or 8 arms) with molecular weights between 5 and 40 kDa and arm lengths between 1 and 40 kDa. 3 kDa and PEG-amine (4 arms or 8 arms) with molecular weights between 5 and 40 kDa, preferably 10.20 kDa or 40 kDa. In one embodiment, PEG-SC (4 arms 10K) is crosslinked with PEG-amine (8 arms 20k). Preferably the PEG solids content is between 6 and 10% by weight, more preferably 8% by weight. In another embodiment, PEG-SC (8 arms 15K) is crosslinked with trilysine amine. In another embodiment, PEG-SC (4 arms 20K) is crosslinked with trilysine amine. Examples of other PEG-SC formulations that form in situ are described in US Pat. No. 6,413,507, incorporated herein by reference. In another embodiment, a 10K 4-arm PEG-succinimidyl glutaramide (SGA-PEG) can be used in combination with 8-arm 20K PEG-amine at 8% solids.
Alternatively, the functionalized PEG can be covalently crosslinked with another reactive polymer or small molecule (eg, trilysine) containing amines or protected amines, maleimides, thiols or protected thiols, acrylates, acrylamides, carboxylic acids or protected carboxylic acids, azides. , alkynes, including cycloalkynes, 1-3 dienes and furans, alpha-hydroxycarbonyls, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl esters or carbonates.
In yet other embodiments, mixtures of more rapidly degrading PEG esters and more slowly degrading PEG-SGA or PEG-SC in ratios of 10:1 or 5:1 may allow slowing of the degradation profile in vivo without an appreciable loss of mechanical resistance during the process. initial period of nerve regeneration. Similarly, mixtures of PEG-SC and multi-arm PEG-amine cross-link to form carbamate linkages and PEG-carbonate ester linkages (delayed reaction of PEG-SC and with hydroxyl functional groups) to form 60:40 hydrogels mixed (Kelmansky et al. al (2017) In situ dual cross-linking of pure biogel with controlled delivery and mechanical properties Molecular Pharmaceutics, 14(10) 3609-3616.
In yet other embodiments, the multi-armed PEGs can be combined with blocks of other hydrolytically degradable polymers that can be used to adjust the degradation time of PEG hydrogels. For example, soft polyester diblock or triblock segments can be synthesized with low molecular weight polyester regions to allow the hydrogel to form in an aqueous environment (polycaprolactone, polylactic acid, polyglycolic acid, polyurethane, polyhydroxyalkanoates (PHAs), poly(ethylene adipate) (PEA), aliphatic diisocyanates such as isophorone diisocyanate (IPDI) or L-lysine ethyl ester diisocyanate (LDI)). These blocks can be composed of regions of lactide, glycolide or caprolactone, depending on the degree of crystallinity (D,L or L,L) to be used to provide additional mechanical resistance to the hydrogels allowing adjustment of the degradation profile. For example, a caprolactone block can be added to a multi-armed PEG, each arm comprising a PEG-PCL-NHS ester. In this embodiment, the PCL domain can extend the degradation of a previously poor in vivo persistent multi-armed PEG with hydrolytic ester linkages. In the preferred embodiment, a PCL block of between 1 and 5 kDa, preferably 1 to 2 kDa, is added to the PEG arm. For example, a 28K 4-arm PEG-PCL-NHS ester can react with a 10K 4-arm PEG-amine to form an in situ crosslinked hydrogel where the PEG is a 2K block. The addition of the block causes the hydrogel to form in situ through chemical and physical crosslinking. Amino acids can also be incorporated as chain extenders into PEG-SC to enhance urethane bond degradation. In some embodiments, low molecular weight trifunctional polyester polyols are selected for incorporation. See figure.1— Common monomers used for the synthesis of biostable and biodegradable polyurethanes, incorporated herein by reference (Chapter: Degradation of Polyurethanes for Cardiovascular Applications, Book: Advances in Biomaterials Science and Biomedical Applications).
In some embodiments, heterobifunctional crosslinkers are used to allow polyesters to conjugate to some arms and NHS esters or other functional groups to other arms.
In yet other embodiments, excipients can be incorporated into the hydrogels to modify the mechanical strength, density, surface tension, flowability, and in vivo persistence of the hydrogels. These modifiers are encapsulated in the hydrogel when the hydrogel is formed. Modifiers can include amphiphilic excipients such as vitamin E TPGS, low molecular weight polyesters such as caprolactone, or solvents such as ethanol. In one embodiment, ethanol is incorporated into the diluent or accelerator solutions to produce a hydrogel loaded with 5% to 70% v/v ethanol. Ethanol improves the elasticity of the hydrogel and reduces the density of the hydrogel precursor solution relative to nerve density. In addition, low concentrations of ethanol can be incorporated into the hydrogel to improve the pot life or pot life of the PEG/diluent solution after suspending the PEG powder. In another embodiment, Pluronic can be incorporated into a diluent or accelerator solution to produce 5 to 15% w/v to produce a PEG-SG hydrogel with improved elasticity and persistence in vivo. In yet another embodiment, low molecular weight caprolactone is incorporated into diluent solutions to produce a combined 1 to 5% w/v PEG/caprolactone hydrogel. In another embodiment, the vitamin TPGS can be incorporated into the diluent solution to produce a 5 to 20% w/v mixture of PEG/vitamin E TPGS.
Swelling. Another critical element of these hydrogels is the swelling of the hydrogels for applications around nerves. Hydrogels, when circumferentially distributed around an object such as a nerve, experience positive swelling in a radial outward direction. Initially, hydrogels undergo equilibrium-mediated swelling as they equilibrate with the surrounding environment fluids, and later, when a critical number of hydrolytic bonds are broken, hydrogels swell as a result of loss of mechanical strength. This last phase of degradation-mediated swelling results in a progressive loss of mechanical strength and softening of the hydrogel, which collapses and is eventually removed from the site. In vivo experiments in which the sciatic nerves of severed rats were wrapped by hydrogels that swelled 5%, 10%, 20%, 30%, and 60% demonstrated that hydrogels that swelled more than 30% were significantly more likely to detachment from the nerve as a result of the creation of a space between the nerve and the hydrogel. Of note, PEG hydrogels that swell by 0% or less contract when equilibrated in vitro or in vivo, and the resulting compression may cause persistent local hydrogel-mediated nerve pain. For example, DuraSeal hydrogel swells significantly and tends to detach from the proximal nerve stump when applied in situ.
Balances puffiness. For applications where hydrogels are administered to nerves to prevent nerve regeneration, it is desirable to maintain strong adhesion and apposition between the nerve and the conformable hydrogel. As a result, it is desirable to minimize equilibrium swelling following hydrogel delivery. Equilibrium swelling occurs from minutes to days as the hydrogel equilibrates with fluids in the in situ environment. In one embodiment, the hydrogel swells more than 0% but less than 40%, preferably more than 5% and less than 30%, more preferably more than 5% and less than 25%.
Furthermore, in some embodiments, it is desirable to avoid shrinking hydrogels, as these hydrogels can compress the nerve and result in aberrant nerve discharge, and it is therefore preferable to use hydrogels that swell more than 0%. Also, the nerve can swell after injury and therefore some swelling is desirable to allow room for the nerve to swell.
Equilibrated swelling can preferably be assessed in vitro under body temperature conditions (37°C in PBS). Hydrogel samples were prepared in cylindrical silicone tubes (6 mm) and cut into dimensions of 6 mm diameter by 12 mm length. Samples were weighed and melted in PBS at 37°C. After swelling in PBS for 12-24 hours at 37°C, the samples were removed and weighed again. Swelling is calculated by the percentage increase in mass.
Degradation swelling. A minor feature of biodegradable or bioerodible hydrogels, after the initial equilibrium swelling, is the appreciation of a continuous second phase of swelling that occurs as a result of hydrogel degradation. Swelling can occur through hydrolytic, enzymatic, or oxidation-sensitive bonds in the hydrogel. This is an equally important feature because the hydrogel needs to remain in the nerve for a period of one month or more, more preferably two months or more, most preferably three months. In an animal model, the time period is shorter and in the clinical setting, this period is longer. In some cases, if the rate of degradation is too fast, the hydrogel can fracture and break away from the nerve or be removed before the hydrogel can do its job of preventing nerve growth and/or preventing neuroma. In other cases, if the hydrogel appears intact in the nerves, there may be a substantial loss of mechanical integrity within the hydrogel as a result of nerve degradation that can extend into the softened or fractured hydrogel and form a neuroma formation. As a result, it is preferable that a biodegradable system has no more than 50% of the hydrolytically labile linkages cleaved in 3 months, more preferably no more than 30% of the linkages, and even more preferably no more than 20% of the linkages. . After the period of time that the hydrogel provides a mechanical barrier to nerve regeneration, the crosslinking density may decrease and degradation may continue until the hydrogel is completely removed. Bond loss can be assessed in part by reducing the mechanical integrity of the hydrogel. Bond loss can be assessed in part by reducing the mechanical integrity of the hydrogel. Therefore, it is desirable that the hydrogel maintain a compression modulus of 40 kPa 3 months after delivery, this hydrogel is rigid enough so that the nerves do not grow.
Pressure. In addition to ensuring that the swelling is not so great that the hydrogel will fall off the nerve or migrate, it is also desirable to confirm that swelling (or little swelling, shrinkage) will not result in compression of the nerve. In one experiment, a pressure transducer catheter was placed next to a nerve and an in situ forming hydrogel was dispensed to form around the nerve/pressure transducer (Millar Mikro-Tip Pressure Catheter, 3.5F, straight single, AD Instruments). The hydrogel was then placed at 37°C in PBS and pressure versus time measurements were taken. Hydrogels with approximately 0% or negative swelling resulted in high and sustained increases in pressure (>150 mmHg) exerted on the inserted nerve as hydrogels shrank (eg, DuraSeal Exact), whereas hydrogels with approximately 0% or negative swelling that swelled 0% or more did not result in any significant increase in pressure. Clinically, sustained pressures of 20 mmHg or greater result in permanent nerve damage as a result of disruptions in microvascular and intracellular neuronal transport. The pressure exerted on a nerve after equilibrium swelling is preferably between negative 20 mmHg and negative 5 mmHg. In preclinical and clinical models, the pressure at the nerve injury site can be between 5 and 15 mmHg (Khaing et al 2015 — Injectable Hydrogels for Spinal Cord Repair). For example, although a variety of materials have been evaluated to modulate nerve regeneration in a spinal cord model, most lack the linear compression modulus (G) necessary to prevent neuroma formation (Table 1, Khaing et al, 2015 ). Therefore, designing hydrogels with minimal to moderate swelling in an outward radial direction avoids nerve compression as the hydrogel equilibrates with the tissue. Avoid high swelling hydrogels, after balancing swelling or degradation, avoid nerve compression of external tissues.
Rigidity. The stiffness of the hydrogel can be measured/inferred by rheology (G'=storage modulus, G*=shear modulus or linear compression modulus (G). Preferably, the stiffness of hydrogels, measured through the linear compression modulus (G) is greater than 10 kPa, preferably greater than 30 kPa, most preferably greater than 50 kPa The stiffness prevents ingrowth of the nerve into the surrounding hydrogel.
Compression and rebound. In addition to injectable gels having minimal swelling, compressible gels are desirable. This way, even if the hydrogel implant is pressed, it will not fracture. The compression and rebound test is performed on cylindrical specimens (6 mm diameter, 6 mm length) that have been incubated for at least one hour at 37°C until equilibration. Specimens are loaded into the Instron and displaced perpendicular to the longitudinal axis of the cylinder at a crosshead speed of 1 mm/min to a final displacement of 60% of the canal diameter. Verification that the hydrogels can withstand compressive forces greater than 0.25 N and that there were no changes in shape and diameter after removal of the compressive forces.
Flexibility. Another critical parameter of these in situ-forming polymers is the ability of the hydrogels to bend and flex at physiologically relevant angles in the body. To evaluate the flexibility of the hydrogels, the hydrogels were formed in 0.1 to 0.25" ID silicone tubing to form cylindrical strands of hydrogel 12 to 24" in length. Preferably, the hydrogels have enough flexibility to bend more than 90° and, more preferably, the cylindrical strands of hydrogel can be easily tied into a knot. Since flexibility and elasticity are determined, in part, by the distance from the nucleus of a multi-armed PEG to the nucleus of the adjacent multi-armed PEG, PEG hydrogels with core-to-core distances of 3 kDa, more preferably 5 kDa or greater . Robust and flexible hydrogels that will not fracture in the highly mobile and compressive environment of the body. As a result, more flexible hydrogels are desired, such as combinations of 4-armed 10K or 20K PEG with 4- or 8-armed 20K PEG-amines.
Goo. Low and medium viscosity precursor solutions can be selected to encapsulate the hydrogel with generally better adhesion in the low viscosity solution and better nerve management in the medium viscosity precursor solutions. In one embodiment of the invention, the fluid medium is a low viscosity hydrogel precursor solution having a viscosity of no more than about 100 cP and, in some embodiments, no more than about 20 cP or no more than about 5 cP. In yet another embodiment, the fluid medium is a medium viscosity hydrogel precursor solution, preferably having a viscosity of 300 to 10 kcP, more preferably 300 to 900 cP. In one embodiment, a viscosity enhancer/modifier or thickening agent may be added to the precursor gel to modify fluidic properties and help position the rib in the cap prior to gelation. The viscosity modifier can be natural hydrocolloids, semi-synthetic hydrocolloids, synthetic hydrocolloids, and clays. Natural hydrocolloids include, but are not limited to, acacia, tragacanth, alginic acid, alginate, karaya, guar gum, locust bean gum, carrageenan, gelatin, collagen, hyaluronic acid, dextran, starch, xanthan gum, galactomannans, konjac mannan, tragacanth gum, chitosan, gellan gum, methoxyl pectin, agar, gum acacia, dammar gum. Semi-synthetic hydrocolloids include, but are not limited to, methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC, 0.3%), modified starches, propylene glycol alginate. Synthetic hydrocolloids include, but are not limited to, polyethylene glycol, polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, polyglycerol, polyglycerol polyricinoleate. Clays include, but are not limited to, magnesium aluminum silicate (Veegum), bentonite, attapulgite.
In another embodiment, the viscosity can be modified by prior crosslinking of PEG-amine and PEG-SC. PEG-amine and PEG-SC can be pre-crosslinked in a ratio of 10,000:1 to 1:10,000 at a total PEG concentration of 0.01% to 100%. The pre-crosslinker can be further crosslinked alone, or with PEG-amine, or with PEG-SCe, or with PEG-amine and PEG-SC to form a higher viscosity precursor solution.
Density of the precursor solution. Nerve tissue, as a result of myelin and adipose tissue, is hydrophobic and therefore tends to float in solutions with a density close to that of water (~1 g/cm3). By adjusting the density of the fluid medium, the rib position can be adjusted to reduce the propensity of smaller diameter ribs to float in the precursor solution without sacrificing the adhesion force that comes with increased precursor viscosity. In some embodiments, the density of the precursor solution or the middle solution is reduced so that the nerve is relatively denser than the solution at <1 g/cm.3, preferably <0.9 g/cm3. In yet other embodiments, the density of the precursor solution is adjusted to be approximately equivalent to that of the nerve. Polar and less dense solvents, including ethanol (10 to 70%), toluene (10%), ethyl acetate, or chlorobenzene can be added to reduce the density of the precursor solution. In another embodiment, vitamin E TPGS (1-2 kDa, 10-20%) may be added to reduce the nerve's propensity to float. Some of these solvents also lower the surface tension of the stock solution, causing the nerve to sink.
Open surgical neuroma procedure. After openly exposing the surgical site and isolating the target nerve, it is desirable to resection the nerve to clean out the nerve end. In some modalities, the physician may choose to cut the nerve at a 90 degree angle, or alternatively at a 45 degree angle. In some modalities, the clinician may choose to use other methods, such as nerve-end electrocautery, nerve stump ligation, PEG application with a low molecular weight tip (eg, 1-5 kDa, 50% w/v hypotonic solution). ) or other approaches they developed to seal or remove the nerve end.
In yet another embodiment, the physician may choose to employ a PEG fusion protocol as described in US Patent 10,398,438 or 10,136,894 to the nerve prior to application of the in situ-forming hydrogel. These PEG fusion approaches can be used to fuse nerves, as it is desirable to seal the nerve ends after transection for the prevention of neuromas. They can also be used to seal nerves together, such as the proximal and distal stump in close apposition to improve nerve regeneration results. By pre-applying this sequence of solutions (Ca2+ free, optional antioxidant, Fusogen, Ca2+ solution), nerve endings can be optimally sealed to enhance neuronal survival or, in the case of nerve regeneration, nerve growth. Kits containing both of the PEG fusion component solutions described in the above patents and incorporated herein by reference in their entirety can be combined with the in situ forming hydrogel kits.
axoplasm. Since axoplasm, a sticky, viscous material that oozes from the severed nerve end after section, can reduce the close apposition between the nerve end and the hydrogel, it may be desirable to remove it from the nerve end. This can be done by touching the nerve with an absorbent material, such as a cotton swab. An absorbable swab can be provided to absorb any part of the axoplasm after nerve section. The tip of the swab is preferably less than 5mm, more preferably less than 2mm so that it can fit snugly within the shape and retain the nerve while the hydrogel is delivered. The swab can be provided as part of the kit. Alternatively, this can be done by bringing the tip of the nerve into contact with the surrounding tissue, resulting in the rapid formation of an adhesion between the nerve and the tissue that must be secondarily severed. Alternatively, for neuroma prevention applications, the nerve tip can be rinsed with a Ca2+-free solution to remove excess axoplasm and growth factors before administering the in situ-forming hydrogel around the nerve. Alternatively or in addition, the low molecular weight biomembrane fusion agent can be delivered into the forming hydrogel in situ to the nerve to seal the membranes along with the delivery of PEG hydrogel. As before, concentrations between 40-70%, preferably 50% and molecular weights of PEG (<5 kDa, 10-50 mM) have been widely shown to seal damaged plasmalemma. Various protocols for PEG fusion (for use in neuroma prevention applications by sealing severed nerves) or PEG sealing (for use in nerve repair procedures). Although Colton Riley et al. al 2017 (PMID: 29053522) illustrated the delivery of PEG molten solution and associated solutions in the form of a wrapper, this could best be achieved by delivering the PEG molten solution and associated solutions in the form of a wrapper, wrapper, or cap.
Coverage of the proximal nerve stump (tip). The hydrogel itself preferably extends at least 0.5mm, preferably 1mm to 20mm, preferably 2mm to 10mm, beyond the end of the proximal nerve stump.
Length coverage. It is preferred that a minimum of 10mm of nerve is embedded/encapsulated in the hydrogel, although in some cases 5mm may be sufficient. A longer length of nerve embedded in the hydrogel accomplishes several things a) by increasing the appositional surface area between the nerve and the hydrogel and b) by decreasing the likelihood of proximal budding of Ranvier's nodes proximal to the transection as these proximal nodes they are embedded in the hydrogel. Again, the greater the length of the encapsulated nerve, the greater the chance that even regions that have been damaged by forceps manipulation, previous trauma, etc. incorporated into the hydrogel, preventing the appearance of nerve fibers.
Once an approximately 10mm section of nerve is isolated, either the nerve is attached to the swab, along with forceps or a rod, or gently held with forceps, the nerve is slightly elevated to allow it to be positioned. a shape below the nerve. In one embodiment, the rib is then gently lowered into a channel or entry zone to align the rib in the center of the shape. See, for example, FIGS.1our1B. The form, once the desired position is achieved, is left in place.
While holding the nerve tip with one hand in the center of the form, the clinician applies the in situ forming hydrogel using the other hand to fill the form and retain the nerve in the center of the form. The top of the silicone mold serves as a guide to know when to stop filling the mold. As the hydrogel fills the top of the nerve, the swab/forceps are withdrawn so that the nerve is retained within the hydrogel and not in the tool. In this way, there is no direct way for a nerve to regenerate through the surrounding tissue and the nerve is completely encased in the hydrogel. In another embodiment, a cap-shaped pin is added to adhere the rib to the cap-form prior to application of the hydrogel. The post is flexible and can be removed after the hydrogel has formed. In one embodiment, the post is constructed of a bioabsorbable polymer that is left in place after delivery of the hydrogel and separated from the cap form after the hydrogel has formed within the cap form. Thus, this pin is embedded in the hydrogel cap that remains in situ. In one embodiment, the post is made of the same material as the hydrogel cap. This allows for a similar or identical swelling behavior to that of the hydrogel layer that has formed around the nail and nerve. In another embodiment, the post is composed of a low molecular weight PEG, which allows the post to be removed more quickly than the hydrogel cap. The pin can be formed from a lyophilized PEG solution in place within a cap shape. Preferably, the pin is withdrawn 2-3 mm from the tip of the transected nerve, so that the regenerating nerves grow retrograde and exit through the void created by the pin.
gel thickness Prevention of nerve regrowth requires providing a conformable barrier at the proximal end of a severed nerve. The hydrogel also preferably surrounds the nerve with a thickness of 100 µm to 5 mm radially. In one embodiment, the hydrogel precursor solution is dripped onto the nerve to form a thin protective layer approximately 100 microns to 2 mm thick circumferentially around the proximal nerve stump and remains in place to block neurite outgrowth. A thin coating is sufficient to provide a barrier to nerve regeneration, and therefore, in some embodiments, the nerve is coated by immersion in the fluid medium and the hydrogel is subsequently formed into a thin layer around the nerve. In this embodiment, the gel time of the hydrogel is set at 10 to 20 seconds to allow removal of the coated nerve prior to conversion to a non-flowable form with gel formation. Thin coatings that provide adhesion and coverage of the circumference and tip of the nerve stump on the order of 50 microns to 500 microns are desirable to cover the nerve end.
