Devices and methods for creating fluid-containing fields for administering therapeutic agents to nerves

Abstract

Severed nerves can be surgically reconnected and severed axons fused via sequential administration of a solution. The solution may include a Ca-free solution containing methylene blue. 2+ A priming solution of saline solution, a fusing solution containing about 50% (w / w) PEG, and a solution containing Ca 2+ The PEG fusion solution can be applied to a nerve treatment device configured to isolate a damaged segment of a nerve. The device can include a containment chamber for creating a fluid containment field around the anastomosis. The device can have slits, slots and / or holes in opposite end walls of the device designed to receive the nerve. The device can have an open bath configuration, or can include a separable lower body and upper body to form a closed bath configuration. The device can include one or more fluid ports in fluid communication with the containment chamber for introducing and / or removing fluid.

Description

[0001] background

[0002] Description of related art

[0003] No known device has the following functions: 1) creates an isolated fluid containment field for local (on-nerve) delivery of drug solutions to the lesion area of the nerve; 2) protects tissues other than the nerve to be treated from exposure to the drug solution; and 3) provides a design that can be placed and withdrawn from the nerve without damaging the anastomosis. No one has provided a method for repairing nerves using PEG fusion in sequence using a delivery device.

[0004] The following patents and published applications may be relevant to this area and are hereby incorporated 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.

[0005] Overview

[0006] Polyethylene glycol fusion (PEG fusion) is an emerging technology for the acute repair of damaged peripheral and central nerves. Damaged peripheral nerve repair is performed by suturing the incision ends together, inserting a bridging device, and implanting a donated nerve segment. Current repairs do not truly restore function and sensation, but only promote the regeneration of natural nerves. In contrast, PEG fusion can immediately restore function and sensation, as well as prevent degeneration, stop atrophy of distal target tissue, and significantly accelerate and significantly improve the recovery of sensation and function.

[0007] PEG fusion involves the sequential administration of a series of pharmacological agents that fuse severed axons within a nerve bundle and reestablish axonal integrity. Without being limited by theory, PEG fusion uses highly hydrophilic PEG as a dehydrating agent that removes bound water from the extracellular surface of the cell's plasma membrane and promotes fusion of the exposed cell plasma membranes. This is performed in the operating room and is an addition to the standard of care, which involves microsuturing the proximal and distal ends through the epineurium (neurorrhaphy).

[0008] The PEG concentration used in the PEG administration 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.

[0009] Thus, the devices contemplated herein can advantageously: 1) provide for placement of the device so as not to disturb a recently sutured nerve; 2) create a fluid containment field around the sutured nerve; 3) provide for continuous and consistent exposure of the injured, sutured ganglion; 4) prevent unnecessary exposure of uninjured segments of the nerve to PEG; 5) prevent unnecessary exposure of adjacent tissue to PEG; 6) provide for convenient and efficient removal of PEG after the administration step; and / or 7) provide for removal of the device so as to avoid disturbing recently fused axons within the recently fused nerve.

[0010] The delivery device disclosed herein can allow for qualitative and / or quantitative assessment of the recovery of electrophysiological activity across repaired nerves by measuring the compound action potential (CAP) across the anastomosis of a nerve that has been severed, sutured, and PEG-fused. The compound action potential (CAP) measures the cumulative electrical signal recorded from the extracellular space of axonal populations (such as within a nerve). The device can also allow for the destruction of electrophysiological activity caused by excessive exposure (time and / or concentration) of PEG to be demonstrated by measuring the compound action potential (CAP) across the anastomosis of a nerve that has been severed, sutured, and PEG-fused. For example, nerves exposed to continuous 50% (w / w) PEG for 20 minutes or longer may show deleterious effects. The design of the device can be configured to minimize the effect on nerves during device placement, PEG administration, and device removal.

[0011] Other applications of the PEG fusion method and delivery device may include repairing damaged spinal nerves; implanting peripheral nerve segments into traumatically resected segments, including allografts, autografts, and xenografts; and any other suitable application.

