Device and method for creating fluid containment field for administering therapeutic agent to nerve

Abstract

The severed nerves may be operatively reconnected and severed axons fused via sequential administration of a solution. The solution may include a pre-charge solution comprising a Ca < 2 + >-free salt solution comprising methylene blue, a fusion solution comprising about 50% (w / w) PEG, and a sealing solution comprising a Ca < 2 + >-containing salt solution. The PEG fusion solution may be applied to a neural treatment device configured to isolate an injured segment of a nerve. The device may include a containment chamber for creating a fluid containment field around the anastomosis. The device may have slits, slots, and / or apertures in opposite end walls of the device designed to receive nerves. The device may have an open bath configuration, or may include separable lower and upper bodies to form a closed bath configuration. The device may include one or more fluid ports in fluid communication with the containment chamber for introducing and / or removing fluid.

Description

[0001] This application is a divisional application of patent application No. 201880055779.3, filed on July 24, 2018, entitled "Apparatus and method for creating a fluid containment field for administering a therapeutic agent to a nerve". Technical Field

[0002] This application relates to apparatus and methods for creating a fluid-containing field for administering therapeutic agents to nerves. Background Technology

[0003] No known device has the following functions: 1) creating an isolated fluid-containing field for local (on the nerve) delivery of a drug solution to the lesion area of ​​the nerve; 2) protecting tissue other than the nerve to be treated from exposure to the drug solution; and 3) providing a design that allows for placement and withdrawal from the nerve without damaging the anastomosis. No method has yet been provided for sequentially using a delivery device to repair a nerve using PEG fusion.

[0004] The following patents and published applications may be relevant to this field and are incorporated herein by reference in their entirety: U.S. Publication No. 2005 / 0028828; U.S. Publication No. 2003 / 0055414; U.S. Publication No. 201 / 0035618; U.S. Publication No. 2004 / 0172045; U.S. Publication No. 2006 / 0259102; U.S. Publication No. 2011 / 0257588; U.S. Publication No. 2002 / 0107527; U.S. Publication No. 2014 / 0107590; and U.S. Patent No. 3,628,524. Summary of the Invention

[0005] Polyethylene glycol fusion (PEG fusion) is an emerging technique for the acute repair of damaged peripheral and central nervous systems. Damaged peripheral nerve repair is performed by suturing the incision ends together, inserting a bridging device, and implanting a donated nerve segment. Current repair methods do not truly restore function and sensation, but only promote the regeneration of natural nerve tissue. In contrast, PEG fusion can immediately restore function and sensation, prevent degenerative changes, halt atrophy of distal target tissues, and significantly accelerate and improve the recovery of sensation and function.

[0006] PEG fusion involves the sequential administration of a series of pharmaceutical agents that fuse severed axons within a nerve bundle and restore axonal integrity. Unbound by conventional wisdom, PEG fusion utilizes highly hydrophilic PEG as a dehydrating agent, which removes bound water from the extracellular surface of the cell membrane and promotes the fusion of exposed cell membranes. This is performed in the operating room and is a complement to the standard of care—microsutures (neurosuction) of the proximal and distal ends of the nerve via the epineurium.

[0007] The PEG concentration used in the PEG application step of this method may be approximately 50% (w / w), and may pose an exposure risk to uninvolved nerves and tissues adjacent to the nerve being repaired. Exposure to high concentrations of PEG has been shown to 1) disrupt the electrophysiological function of nerves; and 2) cause necrosis of other soft tissues.

[0008] Therefore, the device planned herein can advantageously: 1) provide placement of the device so as not to interfere with the recently sutured nerve; 2) create a fluid containment field around the sutured nerve; 3) provide continuous and consistent exposure of the damaged, sutured ganglion; 4) prevent unnecessary exposure of the undamaged segment of the nerve to the PEG; 5) prevent unnecessary exposure of adjacent tissue to the PEG; 6) provide convenient and efficient removal of the PEG after the application step; and / or 7) provide removal of the device to avoid interference with the recently fused axon within the recently fused nerve.

[0009] The delivery device disclosed herein allows for qualitative and / or quantitative assessment of the recovery of electrophysiological activity across repaired nerves by measuring compound action potentials (CAPs) across anastomoses of severed, sutured, and PEG-fused nerves. CAPs measure the cumulative electrical signal from extracellular recordings of axonal populations (e.g., intraneural). The device also allows for the demonstration of disruption of electrophysiological activity caused by excessive PEG exposure (time and / or concentration) by measuring CAPs across anastomoses of severed, sutured, and PEG-fused nerves. For example, nerve exposure to 50% (w / w) PEG for 20 minutes or longer may show detrimental effects. The device can be designed to minimize the impact on the nerves during device placement, PEG administration, and device removal.

[0010] Other applications of the PEG fusion method and delivery device may include repairing damaged spinal nerves; implanting peripheral nerve segments into traumatized resected segments, including allogeneic, autologous, and xenografts; and any other suitable applications.

[0011] This document discloses a neurotherapy device for forming a fluid containment field around at least a portion of an isolation segment of a nerve. The neurotherapy device includes an elongated body and a containment chamber formed within the elongated body. The elongated body extends from a first end wall to a second end wall substantially opposite the first end wall. The elongated body has a top surface and a longitudinal axis extending from the first end wall to the second end wall. The containment chamber extends from the first end wall to the second end wall and has a void volume intersecting the top surface to form an entry area. The entry area is configured to receive the isolation segment of the nerve into the containment chamber, and the containment chamber is configured to substantially maintain a volume of fluid within the void volume surrounding at least a portion of the isolation segment of the nerve. The first end wall includes a first orifice leading to the containment chamber, and the second end wall includes a second orifice leading to the containment chamber. The first orifice and the second orifice are configured to hold a first end and a second end of the isolation segment of the nerve, respectively, and are configured to form a fluid seal around the first end and the second end of the isolation segment of the nerve, respectively. The first end wall includes a first slit extending from the top surface through the first end wall to the first aperture, and the second end wall includes a second slit extending from the top surface through the second end wall to the second aperture. At least a portion of the first end wall is flexible and configured to be biased in a manner that increases the width between opposing edges of the first slit, such that the nerve can be received into the first aperture through the first slit. At least a portion of the second end wall is flexible and configured to be biased in a manner that increases the width between opposing edges of the second slit, such that the nerve can be received into the second aperture through the second slit.

[0012] The flexible portion of the first end wall may include a first flange, the thickness of which gradually decreases in the distal direction. The distal edge of the first flange may be defined by the first slit. The flexible portion of the first end wall may include a second flange, the thickness of which gradually decreases in the distal direction. The distal edge of the second flange may be defined by the first slit, such that the distal edges of the first flange and the distal edges of the second flange form opposing edges of the first slit. The first hole and the second hole may be located in the first end wall and the second end wall, such that the bottom of the first hole and the bottom of the second hole, opposite to the top surface, rise above the bottom plate of the receiving chamber. The receiving chamber may have an inclined surface and / or a curved surface connecting the bottom of the first hole and the bottom of the second hole to the bottom plate of the receiving chamber. The inclined surface and / or the curved surface may be configured to help support the weight of the isolating segment of the nerve.

[0013] The receiving chamber can be configured to retain the volume of the fluid such that the fluid completely surrounds the circumference of the nerve along at least a portion of the isolated segment of the nerve. The width of the entry area can be greater than the width of the first orifice and greater than the width of the second orifice. The first and second orifices can be circular. The first and second orifices can have diameters slightly smaller than the diameter of the nerve in an unbiased configuration, such that the first and second orifices are configured to form a compression seal around the nerve when received within the first and second orifices. The first and second orifices can be longitudinally aligned.

[0014] The bottom surface of the elongated body is typically circular. At least a portion of the bottom surface of the elongated body may be flat, allowing the device to be stably held on a flat surface. The first end wall may have a profile shape corresponding to a portion of an elongated oval. The depth of the receiving chamber may increase between the front and rear ends of the receiving chamber. The front and rear ends may extend from the first end wall to the second end wall. The bottom plate of the receiving chamber may be uneven. The elongated body and the end walls may be integrally formed from the same material. The elongated body may contain silicone. The silicone may include medical-grade polydimethylsiloxane (PDMS).

[0015] The neurotherapy device may include a handle extending laterally from the elongated body. The handle may extend from the rear side of the device between the first end wall and the second end wall. The handle may have an elongated body. The handle may have a textured surface. The handle may have a top surface flush with the top surface of the elongated body. The handle may extend horizontally in a rearward direction. The handle may bend or angled in an upward direction and / or a downward direction. The handle may have a proximal end connected to the elongated body and a distal end opposite to the proximal end. The distal end may be located above or below the top surface of the elongated body. The handle may include a curved portion with an inflection point.

[0016] The first slit can bisect the first hole, and the second slit can bisect the second hole. The first hole and the second hole can be horizontally centered within the first end wall and the second end wall, respectively, between the front and rear ends of the elongated body.

[0017] The first and second holes can be horizontally positioned further towards the front end of the elongated body. The first slit separates the inner front surface of the receiving chamber from the inner surface of the first end wall, and the second slit separates the inner front surface of the receiving chamber from the inner surface of the second end wall, such that the front wall of the elongated body formed between the first and second slits is configured to be offset in the forward direction in a manner that increases the first and second widths. The first slit may intersect the front edge of the first hole, and the second slit may intersect the front edge of the second hole. The front wall of the elongated body may have an angled edge on the top surface that slopes downward toward the receiving chamber.

[0018] The neurotherapy device may include a closed fluid channel formed within the elongated body. The fluid channel may have a first opening engaging with the receiving chamber and a second opening on the outer surface of the device not engaging with the receiving chamber. Fluid may be introduced into and / or removed from the receiving chamber via the fluid channel. The second opening may be formed on a fluid port extending from the elongated body. The fluid port may include a Luer interface connector configured for connection to a syringe. The fluid port may extend from the distal end of a handle extending from the elongated body. The neurotherapy device may include a second closed fluid channel formed within the elongated body, the fluid channel having a third opening engaging with the receiving chamber and a fourth opening on the outer surface of the device not engaging with the receiving chamber. Fluid may be introduced into and / or removed from the receiving chamber via the second fluid channel.

[0019] In another aspect of this disclosure, a neurotherapy device is disclosed for forming a fluid containment field around at least a portion of an isolating segment of a nerve. The neurotherapy device has an elongated body and a containment chamber formed within the elongated body. The elongated body extends from a first end wall to a second end wall substantially opposite the first end wall. The elongated body includes a lower body and an upper body and has a longitudinal axis extending from the first end wall to the second end wall. The containment chamber extends from the first end wall to the second end wall. The containment chamber is configured to substantially maintain a volume of fluid within a void volume surrounding at least a portion of the isolating segment of the nerve. The first end wall includes a first orifice leading to the containment chamber, and the second end wall includes a second orifice leading to the containment chamber. The first orifice and the second orifice are configured to hold a first end and a second end of the isolating segment of the nerve, respectively, and are configured to form a fluid seal around the first end and the second end of the isolating segment of the nerve, respectively. The lower body and the upper body can be at least partially separated by a slit extending the length of the elongated body. The slit extends inwardly from the front side of the elongated body to the first and second holes. The slit defines the top and bottom surfaces of the lower body. The separation distance between the lower and upper bodies can increase along the slit, such that the elongated body is configured to receive the nerve through the slit and enter the first and second holes. The lower and upper bodies are configured to substantially surround the entire circumference of the nerve in a closed configuration.

[0020] The lower body and the upper body are connected together at the rear of the elongated body. The lower body and the upper body are connected by a flexible hinge. The flexible hinge can be a movable hinge. The lower body and the upper body are integral at the rear of the elongated body. The elongated body may have a generally tubular body with sidewalls comprising a defining circumference. The slit may extend along the front side through the sidewall, the circumference being openable along the length of the slit, and the sidewall being uninterrupted along the rear side. The slit does not extend behind the first or second hole. The upper body and the lower body may be completely separable. The void volume of the receiving chamber may be formed in the lower body and the upper body. The void volume of the receiving chamber may be entirely formed in the lower body, and the upper body may be configured to seal an entry area formed on the top surface of the lower body, the entry area leading to the void volume.

[0021] The first end wall may be flat. At least a portion of the first end wall may have a frustoconical shape, wherein the first hole forms the apex of the frustoconical shape. The first end wall may include sidewalls, the thickness of which decreases as the sidewalls extend toward the apex of the frustoconical shape.

[0022] The lower body may include a first locking feature, and the upper body may have a second locking feature configured to engage the first locking feature in a closed configuration to lock the lower body and the upper body together. The first and second locking features may include ridges and grooves configured to mate together to form an interference fit. The neurotherapy device may include a lower lip and an upper lip, with the slit extending between the lower lip and the upper lip. The lower lip and the upper lip may be configured to receive a fixation mechanism to retain the lower body and the upper body in a closed configuration. The lower lip and / or the upper lip may include grooves extending along at least a portion of the length of the lip to retain the fixation mechanism.