In some embodiments, the thin protective layer is distributed around a pinched or intact nerve to provide
For applications where it is desirable to protect long lengths of rib, a casing shape can be designed from 1 cm to 100 cm long, preferably 1 cm to 50 cm long, more preferably 1 cm to 10 cm long. For longer nerve wraps, the gel time of the hydrogel formed in situ can be extended to allow coverage of the entire length of the nerve. Alternatively, the mixer/needle at the end of the hydrogel applicator can be changed so that longer wrappers can be filled with successive gel-forming regions. Alternatively, several wrappers approximately 1.5 cm to 2 cm long can be placed in sequence. These wrappers can be filled with one applicator each.
In yet another embodiment, it is desirable to form the hydrogel around the nerve in an implant or bolus, providing a robust adhesive layer of hydrogel around the nerve, approximately 0.5 to 5 mm, more preferably 1 to 2 mm thick around the nerve. the circumference of the nerve. nerve and 1 to 5 mm beyond the tip of the nerve stump.
pore size. To prevent regeneration of nerves in the biomaterial, the pore size of the hydrogel must be small enough to prevent nerves and other supporting cells from infiltrating the biomaterial. The diameters of nerve axons are between approximately 0.5 and 30 µm. Preferably, the growth inhibitory hydrogel is microporous or mesoporous, with pores less than 1 µm, preferably less than 0.5 microns, most preferably less than 500 nm in diameter.
Demand. Neutral or negatively charged biomaterials are preferred as growth inhibitory gels, since neurites prefer to grow on positively charged biomaterials. Also, hydrophilic or amphiphilic materials are preferred over hydrophobic materials. In some cases, the biomaterials can be combinations of polyanionic and polycationic materials.
Non-degradable hydrogels. If a non-degradable hydrogel system is used, the same equilibrium swelling characteristics apply, but since the hydrogel is non-degradable or biostable, degradation swelling is not relevant. For example, the nondegradable in situ forming thermosensitive copolymer Pluronic (PEO-PPO-PEO), polyvinyl alcohol or PEO can be used to form hydrogels. In some embodiments, the Pluronic (eg, F 127) is modified and crosslinked with the multi-armed PEG to increase the plasticity of the hydrogel.
Clarity. In the preferred embodiment, the hydrogel is clear and transparent to confirm the location of the nerve after formation of the hydrogel. Of particular relevance to nerve repair cases, transparency allows confirmation that the nerve repair was optimal and that no fascicles are forming from the repair site or that the optimal distance between the two nerve stumps has been maintained. A visualization agent can be incorporated into the hydrogel to aid in contrast with background tissues. The color additive or mixture of color additives can be included in the polymer powder solution. In the case of using multiple hydrogels (described below), it is desirable to use one or more different visualization agents to provide visual confirmation, for example, that the growth-enabled hydrogel was correctly distributed among the nerves and that the hydrogel that inhibits growth was handed around. hydrogel that allows growth.
The cap of the present invention can be formed from a hydrogel with sufficient optical clarity that the nerve can be seen visually through the cap material after the cap is formed. With reference to Figs.1Banda1And the lid, once demolded, will have a first (lower) convex side surface that fits the concave surface of the mold and a second (upper) surface aligned with the window.20and has a relatively flat meniscal conformation. At least a part of the first surface has a curvature that can substantially conform to the surface of a cylinder. This, along with the hydrogel's optically transparent feature, works like a lens, magnifying the appearance of the nerve when viewed through the first surface. Thus, the eyelid can function as a convex-concave lens (sometimes called a negative meniscus), where the concave interface on the nerve surface has a narrower radius of curvature than the radius of the first outer surface to produce magnification. The radius of the hydrogel lens is typically between about 1 mm and about 12 mm from the center of the nerve and the thickness of the hydrogel lens along the first surface may be between about 0.5 mm and about 5mm thick, preferably about 1mm to about 1.5mm thick. The refractive index of the convex hydrogel lens is similar to that of objects embedded in glass, between 1.45 and 2.00, effectively bending light rays inward to make the inner rib appear larger than it is. The hydrogel is transparent and more than 90% water, making it suitable
Elasticity. In some embodiments, the elasticity of the hydrogel can be modulated by incorporating the hydrophobic domain into the hydrogel. The hydrophobic domain can be incorporated by crosslinking or mixing molecules, particles, fibers and micelles. The incorporated molecules can be amphiphilic molecules including pluronic acid, polysorbate and tocopheryl polyethylene glycol succinate. Particles, fibers, and micelles can be made from the amphiphilic molecules described in the previous section. In addition, many low molecular weight hydrophobic drugs that are incorporated into the hydrogel (described below) improve the elasticity of the hydrogel.
Team. The in situ formed hydrogel is administered through a dual applicator system comprising a dual channel applicator, a dual adapter, one or more mixers, and one or more blunt needles. Also included in the kit is a powder vial with associated vial adapter, diluent solution, and accelerator solution for use in the dual applicator system. The kit may include one or more forms in which the hydrogel is delivered. The kit may also include one or more blunt mixing syringes. The mixing syringes can be conventional single lumen mixers with a static mixing element or the mixers can be mixers in which there is recirculation and turbulent flow of the contents to improve mixing of the precursor solution.
Chemistry and physics. Preferably, the hydrogel networks are predominantly hydrophilic with a high water content and are formed by physical or chemical crosslinking or synthetic or natural polymers, copolymers, block copolymers or oligomers. Examples of synthetic hydrogels that do not allow growth include agarose, PEG or alginate, PVA hydrogels with a solids content of 2% w/v or higher, preferably a solids content of 6% w/v, more preferably a solids content of solids of 8% w/v or higher. PEG. Multi-arm PEGs are described above, but can be selected according to desired properties from PEG-amine, PEG-carboxyl, PEG-SCM, PEG-SGA, PEG-nitrophenyl carbonate (carbonate linker), PEG-maleimide , PEG-acrylate , PEG-thiol, PEG-vinysulfone, PEG-succinimidyl succinate (SS), PEG-succinimidyl glutarate (SG), PEG-isocyanate, PEG-norbornene or PEG-azide. alginate. A viscous solution of injectable alginate (1-5%) can be applied around the nerve. Likewise, agarose gel at concentrations of 1% w/vol or higher prevents nerve extension.
hypotonic solutions. In one embodiment, a hypotonic solution (Ca2+-free, mildly hypotonic saline containing 1-2 mM EGTA) is administered to the severed nerve to help seal crushed or severed axonal ends prior to repair with the training biomaterial in situ. .
PEG Fusion combined with an in situ cap or nerve wrap. As described in many publications describing methods for nerve fusion with PEG (3.35-5 kDa solution, 30-50% w/v), a PEG solution can be administered to the nerves to fuse them first, only or in combination with methylene. blue. After the membranes are sealed, the regrowth-enhancing hydrogel is administered between and around the pinched or cut nerves.
reticulated particles. In some embodiments, the hydrogel can be prepared with crosslinkable particles, fibers, or micelles. These particles, fibers, or micelles are functionalized with reactive groups, including but not limited to active ester, amine, carboxyl, aldehyde, isocyanate, isothiocyanate, thiol, azide, and alkyne, which can be crosslinked with small molecules, polymers, particle fibers, or micelles. . with reactive groups to form bonds including amide, carbamate, carbonate, urea, thiourea, thioester, disulfide, hydrazone, oxime, imine, amidine, and triazole. In some embodiments, micelles, fibers, and particles can be formed from amphiphilic macromolecules with hydrophilic and hydrophobic segments. Hydrophilic segments can be natural or synthetic polymers, including polyethylene glycol, polyacid, polyvinyl alcohol, polyamino acid, polyvinylpyrrolidone, polyglycerol, polyoxazolines, and polysaccharides. The hydrophobic segments can be fatty acids, lipids, PLA, PGA, PLGA, PCL and the polymer ester copolymer in different ratios. In another embodiment, the functionalized microparticles form physical crosslinks with each other after a pH change and then, when placed in situ, the functionalized particles crosslink to form an interconnected network of microparticles.
Sealants. Some of the in situ forming gels developed for adhesion prevention and sealants can also be adapted for this application to prevent neuromas and aberrant nerve growth in scar tissue, such as low molecular weight polyanhydrides of acids such as sebacic acid, including poly(glycerol-co-sebacate) (PGSA) (US Patent No. 9,724,447, US20190071537, Pellenc et al (2019) Preclinical and clinical evaluation of a new on-demand light-activated, bioabsorbable synthetic sealant in vascular reconstruction, herein incorporated and adapted for use around nerves, for reference). Another sealant that can be adapted for delivery around peripheral nerves is Adherus Dural Sealant, which comprises a PEG-polyethyleneimine (PEI) copolymer that forms in situ because it exhibits little swelling and degrades in approximately 90 days (US Patent No. 9,878,066, incorporated herein). Other sealants include BioGlue (Cryolife) surgical adhesive, a compound of bovine serum albumin and glutaraldehyde, Omnex (Ethicon), ArterX (Baxter), Coseal (Baxter), and TissuGlu, a lysine-based urethane compound (Cohera Medical).
Photosensitive. In some modalities, photosensitive, photopolymerizable, or photocrosslinked biomaterials are envisioned that can be delivered in a liquid state (low to medium viscosity) in a form (cap or wrap) around the nerve and then, when proper positioning of the shaped nerve is obtained, Light curing is initiated with ultraviolet, infrared, and visible light. In one embodiment, the light source can be connected directly or via a fiber optic cable to an opening in the lid or casing. By projecting the light to shine throughout the shape of the cap or wrapper, a consistency in crosslink density can be achieved. The shape of the cap diffracts light to ensure that the entire shape is sufficiently illuminated to achieve uniform and homogeneous cross-linking throughout the gel. In the preferred embodiment, the light source housing mates directly with the shape at the distal end of the cap that faces the nerve stump side to ensure direct penetration of light. Alternatively, the shape can be designed with built-in light-emitting elements that allow light to be distributed circumferentially around the nerve. Hydrogels include PNIPAAM hydrogels modified with a chromophore such as chlorophyllin trisodium salt. Other biomaterials that form in situ include elastomers that can be crosslinked in situ, including US Pat. In it. 10,035,871 (and PMID 31089086), wholly incorporated through a chemical or photocrosslinking process. For these biomaterials, the transparency and color of the cap and cover shape can be adjusted to reflect ultraviolet light back into the shape, such as an opaque white shape.
Other ways. In addition to a crosslinked network, hydrogels can consist of dendrimers, self-assembling hydrogels, or low molecular weight synthetic polymeric liquids.
In one embodiment, low molecular weight (2 kDa, liquid) hydrogels can be formed in situ without water as a solvent, as described in Kelmansky et al (2017) In Situ Dual Cross-Linking of Neat Biogel with Controlled Mechanical and Delivery Properties), Molecular Pharmaceutics, 14(10) 3609-3616, incorporated herein. In yet other embodiments, hydrogels can be photocrosslinked to form hydrogels, as amply described in the literature. Crosslinking agents include eosin). In other embodiments, electroconductive hydrogels are used, including poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), polyaniline, polyacetylene, polythiophene, ester derivative, 3,4-propylenedioxythiophene (ProDOT), natural or synthetic melanin. , derivatives and combinations thereof.
Addition of sulfated proteoglycans. In some embodiments, it may be desirable to provide inhibitory environmental signals to the nerves in addition to the mechanical barrier provided by the hydrogel. This can be achieved by adding inhibitory molecules and/or extracellular matrix to the hydrogel by physical mixing or chemical crosslinking. Sulfated proteoglycans such as negatively charged side chains such as glycosaminoglycans are of interest. Of particular interest is dermatan sulfate (DS).
Mixtures In some embodiments, it may be desirable to create mixtures of two PEGs to improve the degradability of the system. In one embodiment, PEG-SC is combined with PEG-SG prior to crosslinking with trilysine amine to create a hydrogel that has sufficient mechanical support to prevent nerve growth, but then degrades more rapidly than PEG-SC. The in vivo gel persistence time is adjusted by the ratio of the most rapidly degrading PEG to the slowest degrading PEG, e.g. PEG-SG:PEG-SC or PEG-SAP:PEG-SC ratio. With increasing PEG-SC content, the persistence time of the gel in vivo increases. In another embodiment, the PEG carbamates are mixed with the PEG carbonates. Other hydrogels include PEG hydrogels composed of carbamate derivatives (US Patent No. 7,060,259).
Permissive growth gels. In some embodiments, the growth enabling solution comprises a low viscosity collagen solution at 1.5 mg/ml or less, more preferably 0.6 mg/ml or 0.8 mg/ml. In another way. A laminin solution at a concentration of 0.4 mg/ml is preferred. In another embodiment, a formulation of HPMC or CMC (carboxymethyl cellulose) or oxidized cellulose at a concentration of 2% provides a low viscosity solution through which nerves can find pathways without appreciable mechanical barriers.
Incorporation of agents. In some embodiments, the agents can be dissolved or suspended in the diluent or accelerator solution and surfactants or ethanol can be added to stabilize the suspension. The drug can also be encapsulated in microparticles, nanoparticles, or micelles and then suspended in diluent or accelerator. In some embodiments, the hydrogel can be prepared with crosslinkable particles and micelles. These particles or micelles have reactive groups such as the active ester, amine, carboxyl, thiol, and those described in US Pat. 7,347,850 B2 and can crosslink small molecules, polymers, particles, or micelles with reactive groups that react with the first particles or micelles and form bonds including amide, carbamate, carbonate, urea, thiourea, thioester, disulfide, hydrazone, oxime, imine, amidine and triazole. In other embodiments, the gel can be formed by swelling the particles. The large volume of swelling can increase the contact of the particles and lock them in place to form the gel.
solid content. The solids content can be adjusted to adjust the swelling and tensile properties of the hydrogel. For example, the solids content can be adjusted above the critical gel concentration, such as between 2-15% filler, more preferably 7-9% filler, most preferably 8-8.5% solids content. .
Reticulation. Hydrogels can be formed in situ by free radical, or electrophilic-nucleophilic photopolymerization.
In vivo persistence. In some embodiments, a longer in vivo persistence may be preferred, where the hydrogel remains in situ between 3 months and 3 years, more preferably 6 months and 18 months, most preferably 6 months and 12 months.
Accession. Adhesive strength is an important criterion in keeping the hydrogel in close apposition to the nerve. Adhesion can occur through cross-linking reactions between the hydrogel and primary and secondary amines on the tissue surface, e.g. the epineurium or amino groups found on the surface of nerves, glia, and associated cells. The adhesion strength should be greater than 10 kPa, preferably greater than 50 kPa, most preferably greater than 100 kPa. The adhesive force on the nerves can be estimated by incorporating the sciatic nerve into the hydrogels. The rib ends are embedded in super glue between sandpaper and placed in titanium clamps on a Bose ElectroForce 3200-ES. The nerves are pulsed at a rate of 0.08 mm/s to failure. Care was taken to ensure that the nerves were used soon after collection and that the hydrogel and nerve were equilibrated in PBS at 37°C prior to testing.
Other hydrogels. Polyanhydrides that form in situ are also of interest for the development of nerve-targeted applications. In one embodiment, the polyanhydride polymers can be acrylated so that they can be formed in situ by free radical polymerization. Alternatively, they can be formed by photocrosslinking. At lower concentrations, the polymers are soluble in water, e.g. 10% Prevention of nerve regeneration is conferred in part by its hydrophobicity. US20180177913A1, US 62/181270 and US201562181270P are incorporated by reference.
Applicator. Dual-channel applicators used to deliver the in situ-forming hydrogels are commercially available (Nordson Medical Fibrijet Biomaterial Applicators, Medmix Dual Syringe Biomaterial Delivery System, K-System). Delivering between 2.75 and up to 10 mL of hydrogel, however, these mixers feature a single lumen with a static mixing element and are designed to successfully mix and deliver large volumes of hydrogel solution and are not ideal for delivering small volumes. volumes (< 1 mL) of hydrogel solution to one site. As a result, there is a need for a mixer that provides for the mixing of small volumes of two-component systems, since inevitably one of the two solutions generally advances slightly ahead of the other solution, leading to a small volume of partial mixing. or incorrect. gel existing needle first. In one embodiment, a custom mixer is designed to fit into the Nordson Medical or K-System applicator, via either a luer or push fit, as needed for the dual-chamber applicator system, to recirculate some of the initial solutions that they enter the mixer to ensure a better mix of the hydrogel, including the initial components. FIG.18illustrating drawing (transparent) of the central part of the mixer containing an inlet port with at least one static mixer, a larger vessel through which the contents are delivered and recirculated, and a second port that captures the recirculated mixed fluid and delivers it to the mixer's input/output port. The second port may or may not contain additional static mixers.
In some embodiments, the 4-arm PEG 10K-SC is crosslinked with an 8-arm PEG 20K amine. PEG-SC and PEG-amine were dissolved in an acidic diluent in a 1:1 ratio. The suspension was mixed with accelerator buffer and delivered through a static mixer to form a hydrogel. This formulation gels in 4 seconds and provides compressive strength between 50 and 70 kPa. Furthermore, the swelling is between 10 and 30% by weight.
In another example, the 8-armed 15K PEG-SC is crosslinked with trilysine. PEG-SC was suspended in trilysine buffer and then mixed with accelerator buffer via a static mixer. This formulation gelled in 2 seconds and the gel provided a compressive strength of up to 200 kPa.
In another example, the 8-armed 20K PEG-thioisocyanate is crosslinked with trilysine in a 1:1 ratio. The formulation gelled in 3 seconds and has a compressive strength of 120 kPa and 5% swelling.
Form Chap. The method may comprise the step of placing a shape at a treatment site prior to placing the final cutting step. The form is supplied as part of the kit containing the delivery system and is composed of an inert, biocompatible, flexible and non-adhesive material to give the desired shape to the material formed in situ. The form is designed to be filled with fluid media so that it flows around the proximal end of the nerve stump, where it becomes a non-fluid composition, which conforms to the nerve stump and prevents neuroma formation. In the preferred embodiment, the shape creates a low profile rib cap with a smooth transition between rib and cap and a roughly cylindrical shape around the rib.
Mold. A shape is desirable, not only because it reduces off-target spread of the forming material in situ, but because it provides a low profile, circumferential lubricated shape that cannot be achieved with hydrogel application alone. Lubricity is provided, in part, through the use of a hydrophilic hydrogel. The profile and transitions of the shape design reduce friction and interference with surrounding tissue, allowing the hydrogel to glide and rotate relative to the surrounding tissue. The cap is designed to cover at least 5mm, preferably a length of 10mm or more, of rib.
In accordance with another aspect of the present invention, there is provided a way of creating a formed-in-situ nerve cap to inhibit neuroma formation or a nerve sheath to prevent nerve compression or facilitate nerve regeneration. The shape comprises a concave wall defining a cavity, the wall having a top opening for access to the cavity. The upper opening is in a foreground and has an area less than the area of a background in accordance with the internal dimensions of the cavity and spacing in the cavity and parallel to the foreground. A concave nerve guide is brought through the wall and provides lateral access to the cavity to receive a nerve ending. The wall is flexible so that it can be removed from a reticulated nerve capsule formed within the cavity and may comprise silicone, preferably 20 to 40 hardness, preferably 20 to 30, more preferably 20 hardness. The wall shapes the shape it has a slight undercut so that the material, when it fills the shape to the top edge of the shape, forms a convex surface due, in part, to the surface tension of the medium, which completes the cylindrical shape of the hydrogel. This durometer is considerably softer than FDA-cleared silicone nerve tubes, which are so stiff, with 50 or 60 durometers causing constriction and chronic neuropathic pain.
Silicone. In one embodiment, the form is composed of a non-adherent and non-degradable material. In the preferred embodiment, the material is medical grade silicone, flexible enough to be peeled or detached from the material formed in situ (eg, 20 or 30 durometer). After the transition of the medium to a substantially non-flowable state, the silicone form is removed and discarded. In one embodiment, the silicone form is colored to provide contrast to surrounding tissue so that the non-degradable polymer is not accidentally left in situ. Darker colors are preferable to enhance the light coming through the cap and illuminate the rib, such as dark blue, dark purple or dark green.