[0012] Disclosed herein is a neurotherapy device for forming a fluid containment field around at least a portion of an isolated 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 that intersects the top surface to form an entry zone. The entry zone is configured to receive the isolated 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 isolated segment of the nerve. The first end wall includes a first aperture leading to the containment chamber, and the second end wall includes a second aperture leading to the containment chamber. The first aperture and the second aperture are configured to respectively retain a first end and a second end of the isolated segment of the nerve and to form a fluid seal around the first end and the second end of the isolated 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 a first 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 a second width between opposing edges of the second slit, such that the nerve can be received into the second aperture through the second slit.

[0013] The flexible portion of the first end wall may include a first flange having a thickness that gradually decreases in a 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 having a thickness that gradually decreases in a distal direction of the second flange. The distal edge of the second flange may be defined by the first slit, such that the distal edge of the first flange and the distal edge of the second flange form opposing edges of the first slit. The first and second holes may be located in the first and second end walls such that the bottom of the first and second holes, opposite the top surface, are elevated above the floor of the receiving chamber. The receiving chamber may have an inclined surface and / or a curved surface interconnecting the bottom of the first and second holes with the floor of the receiving chamber. The inclined surface and / or the curved surface may be configured to help support the weight of the isolated segment of the nerve.

[0014] The holding chamber can be configured to hold a 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 access zone can be greater than the width of the first aperture and greater than the width of the second aperture. The first aperture and the second aperture can be circular. The first aperture and the second aperture can have a diameter in an unbiased configuration that is slightly smaller than the diameter of the nerve such that the first aperture and the second aperture are configured to form a compression seal around the nerve when received within the first aperture and the second aperture. The first aperture and the second aperture can be longitudinally aligned.

[0015] The bottom surface of the elongated body may be generally circular. At least a portion of the bottom surface of the elongated body may be flat so that the device can be stably maintained on a flat surface. The first end wall may have a profile shape corresponding to a portion of an oblong shape. The depth of the holding chamber may increase between the front and rear ends of the holding chamber. The front and rear ends may extend from the first end wall to the second end wall. The floor of the holding chamber may be uneven. The elongated body and the end wall may be made integrally of the same material. The elongated body may comprise silicone. The silicone may comprise medical grade polydimethylsiloxane (PDMS).

[0016] The neurotherapy device may include a handle extending laterally from the elongated body. The handle may extend from the rear side of the device to 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 that is flush with the top surface of the elongated body. The handle may extend horizontally in a rearward direction. The handle may be bent or angled in an upward direction and / or in a downward direction. The handle may have a proximal end connected to the elongated body and a distal end opposite 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 having an inflection point.

[0017] The first slit may bisect the first aperture, and the second slit may bisect the second aperture.The first aperture and the second aperture may be horizontally centered within the first end wall and the second end wall, respectively, between the front and rear ends of the elongated body.

[0018] The first hole and the second hole can be horizontally arranged more toward the front end of the elongated body. The first slit can separate the inner front surface of the receiving chamber from the inner surface of the first end wall, and the second slit can separate the inner front surface of the receiving chamber from the inner surface of the second end wall, so that the front wall of the elongated body formed between the first slit and the second slit is configured to be biased in a forward direction in a manner that increases the first width and the second width. The first slit can intersect with the front edge of the first hole, and the second slit can intersect with the front edge of the second hole. The front wall of the elongated body can have an angled edge on the top surface that slopes downward toward the receiving chamber.

[0019] The neurotherapy device may include a closed fluid channel formed within the elongated body. The fluid channel may have a first opening engaged with the receiving chamber and a second opening on the outer surface of the device that is not engaged with the receiving chamber. Fluid can be introduced into the receiving chamber and / or removed from the receiving chamber via the fluid channel. The second opening can be formed on a fluid port extending from the elongated body. The fluid port may include a Luer interface connector configured to be connected 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 engaged with the receiving chamber and a fourth opening on the outer surface of the device that is not engaged with the receiving chamber. Fluid can be introduced into the receiving chamber and / or removed from the receiving chamber via the second fluid channel.