[0023] The elongated body may have a generally cylindrical shape. The receiving chamber may include an inclined surface and / or a curved surface connecting the bottoms of the first and second holes to the base plate of the receiving chamber. The inclined surface and / or curved surface may be configured to help support the weight of the isolating segment of the nerve. The receiving chamber may be configured to retain the volume of fluid such that the fluid completely surrounds the circumference of the nerve along at least a portion of the isolating segment. The width of the entry area may be greater than the width of the first hole and greater than the width of the second hole. The first and second holes may be circular. The first and second holes may have diameters slightly smaller than the diameter of the nerve in an unbiased configuration such that the first and second holes are configured to form a compression seal around the nerve when received within the first and second holes. The first and second holes may be longitudinally aligned. The first and second holes are horizontally centered within the first and second end walls, respectively, between the front and rear ends of the elongated body.

[0024] At least a portion of the bottom surface of the elongated body may be flat, allowing the device to be stably held on a flat surface. The depth of the receiving chamber may increase between the front and rear ends of the receiving chamber, the front and rear ends extending from the first end wall to the second end wall. The bottom plate of the receiving chamber may be uneven. The elongated body and the end walls may be integrally made of the same material. The elongated body may contain silicone. The silicone may include medical-grade polydimethylsiloxane (PDMS).

[0025] The neurotherapy device may include a handle extending laterally from the elongated body. The handle may extend from the rear side of the device between the first end wall and the second end wall. The handle may have an elongated body. The handle may have a textured surface. The handle may have a top surface flush with the top surface of the elongated body. The handle may extend horizontally in a rearward direction. The handle may bend or angled in an upward and / or downward direction. The handle may have a proximal end connected to the elongated body and a distal end opposite to the proximal end. The distal end may be located above or below the top surface of the elongated body. The handle may include a bend with an inflection point. The upper body may be indirectly connected to the handle via a connecting arm. The connecting arm can be operated to move the lower body and the upper body between a closed configuration and an open configuration.

[0026] The neurotherapy device may include a closed fluid channel formed within the elongated body. The fluid channel may have a first opening engaging with the receiving chamber and a second opening on the outer surface of the device not engaging with the receiving chamber. Fluid may be introduced into and / or removed from the receiving chamber via the fluid channel. The second opening may be formed on a fluid port extending from the elongated body. The fluid port may include a Luer interface connector configured for connection to a syringe. The fluid port may extend from the distal end of a handle extending from the elongated body. The neurotherapy device may include a second closed fluid channel formed within the elongated body, the fluid channel having a third opening engaging with the receiving chamber and a fourth opening on the outer surface of the device not engaging with the receiving chamber. Fluid may be introduced into and / or removed from the receiving chamber via the second fluid channel.

[0027] In another aspect of this disclosure, a neurotherapy device is disclosed for forming a fluid containment field around at least a portion of an isolated segment of a nerve. The neurotherapy device has an elongated body and a containment chamber formed within the elongated body. The elongated body extends from a first end wall to a second end wall substantially opposite the first end wall. The elongated body has a top surface and a longitudinal axis extending from the first end wall to the second end wall. The containment chamber extends from the first end wall to the second end wall. The containment chamber has a void volume intersecting the top surface to form an entry area. The entry area is configured to receive the isolated segment of the nerve into the containment chamber. The containment chamber is configured to substantially retain a volume of fluid within the void volume surrounding at least a portion of the isolated segment of the nerve. The first end wall includes a first slot extending downward from the top surface, the first slot being configured to receive and retain a first end of the isolated segment of the nerve, and the second end wall includes a second slot extending downward from the top surface, the second slot being configured to receive and retain a second end of the isolated segment of the nerve. The first slot and the second slot are configured to form a fluid seal around at least the bottom portion of the isolation segment of the nerve.

[0028] The first end wall may be formed by the edge of a side wall that forms the front, rear, and bottom sides of the elongated body, such that no part of the end wall forms the inner surface of the receiving chamber. The width of the receiving chamber transverse to the longitudinal axis may vary continuously over the entire length of the receiving chamber. The receiving chamber may have a maximum width between the first and second end walls. The depth of the receiving chamber may vary continuously over the entire length of the receiving chamber. The receiving chamber may have a maximum depth between the first and second end walls. The depth of the receiving chamber may vary continuously over the entire width of the receiving chamber. The receiving chamber may have a maximum depth between the front and rear sides of the receiving chamber. The bottom plate of the receiving chamber does not include a flat surface. The width of the elongated body transverse to the longitudinal axis may vary continuously over the entire length of the elongated body. The elongated body may have a maximum width between the first and second end walls.

[0029] In another aspect of this disclosure, a neurotherapy device is disclosed for forming a fluid containment field around at least a portion of an isolating segment of a nerve. The neurotherapy device has an elongated body and a containment chamber formed within the elongated body. The elongated body extends from a first end wall to a second end wall substantially opposite the first end wall. The elongated body has a top surface and a longitudinal axis extending from the first end wall to the second end wall. The containment chamber extends from the first end wall to the second end wall. The containment chamber has a void volume intersecting the top surface to form an entry region. The entry region is configured to receive the isolating segment of the nerve into the containment chamber, and the containment chamber is configured to substantially maintain a volume of fluid within the void volume surrounding at least a portion of the isolating segment of the nerve. The first end wall includes a first slit extending downward through the first end wall from the top surface, and the second end wall includes a second slit extending downward through the second end wall from the top surface. At least a portion of the first end wall is flexible and configured to be biased in a manner that increases the width between opposing edges of the first slit, such that the nerve can be received through the first slit. At least a portion of the second end wall is flexible and is configured to be biased in a manner that increases the second width between the opposite edges of the second slit, such that the nerve can be received through the second slit.

[0030] The first slit may extend to the bottom of the portion of the receiving chamber adjacent to the first end wall. The first slit may bisect the first end wall. A flexible portion of the first end wall may include a first flange, the thickness of which gradually decreases in the distal direction of the first flange. The distal edge of the first flange may be defined by the first slit. The flexible portion of the first end wall may include a second flange, the thickness of which gradually decreases in the distal direction of the second flange. The distal edge of the second flange may be defined by the first slit such that the distal edges of the first flange and the distal edges of the second flange form opposing edges of the first slit. The first slit may extend along at least a portion of the intersection between the first end wall and the bottom of the receiving chamber adjacent to the first end wall.

[0031] In another aspect of this disclosure, a neurotherapy device is disclosed for forming a fluid containment field around at least a portion of an isolating segment of a nerve. The neurotherapy device has an elongated body extending from a first end wall to a second end wall substantially opposite the first end wall. The elongated body has a lower body and an upper body, and a longitudinal axis extending from the first end wall to the second end wall. The neurotherapy device includes a containment chamber formed within the lower body and extending from the first end wall to the second end wall. The containment chamber has a void volume intersecting the top surface of the lower body to form an entry area. The entry area is configured to receive the isolating segment of the nerve into the containment chamber, and the containment chamber is configured to substantially maintain a volume of fluid within the void volume surrounding at least a portion of the isolating segment of the nerve. The first end wall includes a first orifice leading to the containment chamber, and the second end wall includes a second orifice leading to the containment chamber. The first orifice and the second orifice are configured to hold a first end and a second end of the isolating segment of the nerve, respectively, and are configured to form a fluid seal around the bottom of the first end and the bottom of the second end, respectively. The upper body is configured to be received within the receiving chamber to form a fluid seal with the upper part of the receiving chamber, such that the entire entry area of ​​the top surface is closed. The lower body and the upper body are configured to substantially surround the entire circumference of the nerve in a closed configuration.

[0032] When the device is in an open configuration with the receiving chamber unsealed, the lower body can be connected to the upper body. The lower body can be connected to the upper body via a hinge. The hinge can be a movable hinge. The upper body may include a first downward extension configured to receive within a first hole above a first end of the nerve. The first extension may be configured to seal the first hole around the top of the first end of the nerve. The first extension may form an inner surface of the receiving chamber. The first extension may have a concave bottom edge configured to conform to the shape of the nerve.

[0033] The receiving chamber may include a plurality of support ribs extending vertically along the depth of the receiving chamber. Two support ribs may be disposed opposite each other on the front inner surface and the rear inner surface of the receiving chamber. The support ribs may be spaced apart to support the isolating segment of the nerve on the floor of the receiving chamber.

[0034] In another aspect of the invention, a delivery device for performing a nerve repair procedure is disclosed. The delivery device has an elongated body extending from a first end to a second end and a longitudinal axis. The delivery device includes a receiving chamber within the elongated body for receiving a reconnected nerve. The receiving chamber has a first opening at the first end of the elongated body, a second opening at the second end of the elongated body, and an elongated opening extending parallel to the longitudinal axis from the first opening to the second opening for introducing the reconnected nerve into the receiving chamber. The delivery device includes a port in fluid communication with the receiving chamber and configured to connect to a syringe for injecting a solution into the receiving chamber. The delivery device includes a handle extending from the elongated body configured to facilitate placement of the delivery device around the nerve.

[0035] In another aspect of the invention, a method for repairing severed nerves is disclosed herein. The method includes physically reconnecting the severed nerve to restore axon-to-axon contact; positioning a delivery device around the reconnected nerve; and inducing fusion of the severed axons within the reconnected nerve by introducing a fusion solution into a receiving chamber of the delivery device and incubating the reconnected nerve in the fusion solution. The delivery device has an elongated body and a receiving chamber formed within the elongated body. The elongated body extends from a first end to a second end of the delivery device and has a longitudinal axis. The receiving chamber is configured to receive the reconnected nerve. The receiving chamber has a first opening at the first end of the elongated body, a second opening at the second end of the elongated body, and an elongated opening extending parallel to the longitudinal axis from the first opening to the second opening for introducing the reconnected nerve into the receiving chamber. Positioning the delivery device around the reconnected nerve includes introducing the reconnected nerve into the receiving chamber through the longitudinal opening.

[0036] The method may include, before physically reconnecting the severed nerve, placing the severed axonal ends in a Ca-free environment. 2+ The solution is rinsed or incubated in a pre-filled solution containing a salt solution. The pre-filled solution may include methylene blue, and in some embodiments, the methylene blue may be approximately 1% (w / v). The method may include rinsing or incubating with a solution containing Ca. 2+ The reconnected nerves are flushed or incubated with a sealing solution of salt to seal any remaining membrane discontinuities in the fused axonal membrane. Flushing or incubating the reconnected nerves with the sealing solution can be performed inside and / or outside the containment chamber. The sealing solution may contain calcium chloride (CaCl2), and in some embodiments, the calcium chloride may be approximately 0.02% (w / v).

[0037] Physically reconnecting the severed nerve may include suturing the proximal and distal ends of the severed nerve together. Physical reconnection of the severed nerve may be performed in the presence of the pre-filled solution.

[0038] The method may include removing the fusion solution from the containment chamber by aspiration. The method may also include removing the delivery device from around the nerve. The fusion solution may contain low molecular weight polyethylene glycol (PEG). The concentration of PEG may not exceed approximately 50% (w / w). The concentration of PEG may be approximately 50% (w / w). The PEG may be a low molecular weight PEG with an average molecular weight not exceeding 5,000 Da or 3,500 Da. The average molecular weight of PEG may be approximately 3,350 Da.

[0039] The method may include rinsing or incubating the anastomosis of the reconnected nerve in the pre-filling solution prior to fusion of the axon. The rinsing or incubation of the reconnected nerve in the pre-filling solution may be performed after the delivery device is placed around the reconnected nerve.

[0040] The delivery device may include a port in fluid communication with the containment chamber. Introducing the fusion solution may include introducing the fusion into the containment chamber through the port. The port may be configured to connect to a syringe for injecting the solution into the containment chamber.

[0041] The nerve may be exposed to the fusion solution for no more than 2 minutes. The nerve may be exposed to the pre-filled solution for no more than 2 minutes. The nerve may be exposed to the sealing solution for no more than 2 minutes.

[0042] In another aspect of the invention, a method for repairing severed nerves is disclosed herein. The method includes using a hypotonic, Ca2+-free solution containing 1% (w / v) methylene blue. 2+The severed axon ends are rinsed in a pre-filled saline solution, and the severed nerve is physically reconnected in the presence of the pre-filled solution by suturing the proximal and distal ends of the severed nerve together to restore axon-to-axon contact. The method further includes placing a delivery device around the reconnected nerve. The delivery device has an elongated body extending from a first end to a second end and a longitudinal axis. The delivery device has a receiving chamber within the elongated body for receiving the reconnected nerve. The receiving chamber has a first opening at the first end of the elongated body, a second opening at the second end of the elongated body, and an elongated opening parallel to the longitudinal axis extending from the first opening to the second opening for introducing the reconnected nerve into the receiving chamber. Placing the delivery device around the reconnected nerve includes introducing the reconnected nerve into the receiving chamber through the longitudinal opening. The method further includes inducing fusion of the severed axon within the reconnected nerve by introducing a fusion solution into the receiving chamber and incubating the reconnected nerve in the fusion solution. The fusion solution contains approximately 50% (w / w) of low molecular weight PEG. The method further includes removing the fusion solution from the containment chamber by aspiration and removing the delivery device from around the nerve. The method also includes using a Ca-containing solution containing isotonicity. 2+ A salt-containing sealing solution is used to flush the reconnected nerves to seal any remaining membrane discontinuities in the fused axonal membrane.