Although select natural rubbers can be selected for rib shapes, they are undesirable due to their lack of biocompatibility and poor characterization for applications involving direct tissue contact. As a result, medical grade silicones, such as those sold by NuSil/Avantor, Elkem, Dow, and Momentive, are preferred as most have passed USP Class VI biocompatibility testing. The vast majority of medical grade Liquid Silicone Rubbers (LSR) are designed for high tensile strength applications over 1200 psi psi, not designed to work with relatively more brittle biomaterials. While these properties are desirable for some medical devices (eg, implantable ICDs), their high tensile strength makes them a poor choice for applications that require flexibility to facilitate release of a biomaterial from the mold. As a result, a variety of LSRs were evaluated to determine which material was best suited for the application to deliver a hydrogel in one form. Quickly, the higher tensile strength silicones were phased out and attention turned to a smaller set of heat-curing, two-part silicone injection molding systems. For those applications where direct tissue contact is brief, materials with established biocompatibility for human implantation for less than 29 days are sufficient, although materials with established biocompatibility for a longer implantation period may be desirable.
However, for this application, silicones with lower hardness and lower tensile strength are preferable to facilitate removal of the hydrogel from the form. Therefore, silicones with a hardness of less than 45, preferably less than 30, more preferably around a hardness of 20 are desirable. Although most commercially available liquid silicone rubbers (LSRs) have tensile strengths above 1000 psi, for these applications, LSRs with lower tensile strengths are preferred. For example, tensile strengths of less than 900 psi, preferably less than 800 psi, are desirable. Likewise, elongation is another factor that determines the ease with which the biodegradable biomaterial can be demoulded. Materials with percent elongation greater than 400%, preferably between 400 and 2000%, more preferably between 400 and 1200%, most preferably between 400 and 800% are desirable. Examples of these materials include MED-4920 (NuSil, Type A 20 durometer, 700% elongation, 750 psi tensile strength), MED-4930 (Type A, 30 durometer, 450% elongation, 800 psi tensile strength), durometer), LIM-6010 (15 durometer, 440% elongation, 3 MPa tensile strength), Silopren LSR 4020 (22 durometer, 1000% elongation, 7 MPa tensile strength) or MED50-5338 (30 durometer, 1000% elongation 350%, 650 psi tensile strength) and SIL-5940 (40 durameter, 680% elongation, 1350 psi tensile strength), Silbione LSR 4340 (40 durameter, 605% elongation, 1250 psi tensile strength), Silibione 4325 (26 durameter, 1035% elongation, 1198 psi tensile strength), MED-5840 (40 durameter, 680% elongation, 1350 psi tensile strength) and MED-4840 (43 durameter, 590% elongation, 1350 psi tensile strength). tensile strength 1180 psi), SILASTIC Biomedical Grade LSR 7-6840 (durameter 42, elongation 700%, tensile strength 1430) or SILASTIC BioMedical Grade LSR (Q7-4840 (44 durameter, elongated) 540%, tensile strength 1370 psi). Preferably, the biocompatibility of these raw materials would be established to pass USP Class VI standards.
Alternatively, but less preferable, High Consistency Rubbers (HCR), such as peroxide or platinum cured MED-4035 (35 gauge hardness, 1.055% elongation, 1565 psi tensile strength), MED-4025 (Hardness Gauge 30, 890% elongation, 1285 psi), MED-4020 (25 hardness, 1245% elongation, 1400 tensile strength), or preferably MED-4014 (15 hardness, 1330% elongation, 700 psi tensile strength). tensile), most preferably MED-4920 (20 durameter, 700% elongation, 750 psi tensile strength). High consistency Class VI rubbers can also be carefully selected, although they tend to have significantly higher tensile strength at the acceptable high end above 1000 psi, such as 1300 to 1600 psi. Finally, room temperature cure silicone (e.g., RTV-2) such as P-44 (42 durometer, 250% elongation, 600 psi tensile strength, Silicones Inc. High Point, N.C.) also they are adequate. In some embodiments, the LSR is white instead of translucent (eg, MED-4942) or colored to contrast with fabric using Nusil's healthy color masterbatches in purple or blue. In some embodiments where longer or larger shapes are desirable, a silicone with a higher hardness within this range (for example, Shore A hardness 40) may be desirable to help maintain the shape, for example, for wrapping shapes with a length of 3 cm. Examples of materials include MED-4940 (Nusil).
LSRs with durometers greater than 50 and tensile strength greater than 1300 psi are less desirable (eg, Silbione LSR 4370, Silbione LSR 4365). Also, some silicones are designed to be adhesive, eg for adhesive wound dressings such as Silbione HC2 2031 A&B. These silicones are less desirable because they are designed to adhere to tissue rather than to be easily lubricated and released from tissue.
Demoulding. Easy release can be achieved by decreasing adhesion of the rib cap/wrap to the mold. If the sheath/nerve sheath precursor spreads well in the mold, it will adhere to the surface after gelation. To achieve easy release, the wettability of the sheath/nerve sheath precursor to the mold may be decreased. The interfacial tension, largely determined by polarity, plays a decisive role in wettability. The worst wettability conditions for adhesion are those where the polarity of the liquid is far from the polarity of the surface of the cap/wrap form. In one embodiment, hydrophobic materials including, but not limited to, biomedical grade silicone and mixtures thereof in various ratios may be used to make the mold. The interfacial tension of a liquid with a given solid can also be calculated from the contact angle of the various solids with the liquid.
In another embodiment, polar interactions and nonpolar interaction between the hydrogel sheath/nerve wrap and the shape of the sheath/nerve wrap will make the sheath/nerve wrap difficult to demold. Polar interactions include, but are not limited to, dipole-dipole, dipole-induced dipole, and hydrogen bonding. Materials with less polar interactions with the nerve cap/sheath, especially hydrogen bonding, can be used to make the template.
In another embodiment, increasing the surface tension of the gel precursor will decrease the wettability of the gel precursor on the surface. High polarity materials, including but not limited to salts, can be added to the gel formulation.
In another embodiment, materials that do not chemically react with the rib cap/wrap can be used as template materials. The chemical reaction between the nerve cap/wrap and the impression materials increases adhesiveness.
In another embodiment, the smoothness of the mold surface affects the tack and release of the cap/rib wrap. In general, the smoother the surface of the mold, the easier it will be to demould. For example, the mold material can be hydrophobic and rough on a microscopic scale. It can trap air on its surface, causing the unsolidified nerve sheath to be held together by its own surface tension. Such surfaces are called superhydrophobic. Superhydrophobic surfaces can be designed by forming microscale ridges or patterns in a hydrophobic material.
In one embodiment, the hydrophobicity of the cap/wrap forms generates sufficient surface tension so that when the hydrogel precursor solution is dispensed to fill the cap/wrap form, the hydrogel precursor solution forms a convex cap that rises upwards. above the proper shape of the lid, provide a cylindrical shape or an oblong cross section for the shape of the casing or lid.
Biodegradable. The method may alternatively comprise the step of placing in a biodegradable form before placing the final cutting step. The biodegradable form may be comprised of a non-crosslinked freeze-dried (or dried) synthetic biomaterial that remains in place for approximately 5 to 10 minutes, during which time the hydrogel is administered which forms in situ and then rapidly dissolves and is removed. of the body. in less than, say, a day or two. In one embodiment, the biodegradable form comprises lyophilized multi-arm or non-crosslinked PEG, lyophilized linear PEG (3.35 kDa), or cross-linked multi-arm PEG (eg, 8 arms 15 kDa). The method may alternatively comprise the step of forming a biodegradable shape in situ prior to positioning the final cutting step. In alternate embodiments, the shape is comprised of materials commonly used for nerve conduits and sheaths, such as polyvinyl alcohol, chitosan, polylactic acid, polyglycolic acid, polycaprolactone.
In yet another embodiment, the ex vivo implantable form is composed of the same material as the in situ formed material that is dispensed into the form. In this way, the properties of the balanced form are comparable and combine well with the balanced hydrogel formed in situ. In these embodiments, the biodegradable form remains in place after administration of the hydrogel and is not removed, but is removed from the implant site at approximately the same rate as material formed in situ. In yet another embodiment, the form is comprised of lyophilized non-crosslinked PEG into which the in situ formed hydrogel medium is dispensed. Uncrosslinked PEG is easily solubilized and removed from the site, making the form readily biodegradable. In yet another embodiment, the form is comprised of a crosslinked PEG matrix that will be rapidly removed from the site as a result of a rapidly cleaving hydrolytic bond, such as can be achieved with the ester bond in a PEG succinimidyl succinate (PEG- H.H ).
Shapes can be synthesized by injection molding, crosslinking or polymerization in a cavity, solvent casting, or 3D printing. A variety of synthetic and natural materials can be selected for the implantable form, including collagen, PEG-PEI, alginate, chitosan, or agarose.
The forms can be fast dissolving forms that, when wet, dissolve and clear within one hour after the procedure, leaving the biomaterial formed in situ in place. Alternatively, the shapes may be more slowly decomposed shapes that swell to a similar or greater degree than the in situ formed material that is distributed within them. Swell avoids scenarios where the hydrogel swells during equilibration and compresses the nerve if delivery is being reduced or has minimal compliance.
In some modalities, the positioned nerve is held in the desired location or orientation with forceps in one hand and the medium is delivered with the other hand into the form. As the medium fills the form, the nerve is released and subsequently the medium changes to a non-fluid state. Alternatively, a doctor or nursing assistant can help with the procedure. In another embodiment, the growth inhibitory hydrogel is formed around the nerve in a two-step process. In the first step, the hydrogel is delivered to the nerve tip to encapsulate the nerve end. In the second step, the hydrogel is applied to fill the entire form, including the nerve tip. In another embodiment, the growth inhibitory hydrogel is formed around the nerve in a first layer, and then a second layer of hydrogel is subsequently applied, in a two-step process.
Accordance. Unlike bandages, which still have a gap between the bandage and the nerve, hydrogel fits directly onto the nerve itself, providing a barrier to inflammatory and scar-forming cells at the site, allowing nutrients to pass through. Since the hydrogel adheres to the nerve, it is not necessary to suture the nerve to the hydrogel. The proximity of the hydrogel to the nerve also helps prevent scarring and adhesions around the nerve in the early stages of healing.
Centered. Veins, by virtue of their low density and high fat content and flexibility, particularly the smaller veins, have a tendency to flow upward in a low viscosity solution. The following modalities are designed to ensure that the nerve does not float on this surface after administration of the medium.
Goo. As described above, the viscosity of the fluid solution can be increased to minimize nervous buoyancy within the solution.
Flow. In another approach, the needle supplying the fluid medium is directed such that the flow of the medium allows circumferential delivery of the solution around the nerve prior to gel formation. The top shape can also be designed to improve media flow dynamics and improve rib alignment. In one implementation of the invention, one-step cutting of the target nerve and one-step one-way positioning of the treatment site are performed by a single instrument. In another implementation of the invention, the shape of the nerve cap is designed so that the delivery system and the shape are integrated. In the preferred embodiment, the delivery system is connected to the form via a catheter. The entrance of the catheter in the eyelid resides in the same entrance where the nerve enters the form. The catheter allows the material to flow along the shaft and circumferentially around the nerve so that the medium acts to self-center the nerve within the shape. Similarly, but using shorter gel times, flow and therefore movement of the nerves is limited.
Stabilizer. In another embodiment, a stabilizing bar or piece is aligned directly under or against the rib to provide sufficient adhesive forces so that the hydrogel can be distributed around the rib centered in the shape.
removable ducts. In yet another embodiment, the nerve is positioned in the center of the biomaterial in situ by placing it consecutively within two separable conduits. Briefly, the nerve is placed within the first detachable conduit and training material is delivered in situ to wrap the superior and distal end of the nerve. The detachable conduit may be an open-ended or closed-ended conduit. After the hydrogel forms, the pod is separated along the weakest peel lines of the material and discarded. The resulting nerve hydrogel is then placed in a second, larger detachable conduit. By slightly rotating the nerve, the hydrogel surface can be placed on the bottom of the second sheath so that the nerve is centered approximately in the middle of the second sheath. A second application of the hydrogel that forms in situ results in the cumulative formation of a circumferential hydrogel around the nerve that protects and centers the nerve within the nerve sheath. In one embodiment, the sheath consists of an extruded split PTFE tube with a vertical tab to aid tearing of the piece in the surgical environment, similar to vascular introducers.
In another embodiment, the nerve is positioned so that the proximal stump rests at a downward ninety degree angle in a cup shape and the hydrogel is administered in a cup shape to form around the nerve. The cup-shaped form is subsequently removed and discarded, and the proximal stump is refitted to its resting position in the tissue.
In yet another embodiment, the nerve can be dispensed in an amphiphilic or hydrophobic solution to prevent the nerve from floating to the medial surface. In yet another embodiment, the in situ-forming material can be made more viscous to prevent the nerve from migrating into it.
Inclined. Alternatively, the shape may have an oblique shape to deflect the nerve filler from the distal to the proximal end. In this way, the nerve can be positioned so that the hydrogel first forms circumferentially around the proximal tip of the nerve and then, through a second application or a continuation of the first application, fills in the remainder of the shape.
Input centering. In one embodiment, the shapes are designed so that the rib enters at a lower level than the top of the shape to allow material to be delivered circumferentially around the rib. In another embodiment, the entry region of the shape is angled so that the nerve enters the shape at a downward angle, shifting the location of the proximal end of the nerve downward.
Ribs. Tabs or ribs are provided on the outside of temporary non-degradable shapes, such as silicone shapes, to aid in removal of the shape after gel formation. These tabs are placed to provide additional stability to the shape of the eyelid on uneven surfaces or to provide a surface for grasping with forceps or other surgical instruments. In yet another embodiment, the form is designed to be self-centered. In other words, the mold can settle naturally so that the top surface of the mold is leveled in preparation for delivery of the hydrogel that forms in situ.
Holes In some embodiments, a guide hole or sheath is provided to direct the needle to deliver the media in the form in a specific direction. The direction of media flow can be designed to best position the nerve in the canal. In one embodiment, the hole is provided adjacent to or above where the nerve enters the casing to guide solution from proximal to distal in the conduit and encourage laminar flow within the casing.
Lids In some embodiments, the form contains a full or partial hinged lid to allow centering of the rib depending on the direction of flow within the form.
Delivered volumes. As with the shape of the cap, the volume of media delivered can range from 0.1 cc to 10 cc, typically 0.2 to 5 cc, more typically 0.3 to 1 cc.
Needle size. Kits contain either a 21 or 23 gauge needle for delivering smaller volumes in smaller size wrap (or cap) shapes and 18 gauge needles for filling larger shapes. These needles provide additional control over the speed of delivery of the forming material in situ, allowing for everything from deposition of a hydrogel bead to rapid filling of a larger canal.
Gel time. Likewise, the gel time can be adjusted depending on the fill volume of the wrapper or lid forms, providing longer gel times of 10 to 20 seconds for larger wrappers and a shorter gel time of no more than 10 seconds. or no more than 5 seconds. but usually at least 2-3 seconds for smaller wraps or lids.
Hydrogel thickness and shape sizes. The shape size range is designed with an entry region to accommodate a rib diameter of ±1 to 3mm, or more preferably ±1mm. The diameter of the shape determines the thickness of the gel that forms around the nerve. The thickness of the hydrogel that is formed around the nerves can be from 0.05 mm to 10 mm, more preferably from 1 mm to 5 mm, most preferably from 1 to 3 mm, depending on the size of the nerve.
Kit design. Rather than each kit containing one shape for a single size of nerve, as is the case with implantable nerve conduits and sheaths, kits will contain one to ten, usually one for cap shapes (or sheath shapes, or combinations of them), allowing the physician to select the appropriate size for the procedure, as well as the ability to change the form without having to order an additional kit. Kits can be labeled according to selected shapes, for example, shapes for a variety of nerve sizes, shapes for one type of surgical procedure (groin repair nerve guard), or shapes appropriate for a specific procedure site (groin patch nerve protector for hand surgery, nerve protector for upper limb, nerve form for brachial plexus).
Linen. In some embodiments, the in situ training material can be delivered to a nerve which is placed on a temporary non-adherent biocompatible sheet, such as an Esmarch bandage or other biocompatible sheet or backdrop (Mercian Surgical Visibility Material) that is commonly used for isolate the nerve of the surrounding tissue. The gel time can be shortened to limit the spread of the hydrogel around the nerve, for example, to 10 seconds or less, preferably 5 seconds or less. Any excess hydrogel can be removed from the surgical site and discarded.
Liquid cap shape. In another embodiment, the shape is not a physical shape, but rather is created by injecting a soluble hydrophobic solution, preferably a viscous solution such as glycerol. For example, to secure the nerve out of the way, a viscous oil can be applied to the surrounding tissue to coat it and prevent the hydrogel from adhering to the surrounding tissue. The solution, if viscous enough, can create a readily biodegradable form to provide the hydrogel that forms in situ. In the preferred embodiment, Solution A is administered first to block the amine and tissue binding sites and to create a space or region into which Solution B can be administered. In the next step, Solution B is delivered into the space created by Solution A, or delivered to the center of Solution B, moving Solution B away from the location.
No Form. In some modalities, the space or access does not allow the use of a form. In some cases, such as brachial plexus injuries, the surgical window is so small or the concern for damaging adjacent tissues is so small that it is not possible to place a form in place to apply the hydrogel. In these cases, the hydrogel can be applied directly to a pocket or surgical site on or around the nerve. If the region around the rib is used naturally, the cap has an irregular shape that is defined by the tissue boundaries at the bottom and sides of the rib. In one embodiment, since the hydrogel adheres to both nerve and tissue, the material formed in situ must be carefully removed from the muscle and fascia so that it forms a free floating bolus in contact with the nerve. This will allow the nerve to continue to move within the region without being attached to the surrounding tissue.
In yet other embodiments, it is desirable that the hydrogel take the shape of the tissue surrounding the nerve. For example, in modalities where the nerve must be removed and the hydrogel must fill the potential space where the nerve is/was and the surrounding area to prevent regeneration. Alternatively, when the hydrogel is administered around visceral nerves, where there is often a loose, fine network of tiny nerve fibers and the space around these nerve fibers needs to be filled. In another embodiment, the hydrogel is filled around nerves or irregularly shaped nerve fiber bundles/clusters and/or cell bodies. In this way, the hydrogel can deliver therapeutic agents to the region more effectively.
Hydrogel placed in a controlled manner in situ around a nerve. However, in another embodiment, particularly in dynamic environments where nerves glide during movement between muscles, joints, bones or tendons, such as between muscles at the periphery, it is undesirable for the nerve to be tethered through the hydrogel to the surrounding environment. knitting. . Instead, it is desirable to develop solutions in which the nerve can slide freely within the canal. In these embodiments, the hydrogel can be physically separated from the surrounding tissue during in situ crosslinking or in situ polymerization. This can be accomplished with something as simple as a sterile non-adhesive sheet that can be attached and removed after the gel has formed. This can also be achieved by placing a shape on/around the rib. The shape can take many forms, depending on the size and location of the nerve, the presence or absence of a sheath, the purpose of the therapy applied to the site (nerve stimulation, nerve block, nerve ablation, or nerve barrier). regeneration). In one embodiment, the shape is a cap that can be gently placed around the end of a nerve and in situ training gel injected into this shape to assume the shape of the shape. The cap material can be pushed out and the cap form can be removed and discarded. In still other embodiments, the cap is biocompatible and therefore is not removed. In another embodiment, a half cylinder (cut in half lengthwise) may be placed under the rib and the in situ forming material dispensed into the half cylinder. Also, it is possible to apply a gel circumferentially around the nerve without the gel developing bonds with the surrounding tissue.
Alternative cap shapes. To reduce the chances of adhesion formation, the 3 to 10 mm nerve sections can be placed inside a syringe barrel (with the luer lock end portion removed) and the plunger is withdrawn to the desired appropriate gel distance at the end of the syringe. end of the nerve The hydrogel is delivered into and around the nerve within the plunger where the gel attaches. After the gel forms, the plunger is gently depressed to expel the hydrogel-coated nerve. Using this approach again, minimal or no sutures are needed to avoid further damage or overdrive of the nerve. Preferably the barrel of the syringe has a lubricating coating.
Laparoscopic or endoscopic surgery. The shapes can be advanced through a channel during laparoscopic or endoscopic surgery and placed under a nerve, similar to the approach in open surgery. The form can be folded to allow passage through smaller canals and then released at the procedure location. Alternatively, instruments can be designed with the shape of the nerve (cap or shell) integrated into the tip of one instrument with biomaterial formed in situ delivered through the lumen of another instrument. The gel time of the biomaterial formed in situ should be set to between 20 and 30 seconds or more to allow the hydrogel to pass through the instrument lumen if a catheter is used and gel mixing occurs at a given rate. distance from gel formation. Hernia treatment is particularly suitable for blocking nerve regeneration in transected nerves when performing, for example, inguinal hernia repair via an open, robotic, or laparoscopic approach.
In a needle approach to the procedure, a first material that coats the external tissues may be injected to prevent direct adhesion between the gel and the surrounding tissue. Subsequently, the hydrogel can be applied to the same site, forming a reservoir around the nerves and displacing the first material towards the periphery of the injection site. This can be accomplished with a hydrophobic substance such as oil or a viscous substance such as glycerol. This can also be accomplished with a low molecular weight PEG solution which has the added benefit of helping to seal nerve membranes before the hydrogel forms the nerve block/cap around the nerve.