[0020] In another aspect of the present disclosure, a nerve treatment device is disclosed herein for forming a fluid containment field around at least a portion of an isolated segment of a nerve. The nerve treatment device comprises 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 comprises 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 retain a volume of fluid within a void volume of the containment chamber surrounding at least a portion of the isolated segment of the nerve. The first end wall comprises a first aperture leading to the containment chamber, and the second end wall comprises a second aperture leading to the containment chamber. The first aperture and the second aperture are configured to retain a first end and a second end, respectively, of the isolated segment of the nerve and to form a fluid-tight seal around the first end and the second end, respectively, of the isolated segment of the nerve. The lower body and the upper body may 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 apertures. The slit defines a top surface of the lower body and a bottom surface 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 into the first and second apertures. The lower and upper bodies are configured to substantially surround the entire circumference of the nerve in a closed configuration.

[0021] The lower body and the upper body are connected together at the rear side of the elongated body. The lower body and the upper body are connected together by a flexible hinge. The flexible hinge can be a movable hinge. The lower body and the upper body are integral at the rear side of the elongated body. The elongated body can have a generally tubular body including a sidewall defining a circumference. The slit can extend through the sidewall along the front side, 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 apertures. The upper body can be completely separable from the lower body. The void volume of the storage chamber can be formed in the lower body and the upper body. The void volume of the storage chamber can be formed entirely in the lower body, and the upper body can be configured to seal an access area formed on the top surface of the lower body, the access area leading to the void volume.

[0022] 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 an apex of the frustoconical shape. The first end wall may include a sidewall having a thickness that decreases as the sidewall extends toward the apex of the frustoconical shape.

[0023] The lower body may include a first locking feature and the upper body may have a second locking feature, the second locking feature being configured to engage the first locking feature in a closed configuration to lock the lower body and the upper body together. The first locking feature and the second locking feature may include ridges and grooves, the ridges and grooves being configured to mate together to form an interference fit. The neurotherapy device may include a lower lip and an upper lip, the slit extending between the lower lip and the upper lip. The lower lip and the upper lip may be configured to receive a securing mechanism to maintain the lower body and the upper body in a closed configuration. The lower lip and / or the upper lip may include a groove extending along at least a portion of the length of the lip to retain the securing mechanism.

[0024] The elongated body may have a generally cylindrical shape. The holding chamber may include an inclined surface and / or a curved surface interconnecting the bottoms of the first and second holes with the floor of the holding chamber. The inclined surface and / or the curved surface may be configured to help support the weight of the isolated segment of the nerve. The holding chamber may be configured to maintain a 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 zone 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 a diameter in an unbiased configuration that is slightly smaller than the diameter of the nerve, 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.

[0025] At least a portion of the bottom surface of the elongated body may be flat so that the device can be stably maintained on a flat surface. The depth of the holding chamber may increase between the front and rear ends of the holding chamber, the front and rear ends extending from the first end wall to the second end wall. The floor of the holding chamber may be uneven. The elongated body and the end wall may be made of the same material in one piece. The elongated body may include silicone. The silicone may include medical grade polydimethylsiloxane (PDMS).

[0026] 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 that is flush with the top surface of the elongated body. The handle may extend horizontally in a rearward direction. The handle may be bent 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 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 having an inflection point. The upper body may be indirectly connected to the handle via a connecting arm. The connecting arm is operable to move the lower body and the upper body between the closed configuration and the open configuration.

[0027] The neurotherapy device may include a closed liquid channel formed in the elongated body. The fluid channel may have a first opening engaged with the receiving chamber and a second opening on the outer surface of the device that is not engaged with the receiving chamber. Fluid can be introduced into the receiving chamber and / or removed from the receiving chamber via the fluid channel. The second opening can be formed on a fluid port extending from the elongated body. The fluid port may include a Luer interface connector configured to be connected 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 in the elongated body, the fluid channel having a third opening engaged with the receiving chamber and a fourth opening on the outer surface of the device that is not engaged with the receiving chamber. Fluid can be introduced into the receiving chamber and / or removed from the receiving chamber via the second fluid channel.

[0028] In another aspect of the present disclosure, a nerve treatment device is disclosed herein for forming a fluid containment field around at least a portion of an isolated segment of a nerve. The nerve treatment 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 that intersects the top surface to form an entry zone. The entry zone is configured to receive the isolated segment of the nerve into the containment chamber. The containment chamber is configured to substantially maintain 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 downwardly 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 downwardly 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 a bottom portion of the isolated segment of the nerve.