[0043] In another aspect of the invention, a kit is disclosed herein comprising a neurotherapy device and one or more solutions from any of the solutions described above. Attached Figure Description

[0044] Figure 1 A perspective view of an example of a nerve therapy device is shown, which can be used to deliver a therapeutic solution to an isolated segment of a nerve for nerve repair. The device includes an open configuration and slits and orifices in opposing sidewalls configured to receive and retain the nerve.

[0045] Figure 2 Another example of a neurotherapy device is schematically shown, which has a separable lower body and an upper body, as well as a fluid flushing port.

[0046] Figures 3A-3E Several perspective views schematically illustrate another example of a treatment device comprising an integral upper body and a lower body separated by a slit for receiving nerves. Figure 3A A right cross-sectional view of the treatment device is depicted. Figure 3B A left cross-sectional view of the treatment device is depicted. Figure 3C A rear view of the treatment device is depicted. Figure 3D A front view of the treatment device is depicted. Figure 3E A perspective view of the treatment device is depicted.

[0047] Figures 4A-4D It schematically shows something similar to Figures 3A-3E Multiple perspective views of another example of the treatment device shown. Figure 4A A perspective view of the treatment device is depicted. Figure 4B A front view of the treatment device is depicted. Figure 4C Depicts Figure 4B Figure 4 shows a cross-sectional view of section AA. Figure 4D depicts a view of the left side of the treatment device.

[0048] Figures 5A-5C Several perspective views schematically illustrate another example of a treatment device having an open configuration and a slot configured to receive nerves. Figure 5A A perspective view of the treatment device is depicted. Figure 5B A top view of the treatment device is described. Figure 5C The left side view of the treatment device is depicted.

[0049] Figures 6A-6G Several perspective views schematically illustrate another example of a treatment device comprising a hinged upper body and a lower body as shown in an open configuration. Figure 6A A perspective view of the treatment device is depicted. Figure 6B A top view of the treatment device is depicted. Figure 6C A front view of the treatment device is depicted. Figure 6D Depicts Figure 6C The cross-sectional view of section BB shown. Figure 6E The right-side view of the treatment device is depicted. Figure 6F Depicts Figure 6E A close-up view of the embedded part A shown. Figure 6G Depicts Figure 6A A perspective view of a variant of the treatment device shown.

[0050] Figure 7 A perspective view depicting another example of a treatment device is shown, comprising an open configuration and a curved body having a variable width and an opening slot configured to receive nerves.

[0051] Figures 8A-8E Several perspective views schematically illustrate another example of a treatment device, which includes an open configuration and slits on opposing end walls configured to receive and retain nerves. Figure 8AA perspective view of the treatment device 800 is depicted. Figure 8B A top view of the treatment device is depicted. Figure 8C The left or right view of the treatment device is described. Figure 8D The front or rear view of the treatment device is described. Figure 8E Depicts Figure 8D The cross-sectional view of section AA shown.

[0052] Figure 9 A perspective view of another example of a treatment device is shown. The treatment device includes an upper body hinged to a lower body and configured to be inserted into a receiving chamber to fluid-tighten the chamber.

[0053] Figure 10 A perspective view shows another example of a treatment device. The treatment device is similar to... Figure 1 The treatment device shown is a long-handled spoon-shaped handle.

[0054] Figures 11A-11E It schematically shows something similar to Figure 1 Multiple perspective views of another example of the treatment device shown. The treatment device has opposing slits disposed along its intersection with the front wall to create a flanged end wall. Figure 11A A perspective view of the treatment device is depicted. Figure 11B A top view of the treatment device is depicted. Figure 11C The right-side view of the treatment device is depicted. Figure 11D A rear view is depicted, looking down from a portion of the handle of the treatment device. Figure 11E A cross-sectional view depicting a section taken along the midline transverse to the longitudinal axis between the left and right sides of the treatment device. Detailed Implementation

[0055] The apparatus, methods, and kits described herein are designed for the rapid repair and improvement of the recovery of injured peripheral nerves in acute surgical settings. In some embodiments, the kit for neurotherapy (e.g., peripheral nerve therapy) may include three sterile solutions and, optionally, a device for the local application of the solution to the lesion (directly to the affected nerve). When applied in the order specified in the instructions, the solutions may include a therapeutic addition for surgical repair of patients with acute peripheral nerve injury (PNI). The devices may be used independently of the kits and / or solutions and methods described herein for delivering other therapeutic agents to the nerve and / or for isolating the nerve for further therapeutic treatment. The solutions may be used independently of the devices and may be used to treat nerve injuries according to methods and / or sequences other than those described herein. The methods and / or sequences described herein may be used with variations of the solutions described herein and / or may be used independently of the devices described herein.

[0056] Components

[0057] equipment

[0058] The neurotherapy device can be used in a surgical setting to effectively isolate a segment of nerve for treatment. The device can be used to uniformly and accurately apply a PEG fusion solution to the isolated segment of the nerve at the nerve repair site (e.g., where nerves are sutured together to form an anastomosis). Therefore, the device can be a delivery device. The device can be included in a kit for nerve repair (e.g., a set of solutions such as those for nerve fusion described elsewhere herein) or can be provided as a stand-alone device. The device can allow for the reproducible application of PEG fusion protocols as described elsewhere herein.

[0059] The treatment device can be made of any suitable material, including polymers, plastics, and / or rubber. For example, the treatment device can be made of one or more silicones (e.g., polydimethylsiloxane (PDMS)) and / or plastics (e.g., polyether ether keytone (PEEK), polyurethane, polyethylene, polyolefins, polypropylene, polyether block amides, etc.). The materials used can be medical-grade plastics and / or silicones. In some embodiments, the device or a portion thereof can be transparent or partially transparent to allow visual examination of the treated nerve within the device. The device can be disposable (e.g., configured for single use) or reusable. The device can be sterilizable by conventional methods (e.g., ozone, UV, autoclaving, etc.). The device can be manufactured by any suitable method, such as injection molding or compression molding. In some embodiments, the device can be made as a single integral unit. In other embodiments, the device can include separately manufactured components that are subsequently joined together (e.g., bonded together, molded together, and / or mechanically secured together). In some embodiments, some components can be reversibly connectable / detachable. Some components may be reusable, while others may be disposable.

[0060] In different embodiments, the device or portions thereof may have a stiffness of approximately 20-40 D. The stiffness can be relatively low to prevent damage to the treated nerve. In some embodiments, the stiffness may vary in different portions of the device. For example, the portion of the device that physically contacts and / or holds the nerve may be softer than other portions of the device. In some embodiments, the stiffness of the device can be adjusted by varying the concentration of the polymer and / or crosslinking agent during manufacturing. In some embodiments, the concentration may be variable in different portions of the device to produce variable stiffness. The flexibility of the device in different portions may depend on a combination of the material stiffness and the size of the portion.

[0061] In various embodiments, the treatment device can be a solid, non-articular device that creates a temporary fluid-retaining field around the anastomosis between the proximal and distal ends of the nerve after suturing. The treatment device can be configured to prevent unnecessary exposure of surrounding tissue to the therapeutic agent (such as PEG solution) during drug administration to the nerve, thus enabling local drug delivery. In some embodiments, the treatment device can be configured not to perform any treatment and may only have the function of temporarily containing the therapeutic solution around the nerve. The treatment device can allow for controlled delivery and removal of a series of therapeutic solutions according to the order of administration. The treatment device may only contact the tissue (nerve) being treated. The device may be placed in contact with the treated tissue for only a short time (e.g., 1-10 minutes). The device may only be used as part of a surgical or treatment procedure. The device does not need to remain in the body. The device can be used to protect undamaged nerve segments and surrounding tissue from exposure to PEG during the fusion procedure. The device design provides ease of use and minimizes nerve interference before and after PEG fusion during surgical procedures.

[0062] Figure 1 A perspective view of an example of a neurotherapy device 100 is shown, which can be configured as a delivery device for delivering a therapeutic solution (e.g., a PEG fusion solution) to a nerve. Figure 1Examples of suitable, but non-limiting, dimensions (mm) for different portions of the treatment device 100 are provided. The treatment device 100 may typically include a body 102 having sidewalls 104. The sidewalls 104 may be integral throughout the body 102 or may include multiple components connected (e.g., attached) to each other. The sidewalls 104 may define a receiving chamber 106 having a void volume formed within the body 102. The receiving chamber 106 may be configured to enclose or partially enclose a length or segment of the nerve 50 (“enclosed” may be used herein to mean any degree of closure). For example, the receiving chamber may surround the nerve at approximately 180 degrees, 270 degrees, 360 degrees, or any degree within the range defined therein on the circumference. The receiving chamber 106 may be configured to contain a volume of solution (e.g., a treatment solution) surrounding or partially surrounding the enclosed segment of the nerve 50. The body 102 may be configured to surround or partially surround a segment of the nerve 50 and is configured to create a receiving chamber 106 with a sufficient or precise volume to contain the desired amount of solution. The body 102 and the receiving chamber 106 may include dimensions configured to surround a nerve 50 of a specific length and / or may be configured to surround a nerve 50 having a specific diameter. The shape, size, and / or material properties of the body 102 may be configured to stably surround the desired nerve length and size, while generally minimizing the external contour of the body 102 to facilitate easy insertion, removal, and / or manipulation of the device 100 within the body's internal space. For example, the body 102 may be configured to help separate the target segment of the nerve 50 from the surrounding connective tissue. In some embodiments, a user (e.g., a physician) may select from a variety of sizes of the device 100 depending on the specific nerve to be treated. In some embodiments, the kit may provide multiple devices 100 from which to select those of different sizes and / or those specified for treating a specific nerve.

[0063] The body 102 typically includes a left end wall 108, a right end wall 110, and an intermediate body 112 extending between the left end wall 108 and the right end wall 110. The body 102 may define a longitudinal axis extending from the left end wall 108 to the right end wall 110, typically along the direction in which the nerve 50 to be treated is to be aligned. The body 102 may include a lower body 114 having a top surface 116. The top surface 116 includes an access area 118 through which a segment or at least a portion of the nerve 50 may be received into a receiving chamber 106. The access area 118 may include a width transverse to the longitudinal axis and a length parallel to the longitudinal axis. The width and / or length of the receiving chamber 106 may be maximized or maximized at the access area 124, such that the width and / or length remain constant and / or decrease as the depth of the receiving chamber 106 increases downward from the access area 124. In some embodiments, for example in… Figure 1In the illustrated embodiment, the body 102 can be configured as an open bath in which the treatment device 100 is configured to be used such that the lower body 114 is substantially oriented, thereby causing the top surface 116 to face upwards, and gravity substantially holds the solution within the containment chamber. The containment chamber 106 can be configured such that the segment of the nerve 50 can be completely disposed within the void volume of the containment chamber 106 (e.g., the segment can be completely immersed in the solution), or the segment can be configured to be disposed only partially within the containment chamber 106 such that the top of the nerve 50 extends upwards beyond the top surface 116. The volume within the containment chamber 106 can be configured to immerse the segment of the nerve 50 without filling the top surface 116. The open bath configuration may be particularly advantageous for easy placement and removal of the nerve 50 from the treatment device.

[0064] In other embodiments, body 102 may be configured as a closed bath, as described elsewhere herein, comprising a lower body 114 and an upper body 120. The lower body 114 and upper body 120 may cooperate to form a receiving chamber 106 that substantially surrounds the entire circumference of the segment of nerve 50. In some embodiments, the closed bath may be oriented in any direction during use (e.g., the lower body 114 may be partially or completely oriented above the upper body 120). The lower body 114 and upper body 120 may form a fluid seal that retains the solution within the receiving chamber 106.

[0065] like Figure 1 As shown, the left end wall 108 and / or right end wall 110 of the body 102 may include a substantially flat outer surface. The left end wall 108 and right end wall 110 may each include an aperture 126 extending from the outer surface of the body 102 through the side wall 104 to the inner surface of the body 102, defining a receiving chamber 106. The aperture 126 may include a generally circular cross-section or cross-section of any suitable shape. The aperture 126 may be configured to receive a nerve 50 into the receiving chamber 106. In some embodiments, the aperture 126 may be disposed within the side wall 104 such that the circumference or periphery of the aperture 126 does not intersect with the top surface 116. The left end wall 108 and right end wall 110 may each include a slit 128 extending from the circumference of the aperture 126 to the top surface 116. The slit 128 may extend in a substantially vertical direction. The slit 128 may allow the sidewalls 104 of the body 102 to be offset from each other (e.g., bent apart) along opposite sides of the slit 128 so that the nerve 50 can be received from the top surface 116 through the slit 128 and into the aperture 126.