In another embodiment, the nerve is immersed in the flowable material solution prior to crosslinking to form a thin protective surface on the hydrogel. In some embodiments, only a thin layer of the biodegradable polymer is needed around the nerve. The coating can be as thin as 100 microns to 500 microns. In other embodiments, a coating is not sufficient to prevent inflammatory infiltration and/or prevent early degradation; in these cases, it is desirable to use a coating between 0.5 mm and 10 mm thick.
To date, attempts to develop nerve sheaths have focused on solid physical sheaths that are sutured around the end of a severed nerve. These caps have, by necessity, a space around the end of the nerve at the end of the proximal stump, as well as circumferentially. As a result, neuroma formation occurs at the end of the eyelid. Examples include the resorbable implant of poly(D,L-lactide-co-caprolactone), coated silk fibroin (SF) mixed with scaffolds of poly(L-lactic acid-co-e-caprolactone) (SF/P( LLA -CL)), poly(lactic acid)-co-(glycolic acid)/arginylglycaspartic acid) modified poly(lactic-co-glycolic acid-alt-L-lysine) (PRGD-PDLLA) with pores of the order of 10 microns in diameter [ ), Yi et al 2018, Adv Sci]. The PRGD/PDLLA conduit was 10 mm long with an internal diameter of 2 mm and a tube wall thickness of 200 microns, the SF/P(LLA-CL) conduit was 1.5 cm long with an internal diameter of 1.5mm. These eyelids require the placement of sutures. Another approach, called the Neurocap®, is a synthetic nerve-covering device that includes a solid tube with a closed end that is placed over the nerve bundle and then must be sutured to the nerve to hold the nerve within the covering and sutured to the nerve. surrounding tissue to hold the lid in position, published as WO2016144166A1. Another approach also uses a solid implant, published as US20140094932A1. In contrast, the injectable gel approach can flow around nerves of any size, from small fibers to large nerve bundles, requires no cutting or sutures, and provides reduction in pain and neuralgia. In summary, an injectable flow system is not limited to nerve stumps, but can also prevent abnormal nerve growth into fibers too small to collect.
NERVE PROTECTOR/WRAPPING. In accordance with another aspect of the invention, methods and devices for protecting intact or impinged nerves are provided. In some cases, it may be desirable to protect nerves that are surgically exposed as a result of a procedure or adjacent nerves or tissue, such as where these nerves would otherwise dry out. In some cases, it may be desirable to secure and mark nerves that are exposed as part of other surgery so that additional manipulation, stretching, bruising, and/or compression can be reduced or avoided. In one embodiment, a training material is distributed in situ around the nerve to provide a protective layer and prevent the nerve from being damaged by forceps and other surgical equipment in the region. Additionally, a dye in the hydrogel can provide enough contrast to surrounding tissue so that the physician can also stand visually clear of the nerve during the procedure. This can dramatically reduce the incidence of iatrogenic nerve damage during surgical procedures.
In accordance with another aspect of the invention, a way of creating a capsule formed in situ around a nerve-to-nerve junction is provided. The shape comprises a concave wall defining a cavity, the wall having a top opening for access to the cavity. The upper opening is in a foreground and has an area less than the area of a background in accordance with the internal dimensions of the cavity and spacing in the cavity and parallel to the foreground. A concave first nerve guide is brought through the wall and provides a first lateral access for placing a first nerve end in the cavity; and a second concave nerve guide is brought through the wall and provides a second lateral access to place a second nerve ending in the cavity.
An example of this is the prophylactic treatment of the ilioinguial and iliohypogastric nerves during hernia repair procedures, particularly inguinal hernia repair. These nerves may be partially or fully exposed during hernia repair, resulting in compression, bruising, and partial or complete sectioning. After surgery, the damaged nerve can send aberrant nerve buds to post-surgical scar tissue, which can lead to neuroma formation and nerve entrapment, resulting in a high rate of postoperative and chronic pain. In addition, these nerves may be accidentally or intentionally surgically severed in an attempt to prevent the nerves from becoming surgically entangled or entangled in the mesh used to repair the hernia. In one embodiment, a kit containing the growth inhibitory hydrogel that forms in situ and the appropriate shapes allows the surgeon to select a shape to provide a "cap" or "wrap" shaped cavity. Depending on the surgery, the doctor may select a bandage if the nerve is not severed and the doctor wants to protect the nerve from further damage, or a splint if the nerve is severed and the doctor wants to prevent a distal neuroma from forming in the nerve. cut place. nerve end.
Another example of this is exposure of the sciatic nerve during hip procedures. Although the nerve is not the target of these procedures, the nerve is often exposed and placed in traction, so it is at risk of being damaged and/or dried out during the procedure. In one embodiment, a wrap-like form is provided for delivering hydrogel around the region of the sciatic nerve at risk. For larger ribs, this region may be from 5 to 50 cm or more. Wrap-like shapes can be provided to span this entire length, or alternatively, several cap shapes can be placed in series along the length of the rib to provide protection. In another embodiment, an anti-inflammatory agent is dispensed into the hydrogel to reduce inflammation around the nerve that may result from positioning or movement of the nerve during surgery. In another embodiment, a local anesthetic is administered in the hydrogel that is placed around the nerve.
In another embodiment, the hydrogel is administered around the nerve to reduce inflammatory neuropathies that can result after surgery, particularly peripheral neuropathy that can result in the slow development of severe pain and/or weakness in the affected limb. The hydrogel that forms in situ can be administered after open surgery or via an image-guided percutaneous procedure. For ultrasound- or fluoroscopic-guided percutaneous administration, echogenic needles are desirable to confirm not only the depth but also the location of the needle in relation to relevant structures.
In another embodiment, a hydrogel formed in situ around the nerve is administered into a "wrap" shaped cavity to form a flexible protective wrap around the nerve. The socket of the wrap is left in place, providing additional support and protection during surgery, and then the wrap is removed and discarded after completion of the procedure prior to site closure. The hydrogel stays in place to protect the nerve, prevent abnormal growth of the nerve, and prevent any scar tissue from infiltrating the nerve.
Coaptation Assistance. In some modalities, a nerve that was covered directly with sutures can be placed in a wraparound pocket. The direct coaptation site can be filled with an injected growth-enabling hydrogel or a temporary spacer material (eg, fibrin glue) that can be spread into the interstices of the site and the growth-inhibiting hydrogel delivered directly around the anastomosis site using a wrap. shaped cavity.
Envelope or shield form. The cavity of the enveloping shape comprises a shape with two nerve entry zones with a variable cavity length around the region of the nerve that needs protection. In shorter wrapper shapes, the cavity is designed so that the rib rests in the entry zones and the rib is "floating" between these regions and does not contact the walls of the shape. The in situ forming hydrogel delivering needle delivers the fluid hydrogel solution into the mold surrounding the nerve where it forms a protective hydrogel around the nerve. The shape prevents off-target spread of the hydrogel into adjacent tissues and maintains a constant hydrogel thickness around the nerve.
longer lengths. In situations where there is a long length of rib to protect, a longer form cavity can be used with small posts designed into the bottom of the form to support and provide stability to the rib over greater distances. These posts are then removed when the form is removed, leaving only a small exposure between the nerve and the surrounding environment at a non-critical location away from the proximal nerve stump tip (if present). In yet another embodiment, where it is desirable to protect longer stretches of nerve, the hydrogel solution formed in situ can be delivered in multiple layers or regions. In one embodiment, the form is filled in multiple sections to keep the rib within the center of the form. In another embodiment, a first layer of hydrogel is delivered that forms in situ at the bottom of the form, with or without fully or partially embedded rib, and then a second layer of hydrogel is delivered on top of the first layer to cover and completely protect the nerve.
In one embodiment, kits are provided containing the appropriate volume of form-in-place hydrogel to fill the shell form, as well as various mixers and needle components to allow the clinician to change the mixer needle tip and continue to deliver more media in second or third application, as needed.
Protect anastomosis sites. With the increased use of allograft beyond autograft in repairs of large nerve gaps, it is increasingly recognized that abnormal nerve growth from the peripheral nerve stump into surrounding tissue in nerve allograft, nerve autograft or junction of the nerve canal can cause local pain and reduce the effectiveness of nerve repair. In addition, the compliance mismatch between a solid implantable conduit used to protect two nerve stumps and the nerves themselves can cause friction at the nerve-conduit interface, resulting in additional abnormal clamping of the nerve on the surrounding tissue. . In one embodiment, administration of an in situ-forming hydrogel at the interface between the proximal nerve and the allograft or autograft anastomoses, or administration of the hydrogel between the allograft or autograft and the distal nerve stump, or similarly in the junction between where the nerve stump enters and exits the canal is anticipated. A smaller volume of hydrogel delivered directly or in a shorter segment in the form of a wrap provides protection against neurite outgrowth and reduces scarring and immune cell infiltration into the graft and conduit. Alternatively, a form of wrap can span the entire length of the anastomoses to cover the allograft/autograft/conduit in addition to the nerve. A similar approach can be applied to secure joints between a conventional form of wrap/protection or conduit/rib guide. These tubes/sheets (slotted tube, tube, sheet) can be made of cadaveric, porcine or other tissues or synthetic/natural biomaterials. Administration of the hydrogel at the junction between the native nerve (proximal, distal nerve) and/or along the entire length of the tube provides the nerve with an additional layer of protection against surrounding scar tissue. The hydrogel then forms physical and/or chemical interactions with the nerve tissue as well as the tube/sheet to hold the tube/sheet in place around the nerve. The gel may be of sufficient viscosity to spread around the nerve within the inner lumen of the nerve protector/sheath or nerve guide. Preferably, the gel should cover at least 5mm of nerve tissue at the proximal or distal end of the nerve to ensure that the nerve sheath/guard or nerve guide is secure.
Nervous slip. Some peripheral nerves experience a considerable amount of movement in the fascial plane in which they reside, and therefore the healing and anchoring of these nerves is particularly painful. For example, the median nerve in the carpal tunnel or the location of the ulnar nerve in relation to the elbow are places where the willingness to glide is important. With implantable conduits, sheaths, and protectors, the shape of the implant is such that the biomaterial does not enhance nerve glide and may be further inhibited. In one embodiment, the in situ-forming hydrogel is administered as a shield around these nerves to allow the nerves to continue to glide within their fascial plane. One way of achieving this is to provide a higher swelling in situ forming material that swells significantly, e.g. greater than 10%, preferably greater than 20% radially (volumetrically) outward after administration around a nerve so that the nerve can slide into the channel created after the hydrogel has reached equilibrium. In this way, although the hydrogel eventually becomes trapped in a thin capsular layer, the nerve itself, within the hydrogel, is able to slide freely within the canal and is free of significant scar tissue, nerve growth into surrounding tissue, and is also not compressed at all. these channels critical places.
The hydrogel thus forms a hollow cylindrical sleeve with a central lumen into which a nerve or tendon can slide. Slippage can occur in two ways: Slippage can occur on the outer surface of the formed hydrogel, with the hydrogel and the nerve or tendon moving together. Alternatively, and preferably, the nerve or tendon is slipped into the lumen of the hydrogel form while the hydrogel is anchored in place with minimal capping. In this way, the nerve or tendon can move freely, flexibly and without scarring through the hydrogel.
Indications. Hydrogels that are formed in situ can also be introduced intraoperatively to aid in the maintenance of a successful microsurgical anastomosis of the donor and recipient nerves using a form of wrap. Hydrogels can be injected as a wrap at the junction of anastomoses to protect against aberrant inflammatory response, scar tissue formation, and aid in coaptation of donor and recipient nerves. The transfer of a non-critical nerve to reinnervate a more important sensory or motor nerve is known as neurotization. In one example, a patient undergoing breast reconstruction after a mastectomy may select an autologous flap reconstruction to connect the nerves to the chest wall. Wrap forms can be placed at the junction between the proximal nerve stump and the distal nerve tissue to which the hydrogel is sutured and applied to protect the anastomosis sites. This repair can lead to restoration of sensory function and an improvement in the physique and advancement of the woman's quality of life.
Tendon repair. In another embodiment, hydrogels can be used to aid tendon repair and prevent adhesion/scar tissue formation around tendons. In some embodiments, the hydrogel is placed around the tendon using a similar shape that allows the delivery of solution to form a gel circumferentially around the tendon. In this way, the gel allows the tendon to glide in the same way that can be achieved with gels around the nerves.
Compression repair. In another embodiment, hydrogels that form in situ can be delivered as a wrap around the nerve as a barrier to attachment of surrounding tissue while the nerve is being repaired. This approach allows the hydrogel to infiltrate and conform to the nerve and act as a venous vein substitute, in which the autologous vein is wrapped around the nerve in a spiral-wrapping technique, providing a barrier for attachment of surrounding tissue. . This also provides an alternative to the AxoGuard Nerve Protector, which has to be wrapped around the nerve, potentially stretching and damaging it further. The solid nerve protector requires extensive handling of the nerve with forceps, opening the solid sheath to hold it open, and then suturing the nerve to the sheath. Using a soft and compliant hydrogel-based approach, a fluid or viscous fluid can be delivered directly around the nerve with minimal nerve manipulation. Soft tissue attachments are minimized, swelling is minimized, and the mechanical support provided by the gel reduces tension and stress at the coaptation site. Nutrients can diffuse through the hydrogel network. In addition, the hydrogel can reduce the doctor's procedure time.
In one embodiment, the solution is based on hyaluronic acid. In another embodiment, the solution is based on a hydrogel paste (TraceIT, Boston Scientific) containing polyethylene glycol.
Applied distance. The hydrogel can be administered circumferentially around the nerve using a syringe or applicator tip, thus protecting the nerve from damage. Ideally, the hydrogel would be applied between e.g. 5 and 15 mm at each site of the damaged or cut nerve. Volumes administered may be between 100 microliters and 10 ml, more preferably 0.2 to 3 ml. The syringe containing the hydrogel (or the two hydrogel precursor components) can be designed with the exact volume to be delivered to allow controlled automated delivery of the hydrogel that forms in situ. Alternatively, excess volume may be provided to allow the individual to use their judgment on how much to deliver locally. At a minimum, the hydrogel should form a cellular barrier approximately 200 microns thick around the outside of the nerve, although the hydrogel can also be applied to fill a stain to form a circumferential bolus with a 2 cm radius around the nerve. hydrogel site
End-to-end repair. A window is made in the outer nerve sheath and a nerve transfer is attached to the side of the nerve. After suturing, the hydrogel that forms in situ is placed around to keep them in close juxtaposition to each other.
Internal neurolysis. After a nerve is chronically stretched or pinched, internal scarring and inflammation can result. The outer sheath of these nerves can be opened to relieve pressure and help blood flow.
External neurolysis. If the nerves are scarred or develop neuromas, stretching or moving them can cause additional nerve damage, pain, and additional scarring of the nerves. Neurolysis can be used to remove scar tissue around the nerve without going into the nerve itself. The hydrogel that forms in situ can be administered around the nerve after external neurolysis to prevent further scarring of the nerve and to reduce pain.
Neurotization. In one embodiment, a percutaneous nerve shield is applied around the damaged or crushed nerve. In this embodiment, if applied within a day to several days after injury, the local inflammatory response can be reduced. In situ forming hydrogels that are 1) biocompatible, 2) biodegradable or bioerodible, 3) allow diffusion of nutrients and oxygen into and out of tissue, preventing inflammation, 4) flexible and conformable to protect axons without compressing them, 5) no or minimally swollen, and 6) prevent fibrous growth at the lesion site.
Location. An injectable moldable hydrogel also allows the same product to be delivered in different nerve diameters and in different locations (between bones, fascia, ligaments, muscles) since the material will flow in the region around the nerve.
Place of delivery. In some embodiments, the location of the needle affects the delivery of the hydrogel. In some embodiments, the needle delivers the hydrogel directly onto the top of the nerve or target region. In another embodiment, the needle is passed from distal to proximal to first fill the end of the distal nerve form and stump and then to fill the remainder of the canal.
TMR. In another embodiment, the hydrogels can be administered around the nerve being reconnected as part of targeted muscle reinnervation (TMR) procedures. Because of the frequent size mismatch between the transected donor nerve and the typically smaller denervated recipient nerve, it may be desirable to apply a hydrogel at the junction to help direct the regenerating fibers to the target motor recipient nerve. For these indications, the hydrogel can be applied directly or in the form. Usually this is done between a mixed motor and sensory nerve.
Inhibitor drugs for caps and wraps. Depending on the desired clinical performance, the mechanical barrier can be assisted or reinforced by any of a variety of chemical agents that inhibit or prevent nerve growth (sometimes referred to as "anti-regeneration agents"). These agents include inorganic and organic chemical agents, including small molecule organic chemical agents, biochemical agents, which may be derived from the patient and/or from an external source, such as an animal source and/or a synthetic biochemical source, and agents based on in therapeutic substances. cells. Anti-scarring agents can be applied directly to the target tissue before or after nerve ending formation. Alternatively, anti-regeneration agents can be transported within the medium where they become trapped in the medium and then released over time in the vicinity of the nerve ending.
Some specific examples of anti-regeneration agents that can be used in conjunction with some embodiments of the present invention include, but are not limited to: (a) capsaicin, resiniferatoxin, and other capsaicinoids (see, for example, J. Szolcsanyi et al. , "Resiniferatoxin: an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons", J Pharmacol Exp Ther. 1990 Nov;255(2):923-8); (b) taxols, including paclitaxel and docetaxel (i.e., in concentrations high enough to slow or stop nerve regeneration, as lower concentrations of paclitaxel may facilitate nerve regeneration; see, for example, W. B. Derry, et al ., “Substochiometric binding of taxol suppresses microtubule dynamics”, Biochemistry 1995, Feb 21;34(7):2203-11), botox, purine analogs (see, for example, L A Greene et al., “The Purine analogues inhibit the growth of neuritis promoted by nerve growth factor by sympathetic and sensory action). neurons”, The Journal of Neuroscience, 1990 May 1, 10(5): 1479-1485); (c) organic solvents (for example, acetone, aniline, cyclohexane, ethylene glycol, ethanol, etc.); (d) vinca alkaloids including vincristine, vindesine and vinorelbine, and other antimicrotubule agents such as nocodazole and colchicine; (e) platinum-based antineoplastic drugs (platins) such as cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, and tripplatin; (f)ZnSO4(ie, neurodegenerative factor); (g) latarcins (short linear antimicrobial and cytolytic peptides, which can be derived from the venom of the spider Lachesana tarabaevi); (h) chondroitin sulfate proteoglycans (CSPGs), such as aggrecan (CSPG1), versican (CSPG2), neurocan (CSPG3), melanoma-associated chondroitin sulfate proteoglycan or NG2 (CSPG4), CSPGS, SMC3 (CSPG6), brevican (CSPG7), CD44 (CSPG8), and phosphacane (see, for example, Shen Y et al. “PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration,” Science, 2009 Oct 23;326(5952) :592 -6); (i) myelin-associated glycoprotein (MAG); (j) oligodendrocytes; (k) myelin oligodendrocyte glycoprotein; and (l) Reticulon-4, also known as neurite growth inhibitor or Nogo, which is a protein that in humans is encoded by the RTN4 gene (see, for example, Lynda J.-S. Yang et al., “ Inhibitors of axonal regeneration, Neurological Research, December 1, 2008, Volume 30, Number 10, pp. 1047-1052) (m) ethanol or glycerol.
Other examples of antiregenerative agents include agents that induce inhibitory scar tissue formation, which may be selected from the following, among others: (a) laminin, fibronectin, tenascin C, and proteoglycans, which have been shown to inhibit axonal regeneration (see, for For example, Stephen J. A. Davies et al., "Regeneration of Adult Axons in White Matter Tracts of the Central Nervous System," Nature 390, 680-683 (18 Dec 1997); (b) reactive astrocyte cells, which are the major cellular component of the glial scar, which form a dense network of extensions of the plasma membrane and which modify the extracellular matrix by secreting many molecules, including laminin, fibronectin, tenascin C, and proteoglycans; (c) molecular mediators known to induce the formation glial scarring, including transforming growth factor β (TGFβ) such as TGFβ-1 and TGFβ-2, interleukins, cytokines such as interferon-γ (IFNγ), factor fibroblast growth 2 (FGF2) and ciliary neurotrophic factor; (d) glycoproteins and proteoglycans that promote basement membrane growth (see, for example, C C Stichel et al., "The CNS Injury Scar: New Perspectives on an Ancient Regeneration Barrier," Cell Tissue Res. (October 1999) 1998) 294 (1):1-9); and (e) substances that inactivate Schwann cells. Still other examples of anti-regeneration agents include the protein Semaphorin-3A (SEMA3A) (which can be used to induce collapse and paralysis of neuronal growth cones) to block regeneration which is incorporated into hydrogels to release approximately 1 µg per day up to a total of 2 μg over a few weeks, calcium (which can cause twisting of nerve growth cones induced by localized increases in intracellular calcium ions), f) inhibitory dyes such as methylene blue, and g) radioactive particles. Other inhibitory drugs include ciguatoxins, anandamide, HA-1004, fenamyl, MnTBAB, AM580, PGD2, topoisomerase I inhibitor (10-HCT), anti-NGF, and anti-BDNF.
Pain and inflammation. The means may also include one or more agents intended to relieve pain in the short-term post-procedure period, where increased pain may occur from onset due to local tissue reaction, depending on the ablation procedure. Examples of suitable anesthetic agents that can be incorporated into the hydrogel for this purpose include, for example, bupivcaine, ropivican, lidocaine or the like, which can be administered to provide short-term local postoperative pain relief around the treatment region. Inflammation and scar tissue in the surrounding tissue can also be minimized by incorporating methylprednisolone into the hydrogel.
Permissive form of growth. Referring to the examples of FIGS.5AND-5And in some cases, it is desirable to provide a growth-enabling substance between the proximal and distal nerve stump to stimulate nerve regeneration rather than growth inhibition. In some embodiments, the growth-enabling substance simply provides a temporary barrier against leakage of the growth-inhibiting gel at the anastomosis site or damaged nerve tissue and inhibition of regeneration. In other embodiments, the growth-permitting substance provides a means by which nerves can be regenerated without the need for autograft/allograft or conduit/wrapping.
In accordance with another aspect of the invention, methods and devices are provided for stimulating guided nerve growth, such as to bridge a gap between two opposing nerve stumps and restore nerve function or to fill a small gap between nerves that have been directly coapted. with sutures The method may comprise the steps of placing a first nerve ending and a second nerve ending in a first socket shape; Introducing an in situ growth permissive medium into the cavity and contacting the first nerve ending and the second nerve ending to form a junction; the medium changes from a fluid state to a non-fluid state. The ribs, engaged by the formed-in-situ means, are then removed from the first shaped cavity and placed within a second, larger shaped cavity; e Introduce growth inhibitory medium into the second well to encapsulate the junction. The growth-inhibiting medium changes from a fluid state to a non-fluid state, covering the nerves and the growth-permissive medium; The second shape is then removed and discarded. In another embodiment, the first and/or second shape remains in place.
Also provided is a formed-in-situ nerve regeneration construct comprising a growth-enabling hydrogel bridge having first and second ends and configured to span a space between two nerve endings and stimulate nerve growth across the bridge; and a growth-inhibiting hydrogel shell that encapsulates the regrowth-permitting hydrogel bridge and is configured to extend beyond the first and second ends of the regrowth-permitting region to directly contact the proximal and distal nerves, respectively. In yet another embodiment, the permissive growth medium is distributed in a shape-inhibiting cavity in which it undergoes a change from a substantially fluid state to a non-fluid state. The form stays in place and acts as a growth-inhibiting substrate through which nerves cannot regenerate.
Preferably, the growth-enabling medium comprises a gel that forms in situ such as a hydrogel and the growth-inhibiting medium comprises a gel that forms in situ such as a hydrogel. However, the permissive growth medium may be a gel formed in situ and the form in which it is administered is an ex vivo crosslinked gel.
In some embodiments, it is desirable that the growth-enabled hydrogel adhere to nerve tissue, providing a method of anastomosing the tissue without the need for sutures. In doing so, the nerve-growth gel-nerve unit can be collected and handled as a continuous nerve unit, allowing subsequent placement of the unit in a growth-inhibiting hydrogel. In other embodiments, the growth-enabling hydrogel can provide a temporary glue that lasts for about half an hour. The glue is strong enough to lightly adhere the two ribs, but has a mechanical strength comparable to e.g. fibrin glue
Tension-free repair. Another advantage of in situ formation of hydrogels is that they can be designed to provide tension-free nerve repair. In one embodiment, the shape of the conduit sheath is deep enough so that the directly repaired/anastomosed nerve endings are placed in the shape with the repaired region relaxed within the shape. When the hydrogel forms around the slack nerve, the nerve-to-nerve repair is not under tension; any stress is carried by the surrounding hydrogel. In this way, the nerves are not under tension and the hydrogel carries the load in a more evenly distributed manner than a suture repair.
In another embodiment, the growth inhibitory hydrogel further provides a stress-free repair. In this modality, proximal and distal nerves are placed in the canal and growth-inhibiting hydrogel is dispensed at the nerve-canal interface to prevent nerves from escaping the canal and adhering to surrounding scar tissue. In another embodiment, the ribs are intentionally relaxed within the growth-enabling hydrogel by creating slack in the ribs within the form. In cases where ribs are directly re-anastomosed, care must be taken to ensure that tension, if any, is at the interface between the rib and the form entry on either side of the wraparound form, and that the nerve within the sheath is loose or tension free before applying the growth permissive hydrogel precursor solution to the sheath. In this way, the nerve anastomoses, the nerve-gel-nerve or nerve-nerve interface are free of tension. In the preferred embodiment, the hydrogel unit that allows for nerve growth is completely within the cavity of the second nerve form. Administration of the inhibitory hydrogel provides additional protection and arrest, providing approximately 3 to 10 mm of circumferential coverage around the nerve on both sides of the lesion.
The ceiling. In one embodiment, the permissive growth medium is located substantially between the two ends of the ribs and does not appreciably cover the outer surface of the ribs. Therefore, the diameter of the permissive growth media approximates the diameter of the nerve. As a result of the location of the growth-permissive media, the growth-inhibiting media is distributed around the outer or epineural surface of the proximal and distal nerves, as well as the growth-permissive media, preferably covering 10 mm or 5 mm or more. of the healthy nerve. On both sides This allows the nerves to be guided directly from the proximal nerve stump to the distal nerve stump. The additional coverage provides bond strength and protection against abnormal nerve growth at the proximal nerve gel junction.
Colour. In one embodiment, the growth-enabling hydrogel is colored, such as blue, and the growth-inhibiting hydrogel is colorless. In another embodiment, the growth-enabling hydrogel is blue and the growth-inhibiting hydrogel is green or turquoise.
Preferably, the growth-enabling substance is a hydrogel formed in situ. Preferably, the growth-enabling substance contains growth-inhibiting and growth-enabling microdomains. The nerves will naturally find their way along the growth inhibitory domains and within the growth permissive domains. Permissive growth hydrogels that take advantage of the in situ formation PEG platform are desirable. These hydrogels can be chemically crosslinked or use photocrosslinkable approaches like the non-growth hydrogels described above. Hydrogels that allow growth in situ preferentially degrade faster than hydrogels that inhibit growth, thus stimulating cell growth and replacement of the synthetic matrix by a natural extracellular matrix. As a result, the preferred PEG hydrogels for these applications are formed by crosslinking PEG-NHS esters with hydrolytically labile ester linkages (PEG-SS, PEG-SG, PEG-SAZ, PEG-SAP), preferably PEG-SS. . These PEGs can be crosslinked with PEG-amines or trilysines, for example.
Other hydrogels can be selected to provide non-growth zones of the hydrogel that allow growth, including PEG-PPO-PEG, PEG-polyesters (triblocks, unblocked), alginate, agar, and agarose. Other synthetic hydrogels include PEG-poly(amidoamine), PEO, PVA, PPF, PNIPAAm, PEG-PPO-PEO, PLGA-PEG-PLGA, poly(aldehyde guluronate) or polyanhydride hydrogels. An extensive list of hydrogel matrices that can be adapted for in situ formation is found in Hoffman (2012) Hydrogels for Biomedical Applications. Advanced Drug Delivery Reviews, 64: 18-24, incorporated herein by reference. Other soft hydrogels that may be suitable include InnoCore Liquid Polymer (LQP) (PCLA-PEG-PCLA), which is a liquid polymer that forms a soft macroscopic deposit after administration in vivo and slowly degrades over a period of two to three months. Another potentially suitable hydrogel includes a six-armed shar-shaped poly(ethylene oxide-stat-propylene oxide) with acrylate end groups (star-PEG-A) that can be light cured. Other early form PEGs include a 6-arm NHS ester or 8-arm PEGs include mPEG-SCM (PEG-NHS: Succinimidly Carboxyl Methy Ester) and mPEG-SG (PEG-NHS: Succinimidly Glutarate Ester), PEG-co -poly(lactic acid)/poly(trimethylene carbonate), PEG-NHS and trilysine, PEG-NHS and PEG-thiol, PEG-NHS and PEG-amine, PEG-NHS and albumin, dextran aldehyde and trisfunctionalized PEG-amine (2aminoethyl)amine. PEG concentration. In one embodiment, PEG-SC (PEG-succinimidyl carbonate) and PEG-amine are combined. In some embodiments, PEG-SAP (PEG-succinimidyl adipate) and PEG-amine are combined. If PEG is used in the growth enabling matrix, preferably the concentration of PEG in these hydrogels is preferably between 3 and 8%, more preferably between 3 and 5% by weight for applications to support nerve extension.
In some embodiments, the growth-permitting region is directly conjugated or chemically linked to the non-growth-permitting region of the hydrogel. For example, chitosan can be coupled to the inhibitory region. The chitosan can be between 1 kDa and 1 MDa with degrees of deacetylation between 0.6 and 0.95, preferably a chitosan with a molecular weight of 100 kDa to 350 kDa, more preferably 130 kDa to 160 kDa with a degree of deacetylation of 0.85. In another embodiment, a methacrylamide interpenetrating network of polymerized gelatin with a PEG backbone may be suitable.
Alternative growth permissive matrices. In addition to incorporating positively charged matrix components that stimulate glial invasion, cell division, and three-dimensional cellular organization, growth-enabling components can also support nerve growth with or without the presence of supporting cells. These growth promoting substances are applied in a concentration sufficient to support growth, but not in such a high concentration as to affect the mechanical properties of the hydrogel. The growth-promoting hydrogels contain combinations of natural growth-promoting biomaterials, such as natural type I collagen polymers (0.01-5% by weight, preferably 0.3-0.5% by weight, 1.28 mg /ml), laminin (4 mg/ml), hyaluronic acid, fibrin (9 to 50 mg/ml, potency 2.1 kPa) or synthetic/semi-synthetic polymers such as poly-L-arginine or poly-L-lysine (0.001- 10% by weight). These mixtures support 1) the creation of a pathway through which regenerating nerves can find their way, 2) provide a substrate to which neurites can adhere and Schwann cells can migrate. PEG-SS) crosslinked with trilysine, containing 5% collagen by weight. In another embodiment, the hydrogel comprises 4% PEG (4-arm 10K PEG-SG crosslinked with 4-arm 20K PEG-amine) containing 0.01% poly-L-lysine. By reducing the concentration of the cross-linked PEG solution relative to growth inhibitory PEGs used in neuroma block applications and increasing the concentration of the positively charged growth-permissive biomaterial, an in situ-forming hydrogel with inhibitory domains can be created. and permissive to stimulate the nerve. increase.
In another example, a non-growth hydrogel (eg, cross-linked PEG hydrogel, alginate, MeTro-substituted methacryloyl tropoelastin hydrogel) can be mixed with a growth-enabling hydrogel (eg, GelM composites). of fibrin-methacrylyl gelatin). GelM/PEG or GelMA/MeTro) Soucy et al (2018) Photocrossable tropoelastin-gelatin hydrogel adhesives for peripheral nerve repair, Tissue Engineering, PMID: 29580168. Polylysine incorporation. Forms of polylysine-D, L, or L can be incorporated into the hydrogel region that allows for growth. For example, Epsiliseen (Siveele, Epsilon-poly-L-lysine). The growth-enabling hydrogel can be an in situ formed hydrogel comprising chitosan and polylysine (https://pubs.acs.org/doi/10.1021/acs.biomac.5b01550). The growth-enabled hydrogel can be an in situ formed hydrogel comprising PEG and polylsine (https://pubs.acs.org/doi/10.1021/bm201763n).
The growth-enabling component of the present invention may alternatively comprise a specific decellularized peripheral nerve scaffold formulated as an injectable hydrogel. It is based, at least in part, on the use of decellularized tissue that is substantially free of immunogenic cellular components, but retains sufficient amounts of nerve-specific components to be effective in supporting nerve growth and reducing or prevention of muscle atrophy. In certain non-limiting embodiments, the decellularized tissue scaffold can be formulated into a hydrogel through the use of enzymatic degradation. These hydrogels may not be cytotoxic to neurons and also support neuronal growth from cultured cells. Therefore, one aspect of the methods of the present invention includes the application or injection of a growth-enabling medium that includes a hydrogel comprising a decellularized peripheral nerve structure that has been enzymatically degraded to fill a void in the nerve. The growth-permitting medium can be encapsulated within a growth-inhibiting medium in any of the ways discussed elsewhere herein. The peripheral nerve structure can originate from an organism that is not autologous to an intended recipient of the hydrogel, from an organism that is of the same species as the intended recipient, or from an organism that is not of the same species as the intended recipient. Nerves removed may include, but are not limited to, the sciatic nerve, femoral nerve, median nerve, ulnar nerve, peroneal nerve, or other motor/sensory nerve. Additional details of the decellularized scaffold can be found in the US patent at the. 9,737,635 to Brown, et al., entitled Injectable Peripheral Nerve Specific Hydrogel, issued August 22, 2017, the disclosure of which is expressly incorporated in its entirety herein by reference.
In addition to materials derived from specific nerves or tissues, other growth-permissive components produced from human (autologous) or animal (non-autologous cattle, swine) sources may be used in whole or in part in the growth-permissive solution to be administered between the proximal and distal stump. These include non-viable human umbilical cord allograft, amniotic membrane allograft, amnion and/or chorionic membrane (human placental submucosa) graft, autologous skin graft, raw allogeneic cadaver/pig skin graft, autologous connective tissue, tissue autologous or allogeneic tendon tissue, bovine tendon tissue collagen, fibrillar collagen, fibronectin, laminin, proteoglycans. These components may take the form of a micronized or dehydrated or lyophilized powder, a gel, a sheet or rolled sheet, or a dehydrated powder that can be rehydrated prior to use. The dehydrated products can be rehydrated before use in aqueous solutions, such as saline, or solutions containing 6-9% low molecular weight polyethylene glycol, such as PEG 3350 or PEG 5000. In yet another embodiment, the permissive growth environment can contain cells. Sheets that can be incorporated into the nerve repair system include alginate/hyaluronate or alginate/hyaluronate/chitosan sheets as incorporated by reference herein US20210069388A1.
The solutions that allow growth can be used to support nerve regeneration in repair of direct anastomoses, repair with small clamps (<7 mm) and repair of larger gaps (>7 mm). Solutions that allow growth and/or growth inhibitors can be given acutely after injury, subacutely or several days after injury when injury has had an opportunity to manifest itself, or for chronic nerve repair .
PEG+Collagen in the spine. Alternatively, natural polymers such as type I collagen can be cross-linked with PEG hydrogel (eg, 8 arms 15K SG) with collagen concentrations ranging from 30 to 60 mg/mL and a PEG concentration of 50 or 100 mg/mL (Sargeant et al 2012. A PEG-collagen hydrogel that forms in situ for tissue regeneration Acta Biomaterialia 8, 124-132 and Chan et al (2012) Robust semi-interpenetrating PEG-collagen hydrogels for tissue scaffolds Elastomerics 12(11) 1490-1501.
Other gels. In yet another embodiment, the first growth-enabling material may comprise a viscous solution, nanoparticle- or microparticle-based gel, paste, or macrogel. In one embodiment, a fibrin glue can be distributed around the nerves. In another embodiment, the solution is a paste of biocompatible nanoparticles or microparticles through which nerves can be regenerated. In another embodiment, a microgel or modugel is administered to the site. Microgels are created for stable dispersions with uniform size and large surface area by precipitation polymerization. Modugels, scaffolds formed from microgels, properties can vary depending on the degree of crosslinking and the stiffness of the scaffold (preparation of gels, including PEG-based hydrogels, can be found in Scott et al (2011). to uncouple the effects of stiffness and protein concentration in PC12 cells (Acta Biomater 7(11) 3841-3849, incorporated herein by reference.) In addition, the use of electrically conductive hydrogels such as piezoelectric polymers such as polyvinylidene fluoride (PVDF ) that generate transient surface charges under mechanical stress conditions, may be beneficial in supporting nerve growth through the hydrogel. For example, dendrimers composed of metabolites such as succinic acid, glycerol, and beta-alanine can be incorporated into hydrogels to stimulate extracellular matrix infiltration (Degoricija et al (2008) Hydrogels for Osteochondral Repair Based on Photocrosslinkable Carbamate Dendrimers, Biomacromolecules , 9(10) 2863.
Simple natural hydrogels. In another embodiment, a hydrogel is provided that allows growth entirely without growth inhibitory microdomains. In one embodiment, a fibrin hydrogel (such as those cross-linked with thrombin) with a lower linear compression modulus is selected. Many other biomaterials have also been shown to support nerve regeneration in 2D and 3D scaffolds and include chitosan, chitosan-coupled alginate hydrogels, viscous fibronectin, type I collagen (~1.2 mg/mL), regeneration aid, fibrin ( 9 to 50mg/mL). ml), fibronectin, laminin (https://www.ncbi.nlm.nih.gov/pubmed/15978668)), Puramatrix, heparin sulfate proteoglycans, hyaluronic acid (1% viscous sodium hyaluronate solution), polylysine (poly(D, or L, or D,L) lysine), xyloglucan, polyornithine, agarose (0.5% to 1% w/v) and mixtures of these materials. Additional growth-enabling hydrogels include thermosensitive hydrogels such as chitosan-beta-glycerophosphate (C/G P) hydrogel mixtures. Other thermosensitive hydrogels include poly(N-isopropylacrylamide) (PNIPAAM). In one embodiment, a poly(propylene fumarate) PPF can be injected as a liquid and chemically, thermally or photocrosslinked in situ to form a gel to provide a growth supporting hydrogel. In another embodiment, a photocrosslinkable glycidyl methacrylate hyaluronic acid (GMHA) and HA interpenetrating network provides a substrate that enables growth. Other hydrogels that allow growth include: cross-linked hyaluronic acid gel (Hyaloglide gel) or ADCON-T/N gel (Gliatech). These materials can be physically or covalently crosslinked. Other scaffold materials can be anticipated for the permissive growth region (https://www.nbci.nlm.nih.gov/pmc/articles/PMC5899851/).
Demand. It is well known in the art that nerves prefer to grow on or through positively charged surfaces. In some embodiments, the positive charges are incorporated into the backbone of the polymer. In other embodiments, these cargoes are incorporated into other components, such as extracellular matrix proteins that become entrapped in the hydrogel when it forms in situ.
Incorporation of Adjuvants. In some embodiments, anti-inhibitory molecules can be incorporated into the hydrogel to enhance the permissive environment for growth, such as chondroitinase, which breaks down chondroitin sulfate proteoglycans (CSPGs). https://www.ncbi.nlm.nih.gov/pubmed/20620201. These can be incorporated into the polymer powder, diluent or accelerator depending on the stability requirements of the adjuvant.
Incorporation of lipid domains. Lipid domains can be added to the backbone or side chains or to these polymers to stimulate neural growth. Hydrophobic domains can also be incorporated into the backbone of the hydrogel to support nerve ingrowth through the soft and hard regions of the hydrogel. In one embodiment, lipids are added to diffuse between the polymer chains and act as plasticizers for the polymer material that facilitate chain movement and improve elasticity.
Adhesion force. Media that allow growth and media that inhibit growth can form hydrogels and have sufficient adherence that, once formed, the nerve endings can be easily collected and manipulated. However, the adhesive force of the non-fluid growth-enabling medium subsequently formed allows the nerve-gel-nerve unit to be grasped with forceps. The unit can be gently positioned in a second shape to allow for circumferential delivery of the inhibitory hydrogel. The adhesion strength also allows for good coupling between the nerve end and the hydrogel.