[0066] In some embodiments, the sidewall 104 may include a tapered or reduced thickness toward the slit 128. For example, as Figure 1As shown, the thickness of the sidewall 104 may decrease as it extends from the front side of the intermediate body 112 to the slit 128, and / or the thickness of the sidewall 104 may decrease as it extends from the rear side of the intermediate body 112 to the slit 128, wherein both the front and rear sides of the slit 128 include portions of the sidewall 104 with tapered diameters. The end walls 108, 110 of the receiving chamber 106 may be designed with clustered blades or flanges 130 that allow placement of nerves of a range of diameters within the device. One or more flanges 130 may be formed by the sidewall 104. The flanges 130 may be configured to bend inward toward the receiving chamber 106 and / or outward away from the receiving chamber 106. Each flange 130 may have a distal edge forming the edge of the slit 130 and may have a proximal end near where the sidewall 104 begins to bend. When present, the taper may be constant, forming as... Figure 1 The flange 130 shown is essentially triangular, or may be higher near the proximal end. In some embodiments, the sidewall 104 may be shaped as a flexible hinge (not shown) at the proximal end of the flange 130, such as a divot formed in the sidewall 104, which facilitates bending of the flange 130. The flange 130 may have a constant diameter or a decreasing diameter at the distal end of the hinge. In some embodiments, the flange 130 may be configured to bend only in one direction or be more easily bent in one direction than in the opposite direction. For example, the flange 130 may be configured to bend inward toward the receiving chamber 106, but may be configured not to bend or less inclined to bend outward away from the receiving chamber 106.

[0067] In some embodiments, the hole 126 can serve as a hinge, and a portion of the body 102 on the first side (e.g., the front) of the hinge can be configured to bend away from a portion of the body 102 on the second opposite side (e.g., the rear) of the hinge. For example, relative to Figure 1 The front portion can bend away from the rear portion, such that the width of the slit 130 increases to a maximum where it intersects with the top surface 116 and to a minimum where it intersects with the hole 126. Strain can be distributed across the entire sidewall 104, but can be concentrated along the bottom of the body 102, substantially opposite the top surface 116. In some embodiments, the body 102 can be configured to bend in one or more directions, including any of the movements described herein.

[0068] The slit 128 may include opposing edges (e.g., a front edge and a rear edge) through which the nerve 50 is configured when the opposing edges are offset apart. The distal edges of opposing flanges 130 may form opposing edges of the slit 128. In some embodiments, the opposing edges of the slit 128 may contact or touch each other in an unbiased configuration, such that the slit 128 has a width of approximately 0 mm in the unbiased configuration. In some embodiments, the width of the slit 128 between opposing edges may not exceed approximately 0.01 mm, 0.02 mm, 0.03 mm, 0.04 mm, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.5 mm, 2.0 mm, or 3.0 mm. The width of slit 128 can be sized such that the surface tension of the solution contained within the containment chamber 106 prevents leakage of the solution through slit 128 in a non-biased configuration, or minimizes and / or negligibles leakage. In some embodiments, the opposing edges of slit 128 may overlap in a non-biased configuration. For example, the rear flange 130 may be located inside the front flange 130, and vice versa. The edges may overlap by at least about 0.01 mm, 0.02 mm, 0.03 mm, 0.04 mm, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.5 mm, 2.0 mm, or 3.0 mm. This overlap can prevent or inhibit fluid leakage from the containment chamber 106. The slit 130 may include a length of at least about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.25 mm, 1.5 mm, 1.75 mm, 2.0 mm, 2.5 mm, or 3.0 mm.

[0069] In some embodiments, a user may use tools (e.g., forceps, clamps, or other surgical instruments) and / or fingers to insert the target segment of nerve 50 into treatment device 100 (insertion port 126) to bias the opposing edges of slit 128 in a manner as described elsewhere herein. In some embodiments, slit 128 may be sufficiently biased to create a gap or space that allows nerve 50 to be received through slit 128 without contact with or only with the edges of slit 128, thereby preventing the edges from exerting any significant frictional or other forces on nerve 50 during insertion. In some embodiments, body 102 may be sufficiently soft and flexible, particularly along the edges of slit 130, such that applying force to slit 130 through contact with nerve 50 biases or facilitates the biasing separation of the edges without damaging or harming the nerve, and / or releasing or interfering with anastomoses in nerve 50. During insertion, nerve 50 may be grasped using tools (e.g., forceps, clamps, or other surgical instruments) and / or fingers. In some embodiments, the nerves 50 can be inserted into the left and right holes 126 in any order. In some embodiments, the nerves 50 can be inserted into the left and right holes 126 substantially simultaneously. In various embodiments, such as Figure 1 In the illustrated device 100, the treatment device 100 can be designed to eliminate the need for any articulation components. The absence or minimization of articulation components avoids any area during surgery where nerves or other sensitive tissues may become trapped between parts, potentially causing injury or damage to the tissue. The use of a flexible body 102 (e.g., made of low-hardness silicone) can advantageously provide dynamic characteristics to the treatment device 100 without requiring articulations.

[0070] The aperture 126 may include a diameter approximately equal to the diameter of the target nerve 50. The aperture 126 may be configured to form a fluid seal around the circumference of the nerve 50. In some embodiments, the diameter of the aperture 126 may be slightly smaller than the diameter of the nerve 50. For example, the diameter may be at least approximately 90%, 95%, 96%, 97%, 98%, or 99% of the nerve diameter. At least the sidewalls 104 surrounding the aperture 126 may be sufficiently compliant such that the aperture 126 is configured to accommodate a slightly larger nerve 50. Biasing the opposing edges of the separating slit 130 may increase the effective diameter of the aperture 126. In some embodiments, the flange 130 may be biased inward or outward to increase the effective diameter of the aperture 126. In some embodiments, the aperture 126, or a portion thereof (e.g., the portion adjacent to the slit 128), may be disposed on the flexible flange 130, thereby allowing for a greater expansion of the diameter of the aperture 126. The body 102 can be sufficiently soft and flexible such that the orifice 126 does not apply sufficiently high pressure to the nerve 50 to damage or harm the nerve 50, or loosen or interfere with the anastomosis within the nerve 50. The flange 130 can be configured to apply a mild compressive pressure to the nerve 50 to form a compressible fluid seal around the circumferential portion of the nerve 50. In some embodiments, the diameter of the orifice 126 can be slightly larger than the diameter of the target nerve 50. For example, the diameter can be no larger than approximately 101%, 102%, 103%, 104%, 105%, or 110% of the target nerve diameter. The surface tension of the solution contained within the receiving chamber 106 can prevent, or prohibit, minimize, and / or make negligible leakage of the solution through the orifice 126 in an unbiased configuration.

[0071] In some embodiments, the nerve diameter can range from 1-4 mm, 4-8 mm, 8-12 mm, or overlapping ranges or between these ranges. The treatment device 100 can be manufactured in several different sizes to accommodate different nerve diameter ranges. The treatment device 100 can be applied to any suitable nerve. For example, the treatment device 100 can be applied to a digital nerve (approximately 1-2 mm). In another example, the device can be applied to the median nerve at the wrist (approximately 5-7 mm).

[0072] In some embodiments, the body 102 or even the entire treatment device 100 may be symmetrical about the midline separating the left and right halves of the body 102 or device 100. In some embodiments, the left end wall 108 may be a mirror image of the right end wall 110. For example, the aperture 126 may be aligned along the longitudinal axis of the device 100. Extending from the left end wall 108 to the right end wall 110, the nerve 50 may be placed in the aperture 126, and the distribution of the void volume of the receiving chamber 106 surrounding the segment of the nerve 50 is uniform as the nerve 50 extends from the left end wall 108 to the right end wall 110. The slit 128 may be aligned along the longitudinal axis of the device 100. In some embodiments, the aperture 126 may not exert any significant tension on the nerve 50, such that the nerve 50 can move freely (e.g., translate and / or rotate in the left or right direction) when positioned within the aperture 126. The aperture 126 typically retains the isolated segment of the nerve 50 within the receiving chamber 106. In some embodiments, the orifice 126 may be configured in a non-biased configuration to apply a nominal amount of tension to the segment of the nerve 50 located within the receiving chamber 106. The tension may be large enough to hold or fix the nerve 50 within the treatment device 100. For example, the tension may be configured to prevent or inhibit the nerve 50 from sliding to the right or left through the orifice 126 of the device. The tension may be configured to remove any relaxation from the segment of the nerve 50 disposed within the receiving chamber 106. The tension may prevent the nerve 50 from rotating freely within the orifice 126.

[0073] In some embodiments, the treatment device 100 may be configured to place the nerve 50 within a receiving chamber 106 such that the nerve 50 is suspended between right and left orifices 126, and the contained solution may fill a portion of the void volume between the bottom surface of the receiving chamber 106 and the isolating segment of the nerve 50. In some embodiments, the contained solution may fill to a certain level within the receiving chamber 106 such that it surrounds the entire circumference of the isolating segment of the nerve 50 between the left and right orifices 126. In other embodiments, the orifices 126 may be located in the sidewalls 104 of the left and right end walls 108, 110 such that a portion of the edge or circumference of the orifice 126 is coplanar with a portion of the surface of the receiving chamber 106. In such embodiments, the isolating segment of the nerve 50 may be placed against the surface of the receiving chamber 106 (e.g., along the bottom surface of the receiving chamber 106) along the length of the intermediate body 112. In such embodiments, the body 102 may be used to support the weight of the nerve 50 between the right and left orifices 126, which may allow the body 102 to be configured to apply a small frictional force to the nerve 50 via the orifices 126. In some embodiments, the contained solution may or may not wet the surface of the nerve 50 disposed against the inner surface of the receiving chamber 106.

[0074] In some embodiments, the orifice 126 may be positioned above the bottom surface or base plate of the receiving chamber 106 (near the top surface 116) such that the lowest point of the orifice 126 is higher than the lowest point of the base plate. The inner base plate of the receiving chamber 106 may be sloped or curved so that the nerve 50 is not subjected to tension when placed in the treatment device 100. The base plate may rise to meet the orifice 126 such that the nerve 50 is positioned in a curved direction (e.g., a subtle U-shape) when resting against the base plate of the receiving chamber 106. A variable-depth base plate may fully support the isolation segment of the nerve 50 along the length of the intermediate body 112, but may be configured to position the intermediate portion of the nerve 50 (e.g., the anastomosis) in the lower part of the receiving chamber 106. The variable depth may allow the contained solution to cover, submerge, and / or concentrate more near the intermediate portion, while keeping the contained solution away from the orifice 126 and / or slit 128 or minimizing the amount of solution positioned adjacent to the orifice 126 and / or slit 128. Such a configuration may allow the orifice 126 and / or slit 128 to include larger dimensions, applying less friction, tension, or other forces to the nerve 50, since fluid containment may not be an issue. In some embodiments, the intermediate body 112 and / or the inner chamber 106 may include a length along the longitudinal axis that is at least about 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm.

[0075] In some embodiments, the body 102 may include a cross-sectional profile transverse to the longitudinal axis, having a circular, semi-circular, circular, rectangular, square, or polygonal shape or any other suitable shape. In some embodiments, such as Figure 1 As shown, the shape can be partially field-shaped or elongated oval. In some embodiments, the outer periphery of the cross-section can substantially match the shape of the inner periphery, defining the receiving chamber 106. The sidewalls 104 can have a substantially uniform thickness at least along the length of the intermediate body 112. The cross-sectional shape of the receiving chamber 106 can be configured to minimize the ratio of the surface area to the volume of the receiving chamber. In some embodiments, the bottom surface or base plate of the receiving chamber can be circular along the transverse axis. The base plate can slope downward or deepen toward the center in the transverse direction, which may help to accommodate the isolating segment of the nerve 50 and / or can at least partially support the nerve 50 to provide additional support. The outline of the outer surface of the body 102 can generally be rounded or have rounded edges to allow the treatment device 100 to engage with the body tissue relatively non-invasively. In some embodiments, the outer bottom surface of the body 102 can be flat or have a flat surface to provide stability. For example, a flat surface can allow the body to be stably held on another flat surface. In some embodiments, the body 102 can be symmetrical with respect to a midline extending between the front and rear portions of the body 102.

[0076] In various embodiments, the treatment device 100 may include a handle 132 for operating and / or placing the device 100. The handle 132 may extend from the body 102. In some embodiments, such as Figure 1 As shown, a handle 132 can extend from the intermediate body 112. The handle 132 can bisect the body 102. The handle 132 may include a generally elongated body having a proximal end and a distal end. The proximal end of the handle 132 may be attached to or integral with the body 102. Figure 1 As shown, the distal end of the handle 132 may be vertically aligned with the proximal end, or, as described elsewhere herein, may be located above or below the proximal end. Figure 1 As shown, the distal end of the handle 132 may be horizontally aligned with the proximal end, or located to the left or right of the proximal end. The length of the elongated body of the handle 132 may be transverse to the longitudinal axis of the body 102. The top surface of the handle 132 may be flush with the top surface 116 of the body. In some embodiments, the length of the handle may be at least about 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, or 30 mm. The handle 132 may be designed for grasping with standard forceps, tweezers, or other surgical instruments. In some embodiments, the handle 132 is configured to be grasped by the user's fingers and / or hand. In some embodiments, the handle 132 includes a textured surface that facilitates gripping. The surface of the handle 132 may be textured on any one or more of its surfaces (e.g., top, bottom, left, right). For example, the handle 132 may include a textured surface such as... Figure 1 The ridges, grooves, protrusions, knurled surfaces, etc., shown are illustrated. In some embodiments, the handle 132 may include indentations or recesses specifically configured to correspond to a particular surgical tool. In some embodiments, the handle 132 is integrally formed with the body 102. In some embodiments, the handle 132 is attached to the body 102 (e.g., glued or mechanically joined). The handle 132 may comprise the same or different material as the body 102. In some embodiments, the handle 132 may be more rigid than the body 102 and / or may comprise a more rigid material than the body 102. In some embodiments, there may be more than one handle 132 (e.g., 2, 3, 4 or more handles). The handles disclosed in the various embodiments of the treatment device described herein are generally interchangeable with each other and / or various features of the handles are interchangeable.

[0077] Figures 2-11E Further examples of various embodiments of the treatment device 100 are shown. Various features of the disclosed embodiments of the treatment device 100 may be combined or modified unless it is not possible to do so. For example, in some embodiments, the treatment device 100 may wrap around the nerve at the anastomosis site, with a scraper-like seal at each end, as per [reference to...]. Figure 1As described herein. In some embodiments, as described elsewhere, the wiper-type seal may be formed of more than one flange 130 or flexible wiper blade. Corresponding numerals (e.g., 130, 230, and 330) may be referenced to corresponding features described elsewhere with respect to another drawing or embodiment.

[0078] In various implementation schemes, as described elsewhere in this document, the body may include a lower body and an upper body. Figure 2 An example of a treatment device 200, comprising a lower main body 214 and an upper main body 220, is schematically shown. (For example...) Figure 2 As shown, the lower body 214 and upper body 220 can cooperate to surround the entire circumference of the isolation segment of the nerve 50. The lower body 214 and upper body 220 can each include approximately half the circumference and half the volume of the receiving chamber 206. In some embodiments, the upper body 220 may not include any portion of the void volume of the receiving chamber 206, but can be used to seal the top surface 216 of the lower body 214 to completely enclose the receiving chamber 206. In some embodiments, such as Figure 2 As shown, the upper body 220 is indirectly connected to the lower body 214 via a connecting arm 234. The connecting arm 234 can be connected to the handle 232 at a hinge 236. The hinge 236 can be positioned significantly away from the body 232 to avoid clamping nerves or any surrounding tissue. A control lever 238 can extend from the hinge 236 and allows the user to hinge the upper body 220 between a closed (e.g., sealed) and an open configuration. In some embodiments, the control lever 238 can be an extension of the connecting arm 234. The control lever 238 can extend in a generally distal direction along the handle 232. The control lever 232 can be driven by one or more of the user's fingers or by a tool.

[0079] In various embodiments, the body 202 of the treatment device 200 may be configured to deliver fluid (e.g., a treatment solution) into a receiving chamber 206, particularly in embodiments including a closed bath design. The treatment device 200 may include one or more internal fluid channels extending through the body 202, and optionally a handle 232. The device 200 may include one or more fluid ports 240 extending from the body 202 or the handle 232, configured to introduce fluid into and / or withdraw fluid from the receiving chamber 206. In some embodiments, the fluid port 240 may include or be connectable to a Luer interface lock connector. The Luer interface lock connector may be configured for easy engagement and disengagement of the syringe.

[0080] Figure 2 The therapeutic device 200, schematically shown, includes a fluid port 240 extending from the distal end of a handle 232. Figure 2 The fluid port 240 shown includes a Luer interface lock connector, which can be easily connected to a continuous syringe loaded with an appropriate solution, such as the PEG fusion scheme described elsewhere herein. Therefore, the treatment device 200 can minimize or eliminate variability (e.g., volume) in the delivery of the solution to the containment chamber. Figure 2 The treatment device 200 shown includes a fluid channel extending from a fluid port 240, through a handle 232, to a lower body 214. In some embodiments, the lower body 214 and / or the upper body 220 may be hollow, and the fluid channel may be formed internally. The lower body 214 includes one or more flushing holes 242 fluidly connected to the fluid channel and the receiving chamber 206. In some embodiments, the upper body 220 may include an internal fluid channel and one or more flushing holes 242 fluidly connected to the fluid channel and the receiving chamber 206, at least when in a closed configuration. When the upper body 220 is in a closed configuration, the fluid channel of the upper body 220 may be positioned in fluid communication with the fluid channel in the lower body 214 and / or the handle 232, such that fluid can flow from the lower body 214 and / or the handle 232 into the upper body 220.

[0081] In some embodiments, the treatment device may have a slit extending through the treatment device from the edge of the lip or flange along the length of the intermediate body to the center of the cylindrical or other shaped intermediate portion of the body (e.g., to the receiving chamber) to facilitate placement of the nerve 50 (see example...). Figure 4A The slit can be formed by or resemble slit 130 and can effectively divide the body into portions corresponding to the lower and upper bodies. Once the nerve 50 is placed, the treatment device can be held together with a spring clip (e.g., a custom-made spring clip) that can be fitted into the channel between the lip and the cylinder. The device can have one, two, or more ports that extend directly into the central cavity, thereby defining a receiving chamber. As described elsewhere herein, the ports can be designed to facilitate engagement with a Luer interface lock syringe to allow the nerve to be immersed in a solution (e.g., a fusion solution) and rapidly aspirated with saline after treatment.

[0082] Figures 3A-3E Multiple perspective views of another example of a treatment device 300 are schematically shown. Figures 3A-3E Examples of suitable but non-restrictive dimensions (mm) for the various parts of the treatment device 300. Figure 3A A right cross-sectional view of the treatment device 300 is depicted. Figure 3B A left cross-sectional view of the treatment device 300 is depicted. Figure 3C A rear view of the treatment device 300 is depicted. Figure 3DA front view of the treatment device 300 is depicted. Figure 3E A perspective view of a treatment device 300 is depicted. The treatment device 300 may include a generally cylindrical body 302 having a generally circular left end wall 308 and a generally circular right end wall 310, which are connected by a generally cylindrical intermediate body 312. The body 302 may surround a generally cylindrical receiving chamber 306. The left end wall 308 and the right end wall 310 may each include a generally circular aperture 326 leading to the receiving chamber 306. The aperture 326 may be substantially centered within the end walls 308, 310. The body 302 may include a slit 329 extending longitudinally along the intermediate body 312. The slit 329 may be coplanar with the longitudinal axis (it may not extend circumferentially along the intermediate body 312). The slit may extend from the outer surface of the body 302 to the receiving chamber 306 and may effectively divide or proportionally divide the body 302 into a lower body 314 and an upper body 320. The lower body 314 and the upper body 320 may be connected (e.g., integrated with each other) at a point on the circumference of the body 302 opposite to the slit 329. The upper body 314 and the lower body may be offset apart from each other about this point. The slit 329 may extend (e.g., in the radial direction) through each of the end walls 308, 310 to merge with the aperture 326. The slit 329 may form a slit 328 in the end walls 308, 310. Increasing the width of the slit 329 between the edge of the lower body 314 and the opposite edge of the upper body 320 may place the treatment device 300 in an open configuration configured to receive the target nerve 50 into the receiving chamber 306 through the slit, such that the nerve 50 extends through the right and left apertures 326. In some embodiments, the opposing edges (e.g., the upper and lower edges) along the length of the slit 329 may contact each other, placing the treatment device 300 in a closed configuration in which the body 302 is configured to surround the entire circumference of the isolated segment of the nerve 50 within a receiving chamber 306. In other embodiments, the opposing edges of the slit 329 may approach each other without establishing physical contact between the edges (e.g., at approximately 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, etc.), creating a closed configuration in which substantially the entire circumference of the nerve 50 is surrounded.

[0083] In some embodiments, the treatment device 300 may include one or more inserts 344 configured to be located within the receiving chamber 306 at its left and right ends. The inserts 344 are typically annular or washer-shaped, including a central hole. The inserts 344 typically include substantially flat left and right surfaces. The thickness of the inserts 344 may be less than the width of the annular flat surface from the outer circumference to the inner circumference. The inserts 344 may include the same and / or different material as the body 302. The inserts 344 may include a hardness the same as or less than that of the body 302. The inserts 344 may be grouped in pairs, each pair including identical inserts 344 configured to be located at the right and left ends of the receiving chamber 306. At least one of the inserts 344 may be configured to form at least a portion of the left end wall 308. At least one of the inserts 344 may be configured to form at least a portion of the right end wall 310. Each insert 344 may include a slit passing through its circumference, the slit being configured to align with a slit 328 in an adjacent end wall 308, 310. Each pair of inserts 344 may include an outer diameter approximately equal to the diameter of the receiving chamber 306 and an inner diameter configured to receive nerves 200 of different sizes (e.g., 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, etc.).

[0084] In some embodiments, the insertions 344 of appropriate size can be selected to fit the treatment device 300 to treat different nerves (e.g., nerves of different diameters). In some embodiments, the insertions 344 can be inserted into and connected to the inner diameter of the receiving chamber 306 (e.g., via adhesive). In some embodiments, the insertions 344 can be manufactured together with the body 302. The insertions 344 can be arranged from the outside in (from the inner walls 308, 310 inward) in order of increasing central hole diameter. In some embodiments, all insertions 344 (e.g., 2 pairs, 3 pairs, 4 pairs, 5 pairs, etc.) can be retained in the receiving chamber 306, and insertions 344 with a diameter smaller than that of the isolated nerve 50 can conform to (e.g., around the outwardly curved) the size of the nerve 50. Smaller nerves will encounter less resistance than larger nerves because the smaller the nerve, the fewer insertions 344 are likely to deform the nerve. Increasing the number of circumferentially overlapping inserts 344 surrounding the nerve 50 can enhance the fluid seal around the nerve 50. In some embodiments, the inserts 344 can be removed independently from the receiving chamber 306. For example, the inserts 344 may include a fragile connection to the receiving chamber 306 or may be cut off by a surgical instrument. In some embodiments, the user may selectively remove inserts 344 including holes that are too small to receive the target nerve 50, leaving only inserts 344 large enough to receive the nerve 50.

[0085] In some embodiments, the treatment device 300 may include one or more lips 346 extending longitudinally along the entire or part of the length of the intermediate body 312. The lips 346 may be coplanar with the longitudinal axis (and may not extend circumferentially along the intermediate body 312). The lips 346 may be positioned circumferentially adjacent to the slit 329. For example, as... Figures 3A-3E As shown, the slit 329 separates the upper lip 346 from the lower lip 346. One or more lips 346 may each include a groove 348 extending longitudinally along the entire or part of the length of the lip 346. In some embodiments, the groove 348 may include, for example... Figures 3A-3E The semi-circular cross-section is shown. A groove 348 on the upper lip 346 can be longitudinally aligned above the groove 348 on the lower lip 346. The groove 348 can be configured to receive, retain, and / or frictionally engage part of a fastening device (e.g., a spring clip) configured to secure the upper and lower lips 346 together. In some embodiments, the groove can abut the outer cylindrical surface of the intermediate body 312. Securing the upper and lower lips 356 together allows the body 302 to be placed in a closed configuration as previously described, in which the opposing edges of the slit 329 are concentrated together or at least in which the width of the slit 329 is minimized. In some embodiments, the body 302 can be configured such that the lower body 314 and the upper body 320 are in a closed position in a non-biased configuration. The lower body 314 and the upper body 320 can be separated (e.g., via the lip 346) to place the body 302 in an open configuration for insertion of the nerve 50. In other embodiments, the lower body 314 and the upper body 320 may be naturally biased to an open configuration, and the securing device may hold the body 302 in a closed position. The body 302 may be naturally biased to place the lower body 314 and the upper body 320 in a maximum separation state, a minimum separation state, or any position in between.

[0086] As described elsewhere herein, the treatment device 300 may include one or more fluid ports 340 configured to deliver fluid to and / or remove fluid from the receiving chamber 306. The fluid ports 340 may be generally cylindrical. Figures 3A-3E As shown, fluid port 340 may include a fluid lumen 341 that extends directly into receiving chamber 306. The fluid lumen 341 may be substantially linear. The fluid lumen 341 may be generally cylindrical. In some embodiments, such as Figures 3A-3EAs shown, the treatment device 300 may include two fluid ports 340. The fluid ports 340 may include the same or similar features or may include different features (e.g., shape, size, material properties). In some embodiments, one fluid port 340 may be used to deliver fluid into the receiving chamber 306 (e.g., via a syringe), and the other fluid port 340 may be used to remove or aspirate fluid from the receiving chamber 306 (e.g., via a syringe or vacuum tubing). Delivery and removal may occur sequentially and / or simultaneously. In some embodiments, both fluid ports 340 may be used for delivery and / or removal. For example, two components of a treatment solution may be delivered sequentially and / or simultaneously into the receiving chamber 306 via the fluid ports 340. One or more fluid ports 340 may be circumferentially aligned along the outer circumference of the intermediate body 312 or may be circumferentially offset. The fluid port 340 can be circumferentially offset from the lip 346 at any degree from 0 to 360 degrees (e.g., 30 degrees, 45 degrees, 60 degrees, 90 degrees, 120 degrees, 135 degrees, 165 degrees, 180 degrees, etc.). In some embodiments, the fluid port 340 may be formed in one or more lips 346 and / or may extend from one or more lips 346.