Rigidity. Since the stiffness of the matrix and the compressive strength of the hydrogel play an important role in promoting or inhibiting nerve regeneration, the mechanical properties of growth inhibitory and permissive hydrogels differ substantially. The growth-enabling hydrogel is significantly softer and less rigid to support and stimulate regeneration of the nerve growth cones in the media. The gel stiffness (G*, dynes/cm²) of the growth-enabling hydrogel is preferably softer and more elastic in character with G* less than 800 dynes/cm², more preferably less than 200 dynes/cm². In some embodiments, regions of soft substrate (100-500 Pa) are placed adjacent to regions of stiffer substrate (1000 to 10,000 Pa). The elasticity of this growth-enabling substrate should preferably be less than 0.1-0.2 MPa, preferably less than 1.5 KPa. On the other hand, the growth inhibitory hydrogel provides the necessary mechanical strength to maintain engagement and relationship between the proximal and distal nerve stumps, reduce or eliminate the need for suturing, and potentially allow for a tension-free repair. The extent of the nerve in the matrix that allows growth is highly dependent on the stiffness of the matrix and the interconnectivity of the pores, the charge. As the gel degrades, the length of the nerve may also be affected by hydrolytic, oxidative, or enzymatic degradation of the matrix. For the hydrogel that allows growth, the stiffness of the gel should be closer to the modulus of elasticity of nerve tissue, equal to or less than 1 kPa, preferably 200-300 Pa. Swelling. Given the placement of the growth-inhibiting hydrogel around the growth-enabling hydrogel, the swelling of the growth-inhibiting hydrogel should be less than or equal to the swelling of the growth-inhibiting hydrogel. Alternatively, the growth-enabling hydrogel should be soft enough that it has no force to push against the growth-inhibiting hydrogel. Porosity. In some embodiments, the growth-enabling medium comprises a growth-inhibiting hydrogel filled with highly interconnected growth-enabling macroscopic pores that provide a conduit through which regenerating nerves can proceed. Pores can be created in hydrogels through porogen leaching (solid, liquid), gas foaming, emulsion patterning to generate macroporosity. The pores can be created by a porogen to allow growth and/or contain therapeutic agents or simply filled with saline. Pores can be created by phase separation during hydrogel formation. Mean pore size, pore size distribution, and pore interconnections are difficult to quantify and are therefore included in a term called tortuosity. Preferably, the hydrogel is a macroporous hydrogel with pores greater than 1 µm, more preferably greater than 10 µm, preferably >100 µm, most preferably >150 µm, with an average pore radius of 0.5 to 5%. The pore density should be greater than 60%, or preferably greater than 90% of the pore volume, with a density sufficient for the pores to be interconnected. In this way, the remaining PEG hydrogel provides a non-growth scaffold through which neurons can grow. In one embodiment, the porosity is created by creating air or nitrogen bubbles in the hydrogel through agitation, pushing the plunger in the applicator back and forth, or by introducing air through another port in the applicator. In another embodiment, a surfactant is used as an air-retaining agent to create porosity in the hydrogel, such as sodium dodecyl sulfate (SDS). Gas-in-place foam with up to 60% porosity and 50-500 micron pores and a compression modulus of 20-40 Mpa, described at https://www.nbci.nlm.nih.gov/pmc/articles/ PMC3842433/. In another embodiment, the creation of a foaming agent that generates macroscale pores to allow cell migration and proliferation. In some embodiments, the porogen is a degradation enhancer. Preferably, the pore concentration is sufficient so that the pores are interconnected with each other. Preferably >70% of the pores are interconnected, more preferably 80% or more. The pores create and define zones that allow for growth, and preferably the interconnectivity is high enough so that tortuosity is low and nerves extend into them. Also, if the pore walls are made up of PEG, nerves can find their way along the hydrogel walls. The pores can be created with low molecular weight PEG, such as PEG 3350, which can be supplied in up to 50% by weight solution. The regions or pores that allow growth may contain natural biomaterials such as collagen/gelatin, chitosan, hyaluronic acid, laminin (Matrigel), fibrin that provide a growth-enabling substrate for nerve growth.
channels. In another embodiment, channels are created in the hydrogel in situ to allow nerve guidance. In one embodiment, the channels are approximately 150 µm, 300 µm in diameter, more preferably 500 µm to 1 mm in diameter. Preferably, the channels are filled with saline in situ.
Fibers and other structural elements. Add fibers or structural elements (eg, beads, macrospheres, paste gel particles, microspheres, rods, nanoparticles, liposomes, rods, filaments, sponges) to reinforce the structural integrity of the hydrogel, improve the in vivo persistence of the hydrogels and/or providing a substrate along which neurites can spread and grow for orientation is desirable. Nanofibers can be flexible or rigid and can range in size from nanometers to micrometers in diameter and can be linear or irregular in shape. In the preferred embodiment, the deposition of fibers through the needle containing the shaped medium allows generally parallel longitudinal alignment of the fibers within the passageway. The fiber-loaded medium is placed into the canal by filling the distal end first and advancing the needle to the proximal end of the shape in a smooth, continuous motion while depositing the hydrogel. Rapid gelation (less than 20 seconds, preferably less than 10 seconds, most preferably less than 7 seconds) allows the fibers to be captured in the desired orientation as the medium changes to a non-flowable form. In another embodiment, the medium solutions are more viscous, between 10 and 20 cP, allowing suspension of these fibers within the permissive growth medium. In another embodiment, the fibers are supplied in the kit and are placed in the lumen with forceps.
Fibers, rods, filaments, sponges. In another embodiment, the fibers are added to the form immediately before or after administration of the ingrowth-enabling hydrogel solution in the form of a sheath to provide a surface along which nerves can grow on their way to the brain. distal stump. Fibers can be added using forceps, another syringe, or by spraying into the canal. The gel time of the hydrogel medium is delayed long enough that the fibers can be incorporated into the medium before the medium is changed to a substantially non-flowable form.
Injection of nanorods. Similarly, shorter nanorods can be incorporated into a polymer solution, polymer powder, diluent, or accelerator and then injected in situ. By injecting gently and in one direction and using a fast gelling hydrogel, the alignment of these fibers can be improved. The fibers can be constructed from non-degradable or biodegradable materials. In some embodiments, the fibers are made of chitosan, polycaprolactone, polylactic or glycolic acid, or combinations thereof. The fibers can be inert or functionalized with a positive charge or the addition of a coating such as laminin. https://www.nbci.nlm.nih.gov/pubmed/24083073. In another embodiment, the fibers undergo molecular self-assembly to form a fiber or cable.
In one embodiment, the fibers will be randomly embedded or aligned to provide support for nerve regeneration through a gel. Filaments and sponges can be formed from collagen. Rods can be made of collagen-gag, fibrin, hyaluronic acid, polyamide, polyarylonitrile-co-methacrylate, PAN-MA, PGA, PHBV/PLGA mixtures, PLLA, PLGA or PP. The filaments can be between 0.5 and 500 µm in diameter, more preferably between 15 and 250 µm in diameter. In one embodiment, the rods, fibers, and filaments can be coated with laminin.
Nanofibers can be incorporated into the hydrogel to provide structural support. The fibers can be composed of PEG, PGA, PLA, PCL, PCL mixed with gelatin, PCL coated with laminin, chitosan, hyaluronic acid, gels, hyaluronan, fibrin, or fibrinogen (10 mg/ml). In one embodiment, a fibrillar fibrin hydrogel (AFG), or P(D,L,LA) fibers, made by electrospinning, is incorporated into in situ forming gels. (Electrospinning methods are described in McMurtrey (2014) Patterned and functionalized nanofiber structures into three-dimensional hydrogel constructs enhance neurite outgrowth and functional control. J. Neural Eng 11, 1-15, incorporated here.) In another embodiment, polyethylene glycol is incorporated as a porogen and nanofibers such as cellulose nanofibers are used to provide structural integrity to the soft porous hydrogel (Naseri et al (2016) 3-Dimensional Porous Nanocomposite Scaffolds Based on Cellulose Nanofibers for Cartilage Tissue Engineering: Tailoring of Porosity and Mechanical Performance, RSC Advances, 6, 5999-6007, incorporated by reference herein).
Microparticles. In yet another embodiment, microparticles, nanoparticles, or micelles can be introduced into the permissive growth medium to deliver drugs to nerve tissue. In one embodiment, the microparticles are composed of PEG hydrogels (eg, 15K 8-arm SG, 10%), poly(D,lysine) microparticles. For example, cross-linked PEG particles formed ex vivo can be formulated in a lubricated suspension with low molecular weight (1-6%, 12 kDa) PEG. Alternatively, the particles can be suspended in a solution of collagen or hyaluronic acid to provide a growth-enabled matrix through which nerves can regenerate. Similarly, hydrophobic particles and oils can be incorporated to create growth-enabling voids in the hydrogel to stimulate nerve growth.
Compression module of growth-promoting hydrogels. It may also be advantageous to combine the nerve tissue compression modulus with the hydrogel that allows for growth, approximately 2.6 to 9.2 kPa (Seidlits et al (2010). The effects of hyaluronic acid hydrogels with tunable mechanical properties in neural progenitor cell differentiation are promising (Biomaterials 31, 3930-3940) Also, the linear compression modulus is less than 20 kPa, preferably less than 10 kPa, more preferably less than 1 kPa to stimulate ingrowth of nerve cells and Schwann cells in the gel.
Growth-permissive hydrogels formed in situ that can be delivered as a wrap or thin layer around partially severed, compressed, or completely severed nerve endings are desirable. The use of an in situ training gel eliminates the need to section intact nerves and provides a mechanism to support nerve regeneration through a substrate and into distal tissue. Coupling of the growth-enabling hydrogel with a growth-inhibiting hydrogel helps guide and direct these neurites into the region that allows growth. In one embodiment, the hydrogel that is formed in situ has sufficient adhesive strength and stiffness that it can be distributed between nerve stumps in an appropriate shape and then picked up and removed from the first wrapping shape and placed in a second shape. the growth inhibitory in situ forming hydrogel is dispensed.
hydrogel thickness. Permissive growth gel. The thickness or diameter of the gel that allows for growth should approximately approximate the diameter of the nerves to which it is administered. In case there is only a small defect in the nerve, the growth-enabling gel can be applied directly to the injured tissue to form a thin layer. Growth inhibitor gel. Given the often harsh environment in which a nerve is found, often in a fascial plain between or along muscles, it is desirable in some embodiments that a minimum thickness of growth-inhibiting hydrogel be maintained around the nerve, preferably 1 mm circumferentially, more preferably 2-3 mm. For example, for a shape that would be placed around the common digital nerve, approximately 2-2.5mm in diameter, a conduit of approximately 3-4mm in diameter is used, providing a 0.5-2mm layer of hydrogel. mm around the nerve. For the digital nerve, approximately 1-1.5 mm, a duct of approximately 2-2.5 mm in diameter is selected. For larger nerves embedded in the arm or thigh, between 2 and 10 mm, preferably the thickness of the gel is 2 to 6 mm, preferably 2 to 3 mm around the nerve circumferentially.
Gel time. After 30 seconds or less, preferably 20 seconds or less, more preferably 10 seconds or less, most preferably 3 to 7 seconds, the hydrogel forms around the nerve. The hydrogel is transparent so that the location of the nerve can be confirmed visually in the hydrogel. The clinician visually or mechanically confirms the formation of the hydrogel and the silicone form is removed from the hydrogel cap and discarded. See figure.2. The surrounding tissues (muscle, skin) are again sutured according to the standard surgical technique.
Gel or paste that allows growth in vivo. In vivo persistence can be considerably less in the growth-enabling hydrogel than in the growth-inhibiting gel, allowing for progressive Schwann cell invasion and nerve fiber regeneration. For hydrogels that allow growth, more rapidly degrading hydrogel networks are desirable to allow for cellular infiltration and subsequent nerve regeneration. Preferably, the hydrogels should degrade between 2 months and 6 months, more preferably 3 months. Degradation of the inhibitory region. The inhibitory guide preferably remains in place for 1 month or more, more preferably 3 months or more, to provide support to the regenerating nerve. In some embodiments, the degradation of the hydrogel allowing for growth is days to months, preferably days to weeks, allowing the material to clear as cellular tissue is replaced and regenerated.
Demand. Preferably, the growth-enabling hydrogels are positively charged or contain positively charged domains. Addition of fusogenic PEG. In some embodiments, it may be desirable to add a non-reactive Fusogen to the hydrogel formulation. Thus, in addition to the mechanical blocking properties of the hydrogel, damaged proximal surviving nerves can be protected from excitotoxic damage and their membranes can be resealed. In addition, the hyperexcitability of cell bodies such as the dorsal root ganglia is reduced, thereby reducing the neuropathic paraesthesia and dysesthesia that accompany nerve injury. In one embodiment, non-reactive or low molecular weight (methoxy-PEG) terminated PEG to the formulation. For example, the trilysine buffer may contain low molecular weight nonreactive linear PEG (0.2 kDa, 2 kDa, 3.35 kDa, 4 kDa, or 5 kDa). When mixed with the 8-armed 15K star-shaped PEG, the resulting hydrogel will have low molecular weight PEG (2 kDa, 10-50% w/v) that can help seal damaged nerve endings and thus Thus, further reducing the ingress and egress of ions. In this way, lysosome formation, demyelination, and other membrane debris can be prevented from accumulating at the site. In another embodiment, cyclosporin A can be applied with the solution to improve the survival of the excised axons.
In another embodiment, PEG with a six-arm star-shaped end cap (poly(ethylene oxide-stat-propylene oxide) or star PEG-OH) can be added as Fusogen. Linear PEG that is mixed with the polymer blend can diffuse out of the crosslinked network, creating micropores up to one micron in diameter, facilitating nutrient diffusion but not neurite outgrowth. Linear PEG-based hydrogels are stiffer than star PEG-based fusogen addition. The addition of linear PEG is based on findings that 2 kDa PEG is beneficial in rapidly restoring axonal integrity, termed 'PEG fusion' between severed and crushed axonal nerves (Britt et al 2010, J. Neurofisiol,104: 695-703). The theory is that this is due in part to sealing of the plasmalemma and axolemma at the injury site.
Reapplication or repositioning. If the doctor is not satisfied with the location of the nerve, the hydrogel "cap" can be removed with forceps and the procedure repeated. Nerve saving. In yet another embodiment, it may be desirable to distribute the hydrogel that forms in situ around a nerve to reduce manipulation of the nerve during a procedure. By placing it in and around the nerve bundle, the hydrogel can define and prevent it from being crushed by forceps or any other micromanipulator during the procedure. In addition to protecting the nerve from mechanical damage, the hydrogel can also protect from thermal damage such as cauterization or radiofrequency ablation, cryoablation.
There are several modalities where existing nerve wraps (eg, conduits with a top slit that allows the nerve to be pushed into the semirigid dressing) and/or conduits are still desired, but the clinician would like to provide additional support for regeneration or in the form of application of a growth-enabling hydrogel, a growth-inhibiting hydrogel, or a combination.
The shape of the hydrogel that allows growth is designed to be substantially the same size as the nerves into which they are placed. In one embodiment, a shape of silicon is selected that is a semi-tube with an internal diameter approximately equal to the external diameter of the ribs. The ribs are placed in the form in direct apposition, in close approximation or, with a gap to avoid tension, so that they lie within the form without any tension. The nerves rest directly on the surface of the form itself for delivery of the hydrogel that enables growth.
Drugs to promote nerve regeneration. Medications can be delivered to the nerve directly before the form is placed. For example, local anesthetics, anti-inflammatory agents, and growth factors can be administered directly into the nerve prior to encapsulation with the hydrogel. Alternatively, drugs can be incorporated directly into the hydrogel or incorporated via encapsulation into drug-loaded microspheres, micelles, liposomes or free base to obtain an improved sustained release profile.
Medicines to relieve pain. In some embodiments, drugs used to treat chronic neuropathic pain can be administered in the hydrogels, including tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors, antiepileptics, and opioids. For example, pregabalin and gabapentin may be selected for their analgesic properties. Also, duloxetine, vennlafaxine, the SNRI inhibitor, and their combinations to provide more complete pain relief. Anti-inflammatories such as diclofenac may also show promise. Other potential targets include ligands for the FK506 family of binding proteins, neuroimmunophyllin ligands, which are neuritetrophic, neuroprotective, and neuroregenerative agents.
Local administration of taxol and cetuximab has also shown promise in improving neuronal survival and regeneration and may be suitable for stimulating nerve regeneration when delivered locally in a hydrogel formed in situ. In another embodiment, cyclic AMP (cAMP) or the cAMP analogue dibutyrylcAMP promote nerve regeneration and can be incorporated into a hydrogel that forms in situ to promote nerve regeneration after injury. In another embodiment, Kindlin-1 and Kindlin-2 (family of fermitins) and drugs that bind to the integrin superfamily of cell surface receptors, allow nerves to stretch through the inhibitory matrix and can be incorporated in hydrogels to enhance regeneration through the inhibitory extracellular matrix. .
In another embodiment, tacrolimus (FK506), an immunosuppressant, can be incorporated into the hydrogel to increase axon generation and velocity. The final concentration of FK506 in the hydrogel formed is from 100 µg/ml to 10 mg/ml, more preferably 0.1 mg/ml. The drug is released over weeks or months, preferably at least one month, more preferably at least 3 months to aid in immunosuppression and increase nerve growth. Drugs include FK506, selective drugs for selective inhibition of FKBP12 or FKBP51.
Drugs that are P2X receptor (P2XR) antagonists, P2X3 receptor antagonists (eg, AF-219 Gefapivant, AF-130), P2X4 and P2X7 receptor antagonists that are implicated in visceral and neuropathic pain (as well as in migraine and cancer pain), are of interest. P2X7 receptor antagonists. The purinergic receptor antagonist Brilliant Blue G (BBG) and the structurally similar analog, Brilliant Blue FCF (BB FCF), are of particular interest for their ability to modulate the neural environment after injury (Wang et al. 2013. FD&C food dye Blue No.1 is a selective inhibitor of the Panx1 ATP release channel (J. Gen. Physiol. 141(5) 649-656)). Other dyes of interest include FD&C Green No. 3 which, like BBG and BB FCF, inhibits the Pannexin1 ATP release channel with an IC50 between 0.2 and 3 uM. A structurally similar analog, Brilliant Blue FCF (BB FCF), also known as FD&C #1 (https://pubchem.ncbi.nlm.nih.gov/compound/Acid_Blue_9), has also been shown to improve nerve survival and regeneration after injury when used in combination with a low molecular weight 3350 Da PEG termination (https://www.nbci.nlm.nih.gov/pubmed/23731685). Similar efficacy has been demonstrated using BBG in rat models of sciatic nerve crush (Ribeiro et al 2017) and myenteric plexus ischemia (Palombit et al 2019). Furthermore, BBG is believed to have anti-inflammatory and antinociceptive effects through the reduction of high extracellular ATP concentrations and high calcium inputs after nerve damage. In one embodiment, Brilliant Blue FCF is incorporated into the hydrogel that forms in situ. The dye can be incorporated into the polymer vial, diluent or accelerator solutions to produce a final gel concentration of 0.0001 to 5%, preferably 0.001 to 0.25%, more preferably 0.01 to 0.02 % by weight or about 1 to 1000 ppm, preferably 10 to 100 ppm On an anatomical basis per site, local doses between 5 µg and up to 25 mg of dye can be delivered locally in a hydrogel. For example, FD&C dye #1 can be administered at a concentration of 0.01% in hydrogels to reduce neuronal damage after stroke (Arbeloa et al 2012, referenced in Palmobit et al 2019). By incorporating the dye into the hydrogel, the dye can help improve the survival of severed axons, reduce local inflammation while the hydrogel provides a barrier to regeneration.
In another embodiment, TRPV1 agonists, such as capsaicin, are administered to the nerve to deliver a preconditioning lesion to the nerve that results in a downstream neuroregenerative response to enhance nerve regeneration (PMID: 29854941). In one embodiment, capsaicin-loaded hydrogels (1 to 8% by weight of drug loading) are administered percutaneously to intact nerves to reduce painful diabetic neuropathy). In another embodiment, piphythrin-u or acetyl-L-carnitine is administered in the hydrogel to reduce and treat chemotherapy-induced peripheral neuropathy (CIPN) by reducing neuronal mitochondrial damage.
In another embodiment, drugs that block dysregulated long noncoding RNAs can also be incorporated into hydrogels, as targets of endogenous Kcna2 antisense RNA. In one embodiment, mitomycin C is incorporated into the hydrogel that forms in situ to inhibit Schwann cell proliferation and stimulate apoptosis in fibroblasts. In one embodiment, 0.1 to 5 mg of mitomycin C is loaded into the polymer powder and used to form a gel formed in situ of 0.01 to 0.5% by weight of mitomycin C, releasing between 0. 1 and 0.5 mg/ml per day, preferably for 7 days or more. In yet another embodiment, Rho Kinase (ROCK) inhibitors or ROK antagonists or Rac1 antagonists, such as ripasudil hydrochloride, may be incorporated.
Additional medications include anti-inflammatory curcumin, rapamycin, paclitaxel, cyclosporine A, pyrimidine derivatives (RG2 and RG5) to stimulate remyelination, Axon Slit 3 guide molecule, triptolide, KMUP-1. calcium modulating agents, including calcitonin, calcium antagonist nifedipine, nimodipine, nerve growth factor (NGF, 500 ng), insulin-like growth factor (IGF-1), thymoquinone, duloxetine (10-30 mg), melatonin, c-Jun or mTORC1 agonists may help support Schwann cell differentiation and remyelination of nerves, nicotine and adrenomedullin, which are used as neuroprotective and neurotrophic drugs.
Example 1. Growth inhibitory hydrogel. In the vial containing 80 mg of PEG with reactive NHS ester, 80 µg of BB FCF is added to produce a dye concentration of 0.1% in the PEG hydrogel.
Example 2. Growth inhibitory hydrogel with a Fusogen. In the vial containing 80 PEG with NHS ester reagent, 80 µg BB FCF and 500 mg PEG 3350.
Example 3. Phospholipids are incorporated into the PEG hydrogel, such as cephalin, to enhance fusion. Phospholipids are amphiphilic molecules with surface activity and can be incorporated as emulsifiers, wetting agents, solubilizers, and membrane fusogens. These may include phosphatidylcholine, phosphatidylethanolamine, or phosphatidylglycerol (https://www.nbci.nlm.nih.gov/pmc/articles/PMC4207189/, incorporated herein by reference).