[0087] In some implementation schemes, such as those concerning... Figure 1 and Figure 2 The treatment device 300 may include one or more handles similar to handles 132 or 232. In some embodiments, one or more lips 346 and / or one or more fluid ports 340 may be effectively used as handles and may be configured to be grasped by surgical tools and / or fingers as described elsewhere herein.

[0088] Figures 4A-4D Multiple perspective views of another example of a treatment device 400 are schematically shown. Figures 4A-4D Examples of suitable but non-restrictive dimensions (mm) for the various parts of the treatment device 400. Figure 4A A perspective view of the treatment device 400 is described. Figure 4B A front view of the treatment device 400 is described. Figure 4C Depicts Figure 4B The cross-sectional view of section AA shown. Figure 4D A left-side view of the treatment device 400 is depicted. The treatment device 400 may include the same or similar features as the treatment device 300.

[0089] Figures 5A-5C Multiple perspective views of another example of a treatment device 500 are schematically shown. Figures 5A-5C Examples of suitable but non-restrictive dimensions (mm) for the various parts of the treatment device 500. Figure 5AA perspective view of the treatment device 500 is depicted. Figure 5B A top view of the treatment device 500 is depicted. Figure 5C A left-side view of treatment device 500 is depicted. Treatment device 500 may include an open bath design similar to treatment device 100. Treatment device 500 may include a generally rectangular body 502. One or more edges and / or corners of the rectangular body 502 may be beveled and / or rounded. Body 502 may include left and right end walls 508, 510 interconnected by a rectangular intermediate body 512. Body 502 may include a top surface 516 having an entry area 525 leading to a receiving chamber 506. The introduction and / or removal of fluid (e.g., rinsing and / or aspiration) from the receiving chamber 106 can be readily accomplished in a device including an open bath configuration via the entry area 525. The receiving chamber 506 may have a generally rectangular configuration. In some embodiments, such as Figure 5C As shown, one or more bottom edges (e.g., front edge, rear edge, left edge, right edge) along the base plate of the receiving chamber 506 may include a beveled surface 550 and / or a circular surface 550. The left and right end walls 508, 510 may be generally rectangular in shape. Each end wall 508, 510 may include a slot 528 extending downward from the top surface 516. The slot 528 may open into the receiving chamber 506 and may be configured to receive and hold the nerve 50. The width of the slot 528 may be substantially uniform along the entire height of the slot from the top surface 516 to the bottom of the slot 528, in which the nerve 50 is configured to reside. The bottom of the slot 516 may include a circular (e.g., semi-circular) edge configured to support the nerve 50. The width of the slot 528 may be approximately equal to or greater than the diameter of the target nerve 50. The slot 528 can effectively perform the combined functions provided by the orifice 126 and slit 128 of the treatment device 100. The main body 502 of the treatment device 500 may not include any compliant flanges configured to bend to receive the nerve 50.

[0090] In some embodiments, the bottom of the slot 528 may be positioned at a height above or at the bottom point of the base plate of the receiving chamber 506. As described elsewhere herein, the treatment device 500 may be configured to receive the isolating segment of the nerve 50 in a slightly curved or bent direction, such that the nerve hangs downward between the slots 528. The anastomosis 52 of the nerve 50 may typically be located at the center of the receiving chamber 506. As described elsewhere herein, the inclined or circular surface 550 connecting the bottom edge of the slot 528 to the base plate of the receiving chamber 506 may help support the nerve 50 and distribute the nerve weight more evenly across the entire length of the body 502, preventing excessive pressure on the nerve 50 at the point where it passes through the inner bottom edge of the slot 528. In some embodiments, the height difference between the bottom of the slot 528 and the bottom of the base plate of the receiving chamber 506 may be large enough that the nerve 50 can be completely submerged in the central portion of the receiving chamber 506 without requiring the height of the contained solution to rise above the bottom of the slot 528. In some embodiments, the height difference between the bottom of the slot 528 and the bottom of the base plate of the receiving chamber 506 can be large enough that the nerve 50 can be completely submerged in the central portion of the receiving chamber 506 without the solution level rising above the top of the nerve 50 while the top of the nerve 50 is located in the slot 528, or the solution level does not rise above the lower portion of the nerve 50 while the bottom of the nerve 50 is located in the slot 528 (e.g., the lower 1 / 4, 1 / 3, 1 / 2, 2 / 3, or 3 / 4 of the nerve 50). In this way, when the nerve 50 is located in the slot 528, the nerve 50 can be used to at least partially fluid seal the bottom of the slot 528, and if the nerve 50 forms a substantially fitting fit with the slot 528, the nerve 50 can promote retention of the solution within the receiving chamber 506 based on the increased volume. For example, the height difference can be at least approximately 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm, 5.5 mm, 6.0 mm, 6.0 mm, 6.5 mm, 7.0 mm, 7.5 mm, 8.0 mm, 8.5 mm, 9.0 mm, 9.5 mm, or 10 mm.

[0091] The handle 532 of the treatment device 500 may include a finger stop 533 on which a user can place a finger (e.g., thumb) to facilitate operation of the treatment device 500 with their fingers. The finger stop 533 may have a generally circular shape. Figure 5BAs shown, the diameter of the finger stop can be equal to or greater than the length of the body 502 of the treatment device 500. The finger stop 533 may be surrounded by a thin edge. In some embodiments, both the upper and lower surfaces of the handle 532 may include the finger stop 533. In some embodiments, the finger stop 533 may include the same or different material as the remainder of the handle 532. For example, the finger stop 533 may include a softer material. In some embodiments, the finger stop 533 may be a void space extending from the top surface to the bottom surface of the handle 532.

[0092] In various embodiments, the handle may include one or more bends and / or angles. As the handle 532 extends distally, it includes an upward angle. The proximal end of the handle 532 may be interconnected with the body 502 at or near the top surface 516 of the body 502. The handle 532 may be positioned more towards the top of the body 502 than the bottom. The positioning of the handle 532 on the body 502 and / or the upward angle of the handle 532 can advantageously elevate a large portion of the handle 532 beyond the surgical field of view. In some embodiments, the handle 532 may be positioned more towards the bottom of the body 502. In some embodiments, the handle 532 may be positioned more towards the left or right side of the body 502. In some embodiments, the handle 532 may be positioned towards one of the four common angles toward the rear side of the body 502. In some embodiments, the handle 532 may be angled downwards, to the right, and / or to the left.

[0093] Figures 6A-6G Multiple perspective views of a treatment device 600 schematically illustrate another example of a configuration for receiving an opening of nerve 50. Figures 6A-6G Examples of suitable but non-restrictive dimensions (mm) for the various parts of the treatment device 600. Figure 6A A perspective view of the treatment device 600 is depicted. Figure 6B A top view of the treatment device 600 is depicted. Figure 6C A front view of the treatment device 600 is depicted. Figure 6D Depicts Figure 6C The cross-sectional view of section BB shown. Figure 6E A right-side view of the treatment device 600 is depicted. Figure 6F Depicts Figure 6E A close-up view of the embedded part A shown. Figure 6G Depicts Figure 6AThe diagram shows a perspective view of a variant of the treatment device 600. The treatment device 600 may include many features similar to or the same as those of the treatment device 300. The treatment device 600 may include a lower body 614 and an upper body 620, which are configured in an open configuration to receive a nerve 50 in a receiving chamber 606, and in a closed configuration (not shown) in which the isolating segment of the nerve 50 is completely circumferentially surrounded by the body 602 of the treatment device 600. The body 602 may include a slit 629 between the lower body 614 and the upper body 620 in the closed configuration. The body 602 may include a lip 646, which may include a groove 648 as described elsewhere herein. The groove 648 may be configured to retain a fixing device configured to secure the body 602 in the closed configuration. The main body 602 of the treatment device 600 can typically be cylindrical. For example... Figure 6D and Figure 6E As shown, the body 602 may include a partially flat lower outer surface and / or a partially flat upper outer surface, which can help to stably hold the device 600 on a flat surface. The receiving chamber 606 may be generally cylindrical, at least along the length of the intermediate body 612.

[0094] The lower body 614 and the upper body 620 can be connected together at a hinge 652. The hinge 652 can be positioned circumferentially opposite the lip 646 in a closed configuration. The hinge 652 can form part of a flange 653, or may be part of a flange 653 extending laterally from the intermediate body 612 along at least a portion of its length. The flange 653 can be used similarly to a handle in the closed configuration to facilitate operation of the treatment device 600. The flange connects the lower body 614 to the upper body 620. Figures 3A-3E The examples shown are different, in Figures 3A-3E In this context, the deformation or strain experienced by the main body 302 when the upper main body 314 and the lower main body 320 are offset and separated can typically be distributed circumferentially around the main body 302, and the main body 602 can be configured to isolate the deformation to the hinge 652. For example... Figures 6A-6F As shown, hinge 652 can be a movable hinge. Movable hinge 652 can be a thinner portion of body 602, which, due to its reduced size, is inherently more flexible than the rest of body 602, even if hinge 652 comprises the same material as the rest of body 602. In other embodiments, hinge 652 can be a mechanical hinge including a separable articulation component.

[0095] The body 602 may include a ridge 654 extending from the bottom surface 622 of the upper body 620 along at least a portion of the length of the intermediate body 612, and a corresponding groove 656 extending from the top surface 616 of the lower body 614 along the same length of the intermediate body 612 as the ridge 654. The ridge 654 may be configured to mate with the groove 656 in an interference fit. The interference fit may help to fluidly seal the receiving chamber 606 into a closed configuration, and / or may help to secure the lower body 614 to the upper body 620. In some embodiments, the ridge 654 may be disposed on the lower body 614, and the groove 656 may be disposed on the upper body 620. The ridge 654 and the groove 656 may be disposed on the intermediate body 612, on the lip 346, or between the intermediate body 612 and the lip 346 (e.g., having portions disposed in both). In some implementations, the body 602 may include multiple cooperating interference features (e.g., two or more rows of ridges 654 and grooves 656).

[0096] The main body 602 of the treatment device may include uneven left and right end walls 608, 610. In some embodiments, such as Figures 6A-6C As shown, end walls 608, 610 may comprise a generally conical shape in a closed configuration. In a closed configuration, end walls 608, 610 are typically truncated conical, with a generally circular aperture 626 forming the apex of the conical structure. A slit 629 between the lower body 614 and the upper body 620 can uniformly divide the truncated conical end walls 608, 610 into two halves. The inner surface of the truncated conical end walls 608, 610 may serve as an inclined surface 650, similar to the inclined surfaces described elsewhere herein, which facilitates support for the isolation segment of nerve 50 across the transition from aperture 526 to the lower base plate of receiving chamber 606. In some embodiments, the truncated conical end walls 608, 610 may include a length extending from the intermediate body 612 to aperture 626, with a length of at least about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm. Figure 6A and Figure 6BAs shown, the thickness of the truncated conical end walls 608, 610 may decrease or gradually decrease as the end walls 608, 610 extend outward from the intermediate body 612. The end walls may generally be compliant and may function similarly to the flange 130 described elsewhere herein. The end walls 608, 610 may be more compliant toward and closer to the aperture 626 than near the intermediate body 612. The end walls 608, 610 may be slightly deformable, allowing the circumference of the aperture to expand effectively to accommodate nerves 50 of varying diameters. The truncated conical configuration, extending at least partially longitudinally (as opposed to radially), can facilitate circumferential bending of the end wall flanges 608, 610, which allows for the accommodation of nerves 50 with a diameter greater than the unbiased diameter of the aperture 626. Similarly, this configuration can facilitate the formation of a circumferential compression seal around the nerve 50 within the aperture 626.

[0097] like Figure 6G As illustrated in the variant depicted, the treatment device 600 may include one or more actuating tabs 658 extending (e.g., laterally) from the body 602. The actuating tabs 658 allow a user to manipulate and / or operate the treatment device 600 (e.g., move the lower body 614 and / or the upper body 620 between closed and open positions). The actuating tabs 658 are typically rectangular in shape. The length of the actuating tabs 658 may not exceed approximately 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm. In some embodiments, the actuating tabs 658 may extend laterally from the end walls 608, 610. For example, as... Figure 6G As shown, four actuating tabs 658 can extend from the body 602. Two actuating tabs 658 can extend from the front of the body 602, and two actuating tabs 658 can extend from the rear of the body 602. Two actuating tabs 658 can extend from the left end wall 608, and two actuating tabs 658 can extend from the right end wall 610. The actuating tabs 658 can extend in directions offset from each other by approximately 90 degrees.