Example 4 In some embodiments, hydrogels are loaded with amiodarone with or without the addition of ethanol. For example, a loading of 0.1 to 5% by weight of amiodarone or more can be achieved. This can also be achieved and improved by incorporating ethanol into the solution. For example, 50 to 75% ethanol can be incorporated with 0.25% by weight amiodarone to achieve a rapid release of amiodarone in 3 to 5 days. Also, 1% amiodarone can be administered from hydrogels for a period of 30 to 60 days.
The following are examples of in situ-forming growth inhibitory coating formulations suitable for preventing aberrant nerve growth, scar tissue formation, and supporting nerve gliding within the hydrogel.
Example 5. In some embodiments, 8-arm PEG-SAP 20K is crosslinked with a 4-arm PEG-SAP amine with an excess of PEG-SAP to PEG-amine. For example, PEG-SAP and PEG-amine are dissolved in an acidic diluent in a 1.2:1 ratio. The suspension is mixed with accelerator buffer and delivered through a static mixer to form a hydrogel. The formulation gels in 3 seconds, provides compressive strength between 70 and 100 kPa and swelling between 10 and 30% by weight.
Example 6 In some embodiments, the 8-arm PEG-SAP 15K is crosslinked with an 8-arm PEG-SAP 40K amine. PEG-SAP and PEG-amine are dissolved in an acidic diluent in a ratio of 1.6:1. The suspension is mixed with accelerator buffer and delivered through a static mixer to form a hydrogel. This formulation gels in 4 seconds, provides compressive strength between 30 and 80 kPa and equilibrium swelling between 20 and 60% by weight.
Example 7. In some embodiments, the 8-arm 20K PEG-SG is crosslinked with a 4-arm 20K PEG-amine. PEG-SG and PEG-amine are dissolved in an acidic diluent in a ratio of 1.0:1. The suspension is mixed with accelerator buffer and delivered through a static mixer to form a hydrogel. This formulation gels in 5 seconds, provides compressive strength between 20 and 70 kPa and undergoes equilibrium expansion between 40 and 80% by weight.
The following examples support in situ growth inhibitory wrap formulations suitable for preventing aberrant nerve growth, scar tissue formation, and supporting nerve gliding within the hydrogel as it progressively degrades and softens, preventing cellular infiltration. .
Example 8 In some embodiments, the 8-arm PEG-SG 40K is crosslinked with an 8-arm PEG-SG 40K amine. PEG-SG and PEG-amine are dissolved in an acid diluent in a ratio of 1.2:1. The suspension is mixed with accelerator buffer and delivered through a static mixer to form a hydrogel. This formulation gels in 4 seconds, provides a compressive strength between 30 and 60 kPa and undergoes equilibrium expansion between 40 and 80% by weight.
Example 9. In some embodiments, the 8-arm PEG-SAZ 20K (PEG-succinimidyl azelate) is crosslinked with a 4-arm PEG-40K amine. PEG-SAZ and PEG-amine are dissolved in an acidic diluent in a 1.2:1 ratio. The suspension was mixed with accelerator buffer and delivered through a static mixer to form a hydrogel. This formulation gels in 4 seconds and provides compressive strength between 20 and 50 kPa. Furthermore, the equilibrium swelling is between 50 and 100% by weight.
Example 10. In some embodiments, the 4-arm PEG-SAZ 15K is crosslinked with a 4-arm PEG-SAZ 40K amine. PEG-SAZ and PEG-amine were dissolved in an acidic diluent in a ratio of 1.2:1. The suspension was mixed with accelerator buffer and delivered through a static mixer to form a hydrogel. This formulation gels in 8 seconds and provides compressive strength between 10 and 40 kPa. Furthermore, the equilibrium swelling is between 70 and 130% by weight.
Example 11 In another example, the 3-armed PEG-SS 15K (succinimidylsuccinamate) is crosslinked with a 4-armed PEG-SS 40K amine.
The following are examples of materials that can be used in a biodegradable or sheet form that is delivered around nerve endings in need of repair.
Example 12. In some embodiments, the biodegradable form material is crosslinked or uncrosslinked chitosan. The deacetylation of chitosan ranges from 70 to 100% and the thickness of the shape is between 10 µm and 100 µm, preferably around 30 µm.
Example 13. In some embodiments, the biodegradable form material is composed of crosslinked or non-crosslinked chitosan mixed with HPMC (hydroxypropylmethylcellulose), CMC (carboxymethylcellulose) or HA (hyaluronic acid). Chitosan deacetylation ranges from 70 to 100%. The thickness of the chitosan layer varies from 10 μm to 100 μm. The layer of the other component (HPMC, CMC or HA) is 5 µm to 50 µm.
Example 14 In some embodiments, the biodegradable form material is crosslinked or uncrosslinked gelatin. The thickness of the canal varies from 10 µm to 100 µm.
Example 15. In some embodiments, the conduit material is crosslinked or uncrosslinked CMC/HA blends. The thickness of the conduit ranges from 10 µm to 100 µm, preferably around 40 µm.
Example 16. In some embodiments, the solution that allows growth comprises from 3 to 5% by weight of PEG-diacrylate, preferably 3% by weight of PEG-DA, with a compression modulus of approximately 70 Pa.
Example 17. In one example, the growth enabling solution is composed of a 800 µg/ml collagen solution.
Example 18. In one example, the solution that allows growth is composed of a 2% aqueous solution of hydroxypropylmethylcellulose (HPMC) with a viscosity between 7500 and 14000 mPa-s.
Example 19. In one embodiment, the growth-enabling solution comprises a fibrin solution.
Example 20. In another embodiment, the growth enabling solution comprises a collagen proteoglycan-chrondoitin-6-sulfate solution.
As illustrated in FIG.21In any embodiment described herein, a wrapper and/or lid shape may be designed with external ribs running the length of the shape. The grooves can advantageously stimulate directional growth of the collagen fibers along the shape. Once the low viscosity gel is delivered in situ, the gel will fill these ridges and form a cross-linked hydrogel. After the silicone form is removed, the gel contains parallel aligned ridges on the outer surface of the gel surrounding the nerve. This allows the fibrous capsule to be strengthened and aligned around the nerve.
In some embodiments, the hydrogel is preformed into a sheet with external grooves in the surface of the hydrogel. These ridges can be from 1 to 1000 microns in diameter. For example, the grooves may be 10 to 100 microns or 10 to 20 microns wide. In some cases, the depth of the ridges may be 1 to 1000 microns in diameter, 10 to 100 microns in diameter, or 10 to 20 microns in diameter. These ridges may facilitate longitudinal growth of the nerves along the grooves created by the ridge and/or along the top of the ridge itself to provide passive signals for nerve guidance. After wrapping the nerve with preformed, hydrated cross-linked hydrogel, a low-viscosity growth-permissive gel can be applied between the nerve stumps and placed in the grooves to further facilitate nerve regeneration and provide a gel interface across the nerve. which nerves can find their place. their way to the distal nerve stump as they regenerate.
With reference to Figs.22AND-22And, a hydrogel conduit (using any modality described here) can cover approximately 300 degrees or less around the nerve. For example, the conduit may cover approximately 270 degrees around the nerve. In some cases, the conduit can cover at least 120 degrees around the nerve.
In one embodiment, the surgeon is provided with a preformed flexible hydrogel up to 20 cm in length. For example, the hydrogel can be up to 10 cm or about 5 cm long. Hydrogels are supplied in a variety of widths to accommodate nerves of different sizes, e.g. with a lumen of 0.5 to 1 mm, 1 to 2 mm, 2 to 3 mm, 4 to 5 mm, 5 to 6 mm, 6 to 7 or 8 mm, 7 to 8 or 9 mm, up to nerves with a size 20 mm or more in diameter. The hydrogel can be flexible, allowing the insertion of a larger diameter nerve through a smaller entry slot in the hydrogel. The surgeon determines the length of the nerve that will be covered within the hydrogel. The length can be from about 3mm to 10mm. For example, the length may be about 5mm from the nerve stump which is placed in the hydrogel and into the space. The surgeon can then cut the hydrogel to the desired length for the given procedure (as illustrated in FIG.22A). Nerve stumps can be placed one at a time, allowing only one surgeon to perform the procedure without the need to join the two nerve stumps. In some cases (although it is not necessary), reinforcement of the cross-linking between the nerve and the gel conduit can be achieved by adding an accelerating solution.
The hydrogel can be designed to provide resistance to the coaptation site for a period of at least 1 week or longer. For example, the period could be approximately two weeks, or any amount of time until the nerve regenerates and/or the surrounding tissue bears the load. In one embodiment, the hydrogel contains additional fiber reinforcement, maintaining the elasticity of the hydrogel. Reinforcement may include embedded sutures, such as 4-0, 5-0, or 6-0 sutures, within the gel to provide additional strength. Since strength is not required for more than a few weeks, fast-breaking sutures composed of 50:50 PLGA or 75:25 PLGA may be selected. These sutures can be woven or configured in a variety of designs to provide reinforcement to the gel while allowing the gel to stretch and accommodate movement and flexion, for example, around a joint. The sutures can be configured in braids, a series of loops, and/or a mesh that runs the length of the gel duct.
The hydrogel may contain an internal reactive layer that intersects with the nerve surface in situ. The inner layer can have a thickness of 1 micron to 300 microns. For example, the layer can be between 1 micron and 50 microns thick. In some cases, the layer may be composed of unreacted or partially reacted polymers with reactive functional groups.
As illustrated in FIG.22A, The gel duct, shown here with a slit, is cut with a scalpel or scissors to the desired length. the hydrogel2201It is supplied pre-hydrated or dehydrated and can be cut before or after gel hydration. In some embodiments, the hydrogel fiber reinforcement is provided in the hydrogel, illustrated in FIG.22A, as biodegradable mesh in operation2202embedded in the gel.
As illustrated in FIG.22B, A gel conduit and nerve stump are placed2203it is placed in the canal using forceps or other appropriate tool. accelerator solution2204, a pH buffered solution, is then added to accelerate cross-linking between the gel canal and the nerve. Additional accelerator solutions are easily removed from the site.
As illustrated in FIG.22C, The second stump is held with the desired clearance in the gel canal. The length of the space can be adjusted as desired.
As illustrated in FIG.22D, the accelerator solution2204is added as in fig.22B to connect the nerve to the gel conduit and secure the nerve. If direct apposition of the nerve under tension is desired, the clamps can be held in place to secure the nerve while an accelerating solution is applied to the site to achieve direct coaptation under, for example, minimal tension, as desired.
As illustrated in FIG.22And, the entire procedure is accomplished with direct coaptation of the nerves. The nerves are fixed in place in direct apposition without sutures under minimal tension with the desired spacing. The conduit gel facilitates alignment of the nerves within the conduit and minimal gaps to maximize regeneration. If desired, an additional layer of gel in situ or another gel can be administered over the nerve to provide circumferential protection to the nerve. Also illustrated is the use of the procedure in targeted muscle reinnervation (TMR) procedures where there is a size mismatch between the proximal nerve stump and the distal motor nerve.2205. The hydrogel forms around these two stumps and facilitates the orientation of the regenerating nerve fibers from the proximal stump to the distal motor stump.
In some embodiments, a preformed hydrogel can include an internal adhesive surface. For example, one or more ribs can be pushed into a flexible slit in the hydrogel tube to make contact with the inner surface of the hydrogel. The inner surface may be adhesive, allowing placement of one nerve stump at a time within the lumen of the hydrogel. The inner adhesive layer of the hydrogel can be obtained by spraying a thin layer of unreacted polymer powder into the inner lumen of the duct or tube. In some cases, the inner layer consists of a thin, conformable sheet of reacted polymer fused with polymer adjuvants to impart flexibility to the material.
The inner surface can be a partially crosslinked or non-crosslinked but functionally active polymer. For example, the polymer can be PEG and/or Pluronic.
In one embodiment, the hydrogel conduit can be hydrated and inserted into the surgical site. The reactive layer is then placed in the canal lumen and is activated when it comes into contact with fluid present on the nerve surface. In some embodiments, additional drops of buffer solution can be dispensed onto the nerve and reagent layer to increase in situ crosslinking of the hydrogel and thus adhesion of the nerve to the inner surface of the canal.
In some cases, if there is a gap between the two nerves, as may be the case with a direct repair (eg, as illustrated in FIGS.23AND-23C), one or more of the same steps as in FIGS.22AND-22And it can be applied by leaving a space between the two nerve endings. Right now, a nerve conductive gel2303can be delivered between two nerve endings (see FIG.23B) and the growth-permissive gel2304it can be extended to cover the entire surface of the two nerve stumps (see FIG.23C) at the discretion of the doctor. In one embodiment, the space is filled with fibrin sealant between the nerve spaces.2303or between nerve spaces and running along the surface of the nerves themselves2304. In another embodiment, fibrin glue is used to temporarily join two nerves in direct apposition before distributing the gel that forms in situ around the nerves. In another embodiment, the growth-enabling gel is first dispensed2303and then the in situ growth inhibitory gel is formed around the growth permit and along the nerve to form a complete circumferential gel conduit.
As illustrated in FIG.23A, The gel canal contains the two nerve stumps placed 5 mm or less apart.2302between the nerves2301.
As illustrated in FIG.23B, a gel that allows fluid growth2303with low compressive strength (eg, equal to or less than 5 kPa, such as less than 2 kPa, or less than 1 kPa) is delivered between the two nerve endings.
As illustrated in FIG.23C, in some embodiments, if desired, an additional layer2304of the gel that forms in situ is administered on top of the gel that allows growth and along the nerve to form a circumferential protective layer around the nerve.
In some embodiments, as illustrated in FIG.24To prevent further separation of a nerve after nerve section, in situ forming hydrogel can be applied to secure the nerve in place, reduce further scar tissue around the proximal and distal stump, and further reduce the separation between the nerves. nerves. In some embodiments, the hydrogel is used as a bridge for future nerve repair with an allograft or autograft. By placing the hydrogel around the nerve at the time of the initial index trauma, the hydrogel can prevent an additional 1mm to 10mm gap that is created because the nerves remain under tension.
With reference to Figs.27AND-27F, There has recently been a revival of interest in stimulating nerves intraoperatively to enhance nerve healing, accelerate the rate of nerve regeneration, potentially increase the number of nerves reaching distal target tissues prior to muscle atrophy, and, therefore, driving improvements in functional outcomes, as well as reducing postoperative and chronic pain. Currently, these nerve stimulators are conventionally attached with a sleeve or other non-degradable wrapping material that is placed around a nerve. Surgeons can then further secure the sleeve in place with one or more sutures to prevent device migration and maintain good stimulator-to-nerve contact.
Several modalities described here are aimed at improving fixation of the nerve stimulators intraoperatively to allow for better nerve stimulation, ensure continuous nerve stimulation without loss of contact, allow for hands-free nerve stimulation, and reduce procedure time and improve ease. of the use of nerve stimulation therapy. Several modalities described herein are directed to the use of a hydrogel, particularly a gel that forms in situ, to fix the intraoperative nerve stimulator in the desired location. Devices and kits include both components to form the form-in-situ hydrogel, a silicone sheet, or other way to deliver the hydrogel (if desired) in the same kit as a single-use disposable electrode or nerve stimulation system for nerve stimulation.
In some embodiments, a nerve repair generation kit is provided that contains the components for forming an in situ forming hydrogel around a peripheral nerve electrode and a nerve. The electrode can be connected to a separate nerve stimulator device to provide stimulation to the nerve. In some cases, the nerve stimulator and the electrode can be supplied together in the sterile kit with the components to form the hydrogel.
This can be accomplished with the in situ hydrogel formation devices and kits described above, including the use of temporary silicone forms. In some embodiments, the kit includes a vial of powdered polymer, a diluent solution, an accelerator solution, a dual adapter and a dual channel syringe, one or more mixing or application tips, and a single stimulation electrode lead. corded use. Optionally, these kits can include the nerve stimulator and the electrode itself, including the generator (eg battery) and also a return electrode needle. In some cases, the nerve stimulator, including the generator and battery, is housed in the stimulation electrode.
In some embodiments, the shape (as described in connection with any embodiment herein) in which the nerve is placed and the hydrogel is subsequently administered contains a slit.2701on one side to allow placement of the electrode tip in contact with the nerve (for example, FIG.27D). In some embodiments, a sheet2701can be placed under the nerve2703, the electrode2702it is placed flush with the lamina next to the nerve and the hydrogel is distributed around the electrode and nerve simultaneously (for example, as illustrated in FIG.27B).
In some embodiments, the hydrogel kit is used in combination with the commercially available Checkpoint Guardian™ Intraoperative Electrode single point electrode. According to the instructions for use (IFU), the electrode is connected to the Checkpoint® Nerve Locator/Stimulator. The Checkpoint Guardian™ intraoperative electrode consists of a connector for connection to the nerve stimulator, a flexible cable, a lead wire, and a stimulation electrode. In this embodiment, direct electrical contact with the nerve is not necessary if an in situ formed conductive hydrogel is distributed around the electrode and nerve. Stimulation is delivered according to the Checkpoint Guardian™ Intraoperative Electrode Instructions for Use after fixing the stimulator around the nerve with the hydrogel. Electrodes and electrical stimulators described in the US patent 7,878,981, 7,896,815, 8,172,768, 8,500,652, 10,154,792, US2014/0371622, US being. No. 10/433785, US2011/005434, US2013/024590, WO2021. WO2022119912 incorporated here.
In some cases, a custom intraoperative nerve stimulation electrode that has a compatible connector that can be connected to the Checkpoint® Nerve Locator/Stimulator is preferred over the Checkpoint Guardian™ intraoperative electrode. These nerve stimulation electrodes terminate in a single point electrode or small paddle design electrode and contain no additional silicone or other non-electrode material to secure the electrode around the nerve.
Embedding of an electrode in a conductive hydrogel. When using a conductive hydrogel, the electrode need not be in direct contact with the nerve, allowing for an easy method of attaching the electrode/adjacent electrode to the nerve at the desired location by incorporating the electrode into the hydrogel itself. In some embodiments, the hydrogel is conductive and helps provide stimulation through the hydrogel. Therefore, after circumferential administration of the hydrogel, the hydrogel can provide better directional nerve stimulation and more uniform and complete electrical stimulation of the nerve than can be achieved with a spot electrode.
Types of nerves treated. The nerve can be purely motor, sensitive or mixed. The nerves can vary in diameter from 0.1 mm to 30 mm in diameter, for example, from small digital nerves to the sciatic nerve. The procedure may be performed to treat nerves that are still in continuity, for example, nerves that have sustained trauma but have an external epineurium that is still intact, nerves that have been decompressed or neurolyzed, nerves that have been severed and are undergoing repair directly as part of a procedure and nerves that are repaired by an allograft or autograft. Preferably, the nerve stimulator is placed and then fixed near the injury site during the procedure. The hydrogel formed in situ allows for secure placement of the stimulator without migration or the need for sutures or accessories (eg, a cuff) to secure the stimulator.
In some embodiments, the nerve stimulator can be attached next to the nerve using the gel, the procedure is performed, and then additional gel is dispensed around the nerve to repair and/or protect it.
Electrode distance in a nerve conducting hydrogel. In some cases, the electrode does not measure more than 1 mm. As other examples, the electrode cannot be more than 3mm from the nerve and no more than 20mm from the nerve.
Embedding of an electrode in a non-conductive hydrogel. In some embodiments, the hydrogel is non-conductive and is delivered and formed in situ around the electrode to help direct electrical stimulation to the nerve and prevent off-target stimulation.
Stimulation duration. The nerves can be stimulated for a period of 1 minute, 10 minutes, 15 minutes, 20 minutes, or left in place for the entire duration of the surgery before closing the surgical site. In some cases, the nerves can be stimulated for as long as the doctor wants, including after the completion of surgery for a period of 1-2 hours, 4-6 hours, or even just before discharge, at which time intravenous needles and other invasive needles are used. they are removed. In some cases, electrical stimulation may remain in place for 1 to 7 days after surgery and after discharge, for as long as necessary to minimize the patient's chances of chronic postoperative pain. As needed, the duration of electrical stimulation can be extended from weeks to months to minimize localized and centralized postoperative pain, as well as chronic pain.
Electrode tip configuration. The electrode tip shape can be configured as a dot, paddle, or other high surface area design to allow for increased nerve fiber recruitment, similar to spinal cord stimulator electrode designs.
Electrode removal. The electrode can be easily removed from the hydrogel when the desired duration of electrical stimulation has been reached. The wire is simply gently pulled out of the site and removed from the hydrogel. This can be done after nerve surgery, for example after suturing the nerve or after decompression of the nerve.
waveform. In some embodiments the waveform is biphasic and in other embodiments the waveform is monophasic.
Electrode type. The electrode can be a single point electrode with a unipolar electrode (with a separately placed return electrode), a bipolar cuff electrode, or a tripolar cuff electrode. The electrodes can be made of platinum, iridium or stainless steel. Stimulation device. The device can provide stimulation between 15 and 30 Hz (for example, around 16 Hz), although stimulation can be up to 900 Hz as needed. Stimulation currents can be fixed or variable at 0.5, 2.0 mA, or even 20 mA. The duration of the pulses can vary between 10 and 200 microseconds as needed for smaller to larger nerve fibers. The device can provide impedances down to 1.5 kOhms.
In some embodiments, the shape is left in place to provide additional support for the hydrogel that forms in situ, as well as to provide an insulating outer wall to prevent stimulation from reaching target tissues.
Drug delivery. In some embodiments, the electrical stimulation is administered at the same time as a drug delivery system, to speed up the rate of regeneration. Electrical stimulation can be provided in conjunction with any drug delivery system as described herein. For example, FK506, a drug that has been shown preclinically to accelerate the rate of nerve regeneration, can be administered for approximately one to three days, preferably one to two weeks or longer, to stimulate and support nerve regeneration.
As illustrated in FIG.27A, the electrode2702placement can be followed by delivery of the hydrogel formed in situ2701around the proximal nerve stump2703before repairing the nerve.
As illustrated in FIG.27B, The hydrogel may remain after removal of the temporary electrode after completion of nerve stimulation. The hydrogel has at least two functions: to protect the electrode and then to stay in place to protect the nerve from fascicular escape and to reduce scar tissue formation around the nerve after direct nerve repair. As illustrated in FIG.27Bi, the electrode has been removed and a gap2702formed within the gel2701that the electrode previously occupied. Examples are provided with i) direct nerve repair first with sutures2704followed by delivery of the hydrogel containing the electrode around the proximal nerve stump2703and subsequent removal of the electrode2702. As illustrated in FIG.27Bii, the stimulation electrode can be placed using a hydrogel that forms in situ prior to a nerve decompression procedure. As in i), in ii) illustrates the space created in the hydrogel after lead removal.
As illustrated in FIG.27C, in some cases, the hydrogel2702delivered around the nerve2704on a silicone sheet2701containing the electrode that runs adjacent to the nerve2703. Electrical stimulation can be performed immediately after using the in situ forming hydrogel to achieve sutureless repair of the severed nerve.
As illustrated in FIG.27D, a cleft in the form2701can be included through which the wire can be slipped and fastened along the form. The slit can be placed at the time of surgery with scissors or it can be present in silicone form at the time of fabrication.
As illustrated in FIG.27And different electrode designs allow for better coverage of larger nerves. FIG.27Ei illustrates a single point contact electrode2802with adjacent insulated wire2801suitable for stimulating, for example, minor nerves. FIG.27Eii illustrates a larger surface area paddle electrode suitable for larger nerves, with or without mesh or other design that improves infiltration of the hydrogel formed in situ into the electrode itself.
As illustrated in FIG.27F, There may be sequential delivery of the hydrogel. A first hydrogel2901may be to protect the electrode2902near the proximal nerve stump2903. A second later installment2904can occur after placement of, for example, an allograft2905in a gap repair, with the hydrogel supporting direct coaptation of the proximal nerve2903and distal nerve and/or allograft/autograft placement. The hydrogel can be applied around the nerve with or without sutures.
A way to create a nerve conduit in situ for nerve regeneration, the way comprising one or more of the following:
a wall that at least partially defines a cavity that is configured to receive a nerve;
a slit within the wall being configured to receive an electrode such that the electrode is configured to be positioned adjacent to the nerve when the nerve is received in the socket and when the electrode is placed within the slit.
A form as described in any embodiment herein, in which the cavity is configured to receive a hydrogel that forms in situ when the nerve is received in the cavity.
One way as described in any of the embodiments herein, in which the electrode is placed at most about 1 mm from the nerve when the nerve is received in the socket and when the electrode is placed in the slit.
One way as described in any of the embodiments herein, in which the electrode is placed at most about 3mm from the nerve when the nerve is received in the socket and when the electrode is placed in the slit.
A form as described in any embodiment herein, wherein the electrode comprises at least a single point electrode, a bipolar cuff electrode, or a tripolar cuff electrode.
A form as described in any of the embodiments herein, in which the electrode is configured to enhance fiber recruitment when activated next to the nerve.
A shape as described in any embodiment of this document, in which the electrode is configured to be easily removed from the shape.
Method for forming a nerve conduit in situ for nerve regeneration, the method characterized by comprising one or more of the following:
place a nerve in a cavity one way;
positioning a nerve stimulation device adjacent to the nerve; Y
supply of a forming gel in situ.
A method as described in any embodiment herein, wherein the form further comprises a slot within a wall of the form and wherein positioning the nerve stimulation device comprises inserting the nerve stimulation device into the slot such that the nerve stimulation device is placed next to the nerve. when the nerve is placed within the socket and when the nerve stimulation device is inserted into the slit.
A method as described in any embodiment herein, wherein positioning the nerve stimulation device comprises securing the nerve stimulation device with a sleeve.
A method as described in any embodiment herein, wherein positioning the nerve stimulation device comprises inserting the nerve stimulation device into the in-situ-forming gel after administration of the in-situ-forming gel.
A method as described in any embodiment of this document, wherein the nerve stimulation device comprises an electrode.
A method as described in any embodiment herein, wherein the gel that forms in situ comprises a hydrogel.
A method as described in any embodiment herein, wherein administering the training gel in situ comprises administering the training gel in situ in an open surgical procedure around the nerve and nerve stimulation device.
A method as described in any embodiment herein further comprises removing the nerve stimulation device.
A method as described in any embodiment herein, wherein removing the nerve stimulation device comprises removing the nerve stimulation device during an open surgical procedure.
A method as described in any embodiment herein, wherein removing the nerve stimulation device comprises removing the nerve stimulation device at a desired time after completion of an open surgical procedure.
A method as described in any embodiment of this document, wherein the gel formed in situ is conductive.
A method as described in any embodiment herein, wherein the gel formed in situ is non-conductive.
A method as described in any embodiment of this document, wherein placing the nerve stimulation device adjacent to the nerve comprises placing the nerve stimulation device within 2mm of the nerve.
A method as described in any embodiment herein, wherein administering the in situ forming gel comprises administering the in situ forming gel circumferentially around the nerve.
A method as described in any embodiment herein, wherein the gel that forms in situ is biodegradable.
A method as described in any embodiment herein, wherein the gel that forms in situ is configured to provide nerve protection.
A method as described in any embodiment herein, wherein the gel that forms in situ is configured to support nerve regeneration.
A way to create a nerve conduit in situ to facilitate the growth and prevention of scar tissue across a nerve, the way comprising one or more of the following:
a tubular conduit that is flexible and at least partially defines a cavity; Y
a slit extending along the tubular duct in a longitudinal direction, the shape being configured to receive the nerve through the slit and into the cavity.
A form as described in any embodiment herein, in which the rib comprises a rib diameter greater than the diameter of an open end of the tubular conduit, and in which the tubular conduit is configured to flex to allow insertion of the nerve through the cleft.
A shape as described in any embodiment herein, wherein the shape is configured to receive the rib and a second rib through the slit and into the cavity.
A form as described in any embodiment herein, in which the tubular conduit is configured to cover at most about 300 degrees around a circumference of the nerve.
A form as described in any embodiment herein, in which the tubular conduit is configured to span approximately 270 degrees around a circumference of the nerve.
A form as described in any embodiment herein, in which the tubular conduit is configured to cover at least about 120 degrees around a circumference of the nerve.
A shape as described in any embodiment of this document, further comprising at least one reinforcing fiber.
A form as described in any embodiment herein, wherein at least one reinforcing fiber comprises a rapidly deteriorating suture.
A form as described in any embodiment herein, wherein at least one reinforcing fiber comprises a biodegradable mesh.
A form as described in any embodiment of this document, further comprising a reactive layer along an inner surface of the tubular conduit.
A form as described in any embodiment herein, in which the reactive layer is configured to interlink with a nerve surface in situ.
A form as described in any embodiment herein, in which the tubular conduit is configured to fit along a nerve surface after receiving the nerve in the cavity to minimize gaps between an internal surface of the tubular conduit and the nerve surface.
A form as described in any embodiment of this document, further comprising an adhesive along an inner surface of the tubular conduit.
A way to create a nerve conduit in situ to facilitate the growth and prevention of scar tissue across a nerve, the way comprising one or more of the following:
a concave wall defining a cavity;
a first wall end that provides a first side access for placing a first nerve end into the cavity;
a second wall end providing a second lateral access for placing a second nerve end into the socket; Y
a series of parallel raised edges on an interior surface of the form.
A shape as described in any embodiment herein, wherein each of the series of parallel raised ribs has a diameter of from about 1 micron to about 1000 microns.
A shape as described in any embodiment herein, wherein each of the series of parallel raised ribs is between about 10 microns and about 100 microns in diameter.
A shape as described in any embodiment herein, wherein each of the series of parallel raised ribs is between about 10 microns and about 20 microns in diameter.
Various other modifications, adaptations, and alternative designs are, of course, possible in light of the above teachings. Therefore, it is to be understood at this time that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein. It is contemplated that various combinations or sub-combinations of the specific features and aspects of the embodiments described above may be made and still fall within one or more of the inventions. In addition, the disclosure in this document of any feature, aspect, method, property, feature, quality, attribute, element, or the like in connection with one embodiment may be used in all other embodiments set forth in this document. Accordingly, it is to be understood that various features and aspects of the described embodiments may be combined or substituted for one another to form various modes of the described inventions. Therefore, it is intended that the scope of the present inventions described herein not be limited by the particular embodiments described above. Furthermore, while the invention is susceptible to various modifications and alternate forms, specific examples thereof have been shown in the drawings and are described in detail herein. It is to be understood, however, that the invention is not to be limited to the particular forms or methods disclosed, but rather, the invention is to cover all modifications, equivalents, and alternatives that fall within the spirit and scope of the various described embodiments. . and the appended claims. It is not necessary to perform the methods described in this document in the order listed. The methods disclosed in this document include certain actions performed by a physician; however, they may also include instructions from third parties about these actions, either expressly or implicitly. The ranges described in this document also encompass any and all overlaps, subranges, and combinations thereof. Idioms like "until", "at least", "greater than", "less than", "between" and the like include the recited number. Numbers preceded by a term such as "approximately", "about", and "substantially", as used in this document, include the indicated numbers (eg, about 10% = 10%) and also represent a value close to the declared value that still performs a desired function or achieves a desired result. For example, the terms "about," "about," and "substantially" can refer to less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01%. . declared value. In addition, various theories and possible mechanisms of action are discussed here, but are not intended to be limiting.
FAQs
What is the best way to regenerate nerves? ›
Sometimes a section of a nerve is cut completely or damaged beyond repair. Your surgeon can remove the damaged section and reconnect healthy nerve ends (nerve repair) or implant a piece of nerve from another part of your body (nerve graft). These procedures can help your nerves regrow.
How can I speed up nerve regeneration? ›Electrical stimulation a week before surgery causes nerves to regenerate three to five times faster, leading to better outcomes.
Is there a way to regenerate nerves? ›Nerve cells can regenerate and grow back at a rate of about an inch a month, but recovery is typically incomplete and slow. This is a complete nerve injury, where the nerve sheath and underlying neurons are severed. If there is an open cut, a neurosurgeon can see the cut nerve ends at surgery and repair this.
Can a TENS unit help nerve regeneration? ›Objective: Transcutaneous electrical nerve stimulation (TENS) is a noninvasive electrical stimulation therapy indicated for pain control that has been applied for the regeneration of nerves.
Is there anything that can reverse nerve damage? ›Antioxidants like CoQ10 and acetyl-l-carnitine can help to prevent or reverse nerve damage, and they help to reduce pain. Antioxidant packed foods include blueberries, fish, beans, walnuts, green veggies, and beans.
How long does it take for damaged nerves to regenerate? ›Regeneration time depends on how seriously your nerve was injured and the type of injury that you sustained. If your nerve is bruised or traumatized but is not cut, it should recover over 6-12 weeks. A nerve that is cut will grow at 1mm per day, after about a 4 week period of 'rest' following your injury.
What vitamin is good for nerve regeneration? ›Damage and regeneration naturally occur in the peripheral nervous system. The neurotropic B vitamins thiamine (B1), pyridoxine (B6), and cobalamin (B12) are key players, which maintain the neuronal viability in different ways. Firstly, they constantly protect nerves against damaging environmental influences.
What are the 3 steps for nerve regeneration to occur? ›Regeneration of Neural Tissues
Axon regeneration has three phases: sprouting, elongation, and maturation (McQuarrie, 1983).
Several studies have shown that direct electrical stimulation of the injured nerves can enhance sensory and motor axon regeneration, hasten functional recovery, and facilitate reinnervation [2, 5–11].
Can nerves be reactivated? ›Generally speaking, it has been well reported that the nerves that make up the peripheral nervous system (the nerves outside of the brain and spinal cord) have the ability to regenerate, while those within the central nervous system (CNS) generally do not.
What is the best nerve stimulator? ›
- Best overall: iReliev iRenew TENS + EMS Unit. Courtesy of Amazon. ...
- Editor's pick: TechCare Unit Muscle Stimulator. ...
- Best for low prices: Belifu Dual Channel TENS EMS Unit. ...
- Best smart TENS machine: PowerDot 2.0 Smart Muscle Stimulator. ...
- Best portable massager: RAKZU TENS Unit Muscle Stimulator AS8015.
A massage helps to reduce effects of injury by relieving compression of nerves an encouraging repair of damaged nervous tissues to increase. Relief of compressed nerves and healing of damaged nervous tissues reduces negative sensations such as pins and needles and numbness to improve sensation.
Is electric massage good for nerve damage? ›In cases of nerve damage, massage therapy can be useful to relieve symptoms and improve the overall health of a patient. If you are experiencing a tingling sensation, numbness, or pain in some areas of your body, massage therapy may be able to alleviate these symptoms.
Is magnesium good for nerves? ›In the nervous system, magnesium is important for optimal nerve transmission and neuromuscular coordination, as well as serving to protect against excitotoxicity (excessive excitation leading to cell death) [1,2].
What is the new treatment for neuropathy? ›Intraneural Facilitation (INF) treatment effectively restores blood flow to damaged nerves, decreasing pain caused by diabetic peripheral neuropathy (DPN), according to a new study conducted by researchers at Loma Linda University Health.
What are signs of nerve regeneration? ›It is important to differentiate this tingling from the pain sometimes produced by pressure on an injured nerve. The pain is a sign of irritation of the nerve; tingling is a sign of regeneration; or more precisely, tingling indicates the presence of young axons, in the process of growing.
Does heat help nerve regeneration? ›A “heat” shock to turbocharge the rate of regeneration.
This intervention is likely to be useful in any type of proximal nerve injury, such as severe cubital tunnel syndrome.
Orange juice is rich in vitamin C, with 1 cup (240 mL) providing 93% of the Daily Value (DV). Interestingly, this vitamin may offer neuroprotective benefits ( 10 ).
Are my nerves permanently damaged? ›The outlook for peripheral neuropathy varies, depending on the underlying cause and which nerves have been damaged. Some cases may improve with time if the underlying cause is treated, whereas in some people the damage may be permanent or may get gradually worse with time.
Is magnesium good for nerve regeneration? ›Magnesium is one of the most essential nutrients in the human body. It plays a vital role in nerve regeneration and functional recovery by reducing the inflammation and causing Schwann cell proliferation at the injury site, which increases axonal recovery.
Does B12 regenerate nerves? ›
Vitamin B12 had an antiapoptotic effect and possibly promoted nerve regeneration by inhibiting the apoptosis of damaged neurons and creating conditions for the recovery of nerve function. High-dose vitamin B12 promoted functional recovery of nerves (sciatic nerve) after peripheral nerve injury.
Does turmeric help neuropathy? ›Yes! Turmeric will help address peripheral neuropathy because it contains curcumin, a strong antioxidant. Curcumin has anti-inflammatory, antioxidant, and analgesic properties. These combine to relieve peripheral neuropathy symptoms (numbness and tingling) in the hands and feet and prevent chronic pain.
Can nerve cells be restored and start functioning again? ›Central nervous system (CNS) axons do not spontaneously regenerate after injury in adult mammals. In contrast, peripheral nervous system (PNS) axons readily regenerate, allowing recovery of function after peripheral nerve damage.
Can a TENS unit restore nerve damage? ›TENS unit therapy may reverse nerve damage in people with spinal cord injury (a finding that could help those who suffer from peripheral neuropathy) In patients who are experiencing post-injection sciatic pain, TENS provided significant pain relief.
How can I encourage my nerves to regenerate naturally? ›Broccoli, spinach and asparagus all contain vitamin B, a nutrient important for nerve regeneration and nerve function. Spinach, broccoli and kale also contain a micronutrient called alpha-lipoic acid that prevents nerve damage and improves nerve function.
Can a TENS machine help with nerve damage? ›Studies show that TENS can help relieve pain from diabetic nerve damage, most commonly in the hands and feet. Spinal cord injury pain. At least three studies on TENS and spinal cord injury pain have shown improvements in this kind of pain, which is hard to treat.
Does protein help nerve regeneration? ›Summary: Scientists have identified a group of proteins that help to regenerate damaged nerve cells. Scientists at the German Center for Neurodegenerative Diseases (DZNE) have identified a group of proteins that help to regenerate damaged nerve cells. Their findings are reported in the journal Neuron.
What stimulates nerve repair? ›Electrical Stimulation (ES) accelerates target reinnervation
Electrical stimulation at a frequency of 20Hz for one hour accelerates the outgrowth of axons across the site of surgical repair of transected nerve stumps to result in accelerated target reinnervation.
Recent studies have shown that vibration therapy is effective in improving neurological dysfunction and muscle strength, alleviating neuropathic pain, and correcting spasticity and gait [20].
Is there a pill for nerve damage? ›The main medicines recommended for neuropathic pain include: amitriptyline – also used for treatment of headaches and depression. duloxetine – also used for treatment of bladder problems and depression. pregabalin and gabapentin – also used to treat epilepsy, headaches or anxiety.
Is banana good for nerve? ›
Nerves: Bananas are high in B vitamins, which help calm the nervous system. PMS: The vitamin B6 that bananas contain regulates blood glucose levels, which can affect your mood. Strokes: According to research, eating bananas as part of a regular diet can cut the risk of death by strokes by as much as 40%!
How do you stimulate nerve function? ›Loud gargling with water or loud singing activates our vocal cords which in turn stimulates the vagus nerve. Foot massage: gentle or firm touch can assist in stimulation the vagus nerve. Cold water face immersion: immerse your forehead eyes and at least 2/3 of both cheeks into cold water.
Are there exercises for nerve damage? ›There are three main types of exercises ideal for people with peripheral neuropathy: aerobic, balance, and stretching. Before you start exercises, warm up your muscles with dynamic stretching like arm circles. This promotes flexibility and increases blood flow.
Which massage is best for nerves? ›Neuromuscular Therapy (NMT)
NMT is massage applied to specific muscles, often used to increase blood flow, release knots of muscle tension, or release pain/pressure on nerves.
"It can also help with nerve regeneration and preservation. If there has been nerve damage or diminished sensation, we target treatment in these areas to re-stimulate those nerve fibers." Indeed, studies show that acupuncture is an effective treatment for peripheral neuropathy, with fewer side effects than medications.
Is nerve damage permanent? ›But sometimes, nerve damage can be permanent, even if the cause is treated. Long-term (chronic) pain can be a major problem for some people. Numbness in the feet can lead to skin sores that do not heal. In rare cases, numbness in the feet may lead to amputation.
Can nerve damage be cured? ›Depending on the cause and severity of the damage, people with nerve damage can experience a combination of nerve pain, burning, tingling, weakness, and loss of sensation in the affected body part. Sometimes nerve damage can get better on its own, or with treatments like physical therapy.
How do you tell if a nerve is permanently damaged? ›- Numbness or tingling in the hands and feet.
- Feeling like you're wearing a tight glove or sock.
- Muscle weakness, especially in your arms or legs.
- Regularly dropping objects that you're holding.
- Sharp pains in your hands, arms, legs, or feet.
- A buzzing sensation that feels like a mild electrical shock.
Nerve Pain
It's best to use cold when the pain is still sharp and move on to heat once that sharpness has subsided. The heat will increase blood flow and help tissues heal faster.
Gabapentin is approved to treat nerve pain (neuralgia) that results from nerve damage. Gabapentin may be used to treat: Nerve pain caused by a herpes zoster viral infection, also known as shingles. This pain is called post-herpetic neuralgia (PHN), and it can be severe and chronic.
What is the latest treatment for neuropathy? ›
Intraneural Facilitation (INF) treatment effectively restores blood flow to damaged nerves, decreasing pain caused by diabetic peripheral neuropathy (DPN), according to a new study conducted by researchers at Loma Linda University Health.
How can I fix my nervous system naturally? ›Improving Nervous System Naturally
Get plenty of rest and sleep after a long, hectic day. Get blood sugar and high blood pressure under control. Drink plenty of water and other fluids, as dehydration is not good for the nervous system. Limit your intake of caffeinated as well as alcoholic drinks.