[0098] Figure 7A perspective view depicting another example of a treatment device 700 is shown. Treatment device 700 includes an open bath configuration as described elsewhere herein. Treatment device 700 may include a non-uniform width spanning the length of a body 702. Receiving chamber 706 may include a non-uniform width spanning the length of the body 702. In some embodiments, the width profile of the body 702 may reflect the width profile of the receiving chamber 706. In some embodiments, the height profile of the body 702 may reflect the depth profile of the receiving chamber 706. The width may be minimum at the left and right ends of the body 702 and maximum at the central portion of the length (e.g., at the center). The body 702 may be symmetrical relative to the midline separating the left and right sides of the treatment device 700. In some embodiments, the left and / or right ends of the body 702 may include a sufficiently narrow width to facilitate manipulation (e.g., gripping with a user's fingers or tools). The body 702 may be symmetrical relative to the midline separating the front and rear sides of the treatment device 700. The body 702 may include a generally curved front surface and a generally curved rear surface. The main body 702 may include a generally circular bottom. The treatment device 700 may include a receiving chamber 702 containing a generally uneven base plate. The base plate of the receiving chamber 702 may include a continuous, smooth surface. The base plate of the receiving chamber 702 may be deepest at the center point of the receiving chamber 702, which may be configured to receive the anastomosis 52. The depth of the base plate may increase from the left and right sides toward the center of the treatment device 700. The continuous, smooth base plate may serve the same function as the inclined surface 550 described elsewhere herein, as it descends from the left and right sides toward the center. The depth of the base plate may increase from the front and rear sides of the treatment device 700 toward the center. The left and right end walls 708, 710 may only include the thickness of the left and right edges of the side walls 704 forming the intermediate body 712, which extends from the left end to the right end of the main body 702. Sidewall 704 may be shaped on left and right endwalls 708, 710 to define a slot 728, similar to slot 528 described elsewhere herein, slot 728 being configured to receive nerve 50. As described elsewhere herein, treatment device 700 may be configured to receive nerve 50 such that when nerve 50 is located in slot 528, nerve 50 at least partially seals slot 528. A base plate may reach a height at the anterior center and / or rear center of receiving chamber 706, said height being lower than, approximately equal to, or higher than the height reached near slot 728. The base plate of receiving chamber 706 may be designed to substantially isolate the volume of contained solution near the central portion of treatment device 700 (e.g., around anastomosis 52 of nerve 50).

[0099] Figures 8A-8E Several perspective views of another example of a treatment device 800 are schematically shown. Figures 8A-8E Examples of suitable but non-restrictive dimensions (mm) for the various parts of the treatment device 800. Figure 8AA perspective view of the treatment device 800 is depicted. Figure 8B A top view of the treatment device 800 is depicted. Figure 8C A left-side view or a right-side view of the treatment device 800 is depicted. Figure 8D A front or rear view of the treatment device 800 is depicted. Figure 8E Depicts Figure 8D The cross-sectional view of section AA shown. The body 802 of the treatment device may include a configuration with the same or similar shape as the body 702, the shape referring to Figure 7 Description. The treatment device 800 may include left and right end walls 808, 810, which extend inwardly in a generally radial direction from the left and right edges of the central body 812 to form the left and right surfaces of the receiving chamber 806. The left and right end walls 808, 810 may include slits 828 similar to slits 128 described elsewhere herein. Slits 828 may extend from the upper surface 816 of the body 808. Slits 828 may extend in a substantially vertical direction. Figure 8E As shown, the slit can extend all the way to the bottom edges of the left and right end walls 808, 810. The slit 828 can divide the end walls 808, 810 into one or two flanges 830. The flanges 830 can be the same as or similar to the flanges 130 described elsewhere herein. The distal edges of the flanges 830 can form the opposing edges of the slit 828. Unlike the treatment device 100, the end walls 808, 810 may not include any holes. As described elsewhere herein, the treatment device 800 can be configured to receive and support or retain a nerve 50 between the opposing edges of the flanges 830, which can be biased inward and / or outward to accommodate the diameter of the nerve 50. In some embodiments, the slit includes only a single vertical spacer within the sidewall 804 that separates the flange 830 from another flange 830 or from a less compliant portion of the sidewall 804. In some embodiments, the spacing forming the slit 828 may extend in at least a certain horizontal direction near the bottom of one or both flanges 830, such that the slit 828 extends below at least a portion of one or both flanges 830, allowing for greater flexibility of the flanges 830. In the case of two flanges 830, the slit may branch in opposite directions to extend below both flanges 830. For example, the slit 829 may at least partially extend along the left and / or right semicircles of the end walls 808, 810. Figure 8E The bottom plate of the accommodating chamber 806 shown extends at the intersection.

[0100] The treatment device 800 may include one or more actuating tabs 858, which may include features similar to those of the actuating tabs 658 described elsewhere herein. The actuating tab 858 may include a generally thin, flat surface extending laterally from the body 802 of the treatment device 800. The flat surface of the actuating tab 858 may include a large surface area that facilitates gripping by a user's fingers or surgical instruments. In some embodiments, such as Figures 8A-8E As shown, the operating tab 858 may include a generally triangular shape having a substantially uniform thickness between the upper and lower surfaces. The operating tab 858 may be coplanar with the rest of the top surface 816 of the body 802. The left and right edges of the operating tab may not extend further longitudinally than the left and right end walls 808, 810 of the device. Figures 8A-8E As shown, the treatment device 800 may include four operating tabs 858. The operating tabs 858 may typically be located at the left front corner, right front corner, left rear corner, and right rear corner of the body 802.

[0101] Figure 9 A perspective view of another example of a treatment device 900 is shown. The treatment device 900 may include a lower body 914 having features generally similar to those of the lower body 614 of the treatment device 600. For example... Figure 9 As shown, the left and right end walls 908 and 910 may each include the lower half of a truncated conical shell that continues vertically upward in a linear manner at a certain height. The left and right end walls may define a slot 928, similar to slot 528 described elsewhere herein. As described elsewhere herein, the configuration of end walls 908 and 910 may be configured to apply a compressive force to a nerve 50 received in slot 528 and form a compression seal with the nerve 50.

[0102] As described elsewhere herein, the body 902 of the treatment device 900 may include an upper body 920 connected to a lower body 914 via a hinge 952 (e.g., a movable hinge). The upper body 920, or at least a portion thereof, may be configured to be at least partially received within a receiving chamber 906 to fluidly seal the entry area 924 formed in the top surface 916 of the lower body 914 and / or at least a portion (e.g., the upper portion) of the slot 928 when the treatment device 900 is placed in a closed configuration. Figure 9As shown, the insertion portion 921 of the upper body 920 may include a shape or outer periphery configured to substantially mate with the inner periphery of the receiving chamber 906. The upper body 920 may include or may not include portions other than the hinge 952, which extends beyond or covers the top surface 916 of the lower body 914, located outside the entry area 924 of the receiving chamber 906. The insertion portion 921 configured to be received in the receiving chamber 906 may include left and / or right vertical extensions 927 configured to at least partially fill the left and / or right slots 928. The left and right vertical extensions 927 may be configured to extend longitudinally outward beyond the left and right end walls 908, 910, respectively. The left and right vertical extensions 927 may be configured to extend longitudinally inward beyond the left and right slots 928, respectively. The vertical extension 927 can be configured to extend below the bottom of the remaining portion of the insertion portion 921 in the closed position, such that the inner surface of the vertical extension 927 can at least partially form the left and right inner surfaces of the receiving chamber 1106. The bottom of the vertical extension 927 may include a concave surface configured to be pressed into contact with the generally circular nerve 50 to form a fluid seal around the top of the nerve 50 within the slot 928. The concave surface may typically be semi-circular (e.g., an upper semi-circle or a smaller circle) to conform to the nerve 50 having a generally circular cross-section. In some embodiments, the vertical extension 927 may include the same material as the remainder of the upper body 920 and / or the lower body 914. In some embodiments, the vertical extension 927 may include a different material from the upper body 920 and / or the remainder of the lower body 914 (e.g., a softer or more compliant material).

[0103] The lower body 914 of the treatment device 900 may include one or more support ribs 960 disposed within a receiving chamber 906. The support ribs 960 may extend in a generally vertical direction and may extend from the top surface 916 of the lower body 914 to the bottom plate of the receiving chamber 906. The support ribs 960 may have a generally circular (e.g., semi-circular) cross-sectional shape. The support ribs 960 may comprise the same material as the remainder of the lower body 914 or a different material (e.g., a softer material). The support ribs may provide structural support to the receiving chamber 906, particularly by increasing the rigidity of the receiving chamber 906 in the lateral direction. The support ribs 960 may be configured to frictionally engage an isolating segment of the nerve 50 extending between left and right slots 928. The support ribs 960 may facilitate lifting or suspending the nerve 50 from the bottom plate of the receiving chamber 906, which may advantageously allow for more thorough fluid encapsulation of the nerve 50, particularly around the central portion (e.g., where an anastomosis may be placed). In some embodiments, the nerve 50 may be located between opposing support ribs 960. By separating the support ribs 960 (e.g., by separating the front and rear portions of the lower body 914 (separated by slot 928)), the nerve 50 is positioned at an appropriate height between the support ribs 960, allowing the nerve 50 to slide or fall into place under gravity before the force that relaxes the separating support ribs 960 is applied. The support ribs 960 may be separated by the user's fingers and / or by the use of suitable surgical instruments as described elsewhere herein.

[0104] Figure 10 A perspective view of another example of a treatment device 1000 is shown. Treatment device 1000 may include features similar to those of treatment device 100. Handle 1032 may include a long-handled spoon configuration. Handle 1032 may include a bend in an upward direction. The bend may be gradually spaced apart over at least a majority of the length of handle 1032. Figure 10 As shown, the bending may include an inflection point where the direction of the bending changes. The distal end of the handle may be located above the top surface 1016 of the body 1002 of the treatment device 1000. The distal end of the handle 1032 may be positioned in a substantially horizontal direction.

[0105] Figures 11A-11E Several perspective views of another example of the treatment device 1100 are schematically shown. Figures 11A-11E Examples of suitable but non-restrictive dimensions (mm) for the various parts of the treatment device 1100. Figure 11A A perspective view of the treatment device 1100 is depicted. Figure 11B A top view of the treatment device 1100 is depicted. Figure 11C A right-side view of the treatment device 1100 is depicted. Figure 11DA rear view is depicted, looking down from a portion of the handle 1132 of the treatment device 1100. Figure 11E A cross-sectional view is depicted, showing a section taken transversely to the midline of the longitudinal axis between the left and right sides of the treatment device 1100. The treatment device 1100 may include features similar to those of treatment device 100 and / or treatment device 1000. A slit 1128 may be provided along the left and right end walls 1108, 1110, at the intersection between the front portion 1105 of the side wall 1104 forming the front inner surface of the receiving chamber 1106 and the left and right portions 1109, 1111 of the side wall 1104 forming the left and right inner surfaces of the receiving chamber. The slit 1128 may define a single flange 1130 on each end wall 1108, 1110. The flange 1130 may form a large portion of the surface area of ​​the inner walls 1108, 1110 and may form the entire inner surface of the receiving chamber 1106. The distal edge of the flange 1130 may be opposite to the front side wall 1105 forming an intermediate body 1112 along the front surface of the treatment device 1100. Similar to the distal edge of flange 130 described elsewhere herein, the distal edge of flange 1130, in a non-biased configuration, may be positioned adjacent to, in contact with, or partially overlapping with the left and right edges of the front sidewall 1105. As described, the arrangement of slits 1128 between the front sidewall 1105 and the left and right sidewalls 1109, 1111, which makes the sidewall 1104 more proportionally defined, can make the front sidewall 1105 relatively more compliant. The front sidewall 1105 can be easily bent in the forward direction distal to flange 1130, which advantageously facilitates the insertion of nerve 50 through slit 1128 and its reception in aperture 1136. The top edge of the anterior sidewall 1105 may be angled or tilted downward along the direction of the receiving chamber 1106, which may advantageously help guide the nerve 50 into the slit 1128 during the introduction of the nerve 50 into the treatment device 1100.

[0106] The hole 1136 of the treatment device 1100 can be eccentrically positioned in a direction transverse to the longitudinal axis of the end walls 1108 and 1110. For example, the hole 1136 can be positioned along the intersection of the front side wall 1105 and the left and right side walls 1109 and 1111. Figure 11A and Figure 11C As shown, slit 1128 can target the circumference of hole 1126 along its foremost point. Front wall 1105 can merge with left and right side walls 1109, 1111 substantially along the bottom and / or rear of the circumference of hole 1126. The arrangement of the entire hole 1136 below a single flange 1130 can advantageously make flange 1130 more flexible because the longer horizontal length of flange 1130 can be separated from the remainder of end walls 1108, 1110.

[0107] like Figure 11CAs shown, the receiving chamber 1106 may include an inclined surface 1150, as described elsewhere herein, connecting the front, rear, left, and / or right inner surfaces of the receiving chamber 1106 to the base plate of the receiving chamber 1106. Positioning the slit 1128 and the hole 1126 more towards the front wall 1105 allows the base plate of the receiving chamber 1106 to be moved more towards the front of the body 1102 of the treatment device 1100.

[0108] The treatment device 1100 may include, for example Figure 11C The handle 1132 shown has a downward angle. The handle 1132 can extend laterally from the body 1102 of the treatment device 1100 (e.g., from the top of the treatment device 1100) and then bend downwards. The distal end of the handle 1132 can extend to a vertical position above the bottom of the body 1102, approximately parallel to the bottom of the body 1102 (e.g., ...). Figure 11C (as shown) at the same level, or below the bottom of body 1102.

[0109] In various embodiments, the treatment device may be configured to facilitate the measurement of action potentials (e.g., compound action potentials) and / or the application of electrical stimulation to an isolated segment of nerve 50. In some embodiments, the electrodes of the device may be configured to receive electrodes and to make the electrodes disposed in contact with the nerve. For example, in some embodiments, a needle electrode may be received through a fluid port 340 of the treatment device 300. The electrodes may be located at the left and right ends of nerve 50 on opposite sides of the anastomosis 52. In other embodiments, the treatment device may include specific access ports or windows configured to receive and / or secure electrodes to the device. In some embodiments, the electrodes may be embedded in the device. For example, the electrodes may be disposed within the inner surface of a receiving chamber and configured to contact nerve 50 (e.g., on the left and / or right side of the device). In some embodiments, there may be electrodes configured to serve as positive terminals and electrodes configured to serve as negative terminals. In some embodiments, the device may include a ground terminal and / or the negative terminal may be grounded. In some embodiments, the electrodes may be embedded in a polymer device. The electrodes may be connected via electrical wires to electrical contacts disposed on the outer surface of the device. The body of the treatment device may generally be made of a non-conductive material.

[0110] In some embodiments, the therapeutic device can be used for clinical and / or academic research purposes. The therapeutic device can be used solely for isolating nerves for in situ studies or experiments, such as pharmacological and / or electrophysiological studies. In some embodiments, the therapeutic device can be used to perform cell fusion according to protocols other than those described elsewhere herein. For example, in some embodiments, the device can be used with a fusion agent other than PEG. In some embodiments, the therapeutic device can be used during an electrofusion (e-fusion) protocol, where an electric shock is applied to the nerve to stimulate cell fusion (similar to an electroporation protocol). Electrodes described elsewhere herein may be useful for performing electrofusion protocols. In some methods, the nerve therapeutic device can be used to hold and stably maintain the severed nerve ends in a lateral position during the physical reattachment (e.g., suturing) of the severed nerve ends.

[0111] solution

[0112] In various embodiments, the solutions applied to the nerves may include commonly used USP-grade reagents. The solutions may not contain novel chemical entities and / or non-USP components. When applied in the appropriate order, the reagents in the solutions are responsible for the principal mechanism of action (PMOA) of the components and methods disclosed herein. In some embodiments, exposure to any or all of the solutions described herein during treatment may each not exceed approximately 1, 2, 3, 4, or 5 minutes. In a preferred embodiment, exposure may not exceed 2 minutes.

[0113] In some embodiments, the kit components may include three solutions and the therapeutic device described elsewhere herein. The prefill solution (solution 1) may contain methylene blue, which may be an active agent. The prefill solution may be hypotonic. The prefill solution may be a calcium-free solution (e.g., free of divalent calcium ions, Ca...). 2+ (The presence of calcium may interfere with cellular biochemical processes and / or may induce mass cell aggregation and potential premature fusion.) The prefill solution may contain a saline solution. The prefill solution may be sterile. The prefill solution may be pyrogen-free. In some embodiments, the prefill solution may contain methylene blue. Without being theoretically limited, methylene blue may act as an antioxidant, provide protection to cells, inhibit or delay Wallerian degeneration of damaged axons, and / or prevent the sealing of damaged cell membranes.

[0114] In some embodiments, a 100 mL volume of prefilled solution may contain approximately: 526 mg sodium chloride, USP (NaCl); 502 mg sodium gluconate, USP (C6H2O). 11 NaO7); 368 mg sodium acetate trihydrate, USP(C2H3NaO2) 3H₂O); 37 mg potassium chloride, USP(KCl); 30 mg magnesium chloride, USP(MgCl₂) 6H2O); and 1 mg methylene blue, USP(C 16 H 18 ClN3S). The pre-charged solution can be prepared in ddi-H2O at a pH of approximately 7.4. In some embodiments, the pH can be approximately 6.5-8.0. In some embodiments, the pre-charged solution can be or may include Plasma-Lyte. TM (Baxter International Inc., Deerfield, IL).

[0115] The fusion solution (solution 2) may include polyethylene glycol (PEG). PEG may be a low molecular weight PEG. In some embodiments, PEG may include (e.g., the number-average molecular weight or weight-average molecular weight of a polydisperse sample) a molecular weight not greater than 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or 5,000 Da. In some embodiments, PEG may include linear chain molecules. In some embodiments, the chain may include branched molecules (e.g., 4-arm, 6-arm, or 8-arm star-shaped molecules). The fusion solution may be sterile. The fusion solution may be pyrogen-free. In some embodiments, 100 mL of the fusion solution may contain approximately 100 mg of PEG 3350 (e.g., USPPEG-3350). In some embodiments, the concentration of PEG may be approximately 30% to 60%, approximately 40% to 55%, or approximately 45% to 50% (w / w). In some embodiments, the PEG content is approximately 50% (w / w). The fusion solution can be prepared in ddi-H2O at a pH of approximately 7.4. In some embodiments, the pH can be approximately 7.0 to 7.9.

[0116] The sealing solution (solution 3) may contain a salt solution. The sealing solution may be isotonic. The sealing solution may contain calcium. The sealing solution may be sterile. The sealing solution may be pyrogen-free. In some embodiments, a 100 mL volume of the sealing solution may contain approximately: 600 mg sodium chloride, USP (NaCl); 310 mg sodium lactate, USP (C3H5NaO3); 30 mg potassium chloride, USP (KCl); and 20 mg calcium chloride, USP (CaCl2). (2H2O). The sealing solution can be prepared in ddi-H2O at a pH of approximately 5.0. In some embodiments, the pH can be approximately 4.0 to 6.5. In some embodiments, the sealing solution can be or may include lactated Ringer's solution.

[0117] PEG fusion scheme

[0118] The methods of using kits and / or solutions described elsewhere herein may include the sequential delivery of pharmaceutical reagents in solution. In a preferred embodiment, the delivery of a therapeutic PEG fusion solution may be combined with nerve suturing to repair severed nerves. The method may include a multi-step procedure as described herein. In various embodiments, one or more steps may be removed or modified where unnecessary for the outcome. In various embodiments, one or more steps may be added to the method.

[0119] Modern surgical repair of severed peripheral nerves is an open surgical procedure in which the proximal and distal ends of the severed nerve are reconnected using microsurgical sutures (neurosuction). Treatment devices disclosed elsewhere in this document can be configured in conjunction with neurosuction for the surgical repair of severed peripheral nerves.

[0120] In the first step, the surgical area for nerve repair can be prepared. The mechanism of nerve injury may be important. Treatment devices and / or protocols can be configured to treat the stenosis or injury indication. In most cases, neurodecomposition procedures can be used to allow for near-tension-free repair. Neurodecomposition can temporarily degenerate nerve fibers and / or relieve patient pain. In some implementations, clean transection of the nerve stump may be desirable. Preparation may include trimming if necessary. A calcium-free hypotonic saline solution can be used for irrigation.

[0121] In the second step, the ends of the severed axons can be flushed. As described elsewhere in this document, the ends can be flushed in a pre-filling solution (Solution 1). The pre-filling solution may contain a hypotonic, Ca-free solution with 1% methylene blue. 2+ Salt solution. In some embodiments, the ends may be rinsed for approximately 1–2 minutes. Rinsing can advantageously increase axoplasmic volume, cleave the axonal ends, expel intracellular membrane-bound vesicles, and / or prevent the formation of new intracellular vesicles. These various effects of the pre-filled solution can prepare axonal severts for cell fusion, such as by promoting axon-to-axon contact in an optimal configuration of the cell membrane, for use in cell aggregation and / or fusion.

[0122] In the third step, the severed nerve can be physically reconnected to create an anastomosis. Reconnection can be performed using a manipulator microscope. Reconnection may include suturing the proximal and distal ends of the nerve together (“nerve suture,” which is the standard of care in the clinical repair of severed nerves). Reconnection can be performed in the presence of a pre-filling solution. The pre-filling solution can be the same as the solution used in the second step (solution 1). Reconnection can establish axon-to-axon contact within the epineurium sheath. In some cases, fusion may not occur if the axon is not in direct contact with the repair site. In some implementations, the nerve can be sutured using 8-0 nylon sutures or another suitable suture.

[0123] In the fourth step, as described elsewhere herein, the treatment device may be placed (e.g., gently positioned) such that the sutured nerve remains within the device's receiving chamber. In various embodiments, the anastomosis 52 of the nerve may be positioned substantially centrally within the receiving chamber of the treatment device and / or the deepest portion of the receiving chamber, which is configured to maximize exposure of the anastomosis to the applied solution. A delivery device may provide a fluid receiving field for isolating the application of the fusion solution and for effectively removing the fusion solution. In some embodiments, in addition to or alternative to an earlier pre-filling step, the reconnected nerve may be flushed in a pre-filling solution after placement within the treatment device. The pre-filling solution may be the same solution (solution 1) from the second step.

[0124] In step five, fusion of the closely approximate axonal membranes of the severed axons can be induced. Fusion may be induced by exposure to a fusion solution (Solution 2). In some embodiments, the fusion solution may contain approximately 50% w / w PEG / distilled water. The exposure time may be approximately 1–2 minutes. The fusion solution can cause the removal of bound cellular water, thereby inducing membrane fusion. In various embodiments, the PEG concentration may be reduced to below 50% or increased to above 50%. The exposure time may increase with decreasing PEG concentration or decrease with increasing PEG concentration. In some embodiments, the PEG solution may not contain more than approximately 50% (w / w) to prevent or minimize any harmful effects of PEG on the treated neurons.

[0125] In step six, the fusion solution can be removed. The fusion solution can be removed from the delivery device containment chamber by aspiration. Aspiration can be performed using a pipette, vacuum, syringe, or any other suitable fluid removal technique.

[0126] In the seventh step, the delivery device can be removed (e.g., gently) from around the nerve.

[0127] In step eight, any remaining membrane discontinuities in the fused axonal membrane can be sealed. These discontinuities can be sealed by flushing with an excess volume of sealing solution (solution 3). The sealing solution may contain isotonic Ca2+ as described elsewhere in this document. 2+ A saline solution. The sealing solution can be applied for approximately 1-2 minutes. The sealing solution can induce vesicle formation, which seals any remaining axonal membrane pores. In some embodiments, the sealing solution can be applied to the nerve, either after the treatment device has been removed or before it is removed from the nerve.

[0128] In step nine, routine wound closure and incision care may be performed if necessary.

[0129] In some embodiments, the order of these steps may be effective. In some embodiments, one or more solution application steps may be repeated more than once (e.g., twice, three times, etc.). The solution may be applied sequentially again after a previous volume of solution has been removed. In some embodiments, the nerve may be flushed between steps and / or repeated application of the solution. The flushing solution may be a saline solution, such as a hypotonic, Ca-free solution. 2+ A saline solution or any other suitable solution. In some embodiments, the procedure can be performed without the use of a treatment device, or with a device other than those described herein.

[0130] Animal studies of neural-PEG fusion technology have demonstrated superior recovery speed and functional restoration compared to traditional neural repair techniques. PEG fusion protocols may include a well-defined sequence of bioengineered chemicals that may not be readily available from the shelf (e.g., PEG 3,350kD). Kits of solutions (and, in some embodiments, therapeutic devices) can provide significant convenience to surgeons. In some embodiments, the kit may have a shelf life of at least 1-2 years (e.g., the shelf life of the PEG fusion solution). In various embodiments, one or more solutions may be stored in containers under vacuum or inert gases (e.g., nitrogen or argon) to prevent oxidation. Solutions may be contained in containers that protect the solutions from radiation. Kits may include instructions for use and / or recommended quantities. Kits may contain sufficient reagents for multiple procedures or may be configured for single-use operations. As described elsewhere herein, kits may optionally include one or more surgical instruments or other tools, such as those configured for manipulating and / or operating the therapeutic device.

Claims

1. A reagent kit, comprising: A neurotherapy device for forming a fluid-containing field around at least a portion of an isolated segment of a nerve; and Suitable for application of one or more drug solutions to nerves via the aforementioned nerve therapy device.

2. The kit according to claim 1, wherein the one or more drug solutions comprise at least a pre-filled solution, a fusion solution, or a sealing solution.

3. The kit according to claim 2, wherein the one or more drug solutions comprise at least three solutions, including at least a pre-filled solution, a fusion solution, and a sealing solution.

4. The kit according to claim 2, wherein the one or more drug solutions comprise a pre-filled solution.

5. The kit according to claim 4, wherein the pre-filled solution comprises methylene blue.

6. The kit according to claim 5, wherein the pre-filled solution further comprises one or more of sodium chloride, sodium gluconate, sodium acetate trihydrate, potassium chloride, and magnesium chloride.

7. The kit according to claim 4, wherein the pre-filled solution is calcium-free.

8. The kit according to claim 4, wherein the pH of the pre-filled solution is approximately 6.5 to 8.

0.

9. The kit according to claim 2, wherein the one or more drug solutions comprise a fusion solution.

10. The kit of claim 9, wherein the fusion solution comprises polyethylene glycol (PEG).

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