[0029] The first end wall may be formed by the edges of side walls that form the front, rear, and bottom sides of the elongated body, such that no portion of the end walls forms an interior 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 end wall and the second end wall. 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 end wall and the second end wall. 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 floor 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 has a maximum width between the first end wall and the second end wall.

[0030] In another aspect of the present disclosure, a nerve treatment device is disclosed herein for forming a fluid containment field around at least a portion of an isolated segment of a nerve. The nerve treatment device comprises 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 that intersects the top surface to form an entry zone. The entry zone is configured to receive the isolated 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 isolated segment of the nerve. The first end wall includes a first slit extending downwardly from the top surface through the first end wall, and the second end wall includes a second slit extending downwardly from the top surface through the second end wall. At least a portion of the first end wall is flexible and configured to be biased in a manner that increases a first 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 configured to be biased in a manner that increases a second width between opposing edges of the second slit such that the nerve can be received through the second slit.

[0031] 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. The flexible portion of the first end wall may include a first flange, the thickness of which gradually decreases in a 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 a distal direction of the second flange. The distal edge of the second flange may be defined by the first slit, such that the distal edge of the first flange and the distal edge 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.

[0032] In another aspect of the present disclosure, a nerve treatment device is disclosed herein for forming a fluid containment field around at least a portion of an isolated segment of a nerve. The nerve treatment 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 nerve treatment 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 that intersects with a top surface of the lower body to form an entry zone. The entry zone is configured to receive the isolated segment of the nerve into the containment chamber, and 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 aperture leading to the containment chamber, and the second end wall includes a second aperture leading to the containment chamber. The first aperture and the second aperture are configured to retain a first end and a second end of the isolated 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 an upper portion of the receiving chamber such that the entire access area of the top surface is enclosed. The lower body and the upper body are configured to substantially surround the entire circumference of the nerve in a closed configuration.

[0033] The lower body may be connected to the upper body when the device is in an open configuration in which the receiving chamber is unsealed. The lower body may be connected to the upper body by a hinge. The hinge may be a movable hinge. The upper body may include a first downward extension configured to be received in the first hole above the 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 side surface of the receiving chamber. The first extension may have a concave bottom edge configured to conform to the shape of the nerve.

[0034] 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 back inner surface of the receiving chamber. The support ribs may be spaced apart to support the isolated segment of the nerve on the floor of the receiving chamber.

[0035] In another aspect of the present invention, disclosed herein is a delivery device for performing a nerve repair procedure. 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, the elongated opening being used to introduce the reconnected nerve into the receiving chamber. The delivery device includes a port that is in fluid communication with the receiving chamber and is configured to be connected to a syringe for injecting a solution into the receiving chamber. The delivery device includes a handle that extends from the elongated body configured to facilitate placement of the delivery device around the nerve.

[0036] In another aspect of the present invention, a method for repairing a severed nerve is disclosed herein. The method includes physically reconnecting the severed nerve so that axon-to-axon contact is restored; placing a delivery device around the reconnected nerve; and inducing severed axonal fusion 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, the elongated opening being used to introduce 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.

[0037] The method may include placing the severed axon terminals in a medium containing a Ca-free 2+ The method may include rinsing or incubating the cells in a priming solution of a saline solution. The priming solution may include methylene blue, and in some embodiments, the methylene blue may be approximately 1% (w / v). 2+ The reconnected nerve is rinsed or incubated with a sealing solution of a saline solution to seal any remaining membrane discontinuities of the fused axonal membrane. The rinsing or incubation of the reconnected nerve with the sealing solution can be performed inside the holding chamber and / or outside the holding chamber. The sealing solution can include calcium chloride (CaCl2), and in some embodiments, the calcium chloride can be approximately 0.02% (w / v).

[0038] Physically reconnecting the severed nerve may include suturing together the proximal and distal ends of the severed nerve.Physically reconnecting the severed nerve may be performed in the presence of the priming solution.

[0039] The method may include removing the fusion solution from the holding chamber by aspiration. The method may include removing the delivery device from around the nerve. The fusion solution may include low molecular weight polyethylene glycol (PEG). The concentration of PEG may be no greater than about 50% (w / w). The concentration of PEG may be about 50% (w / w). The PEG may be a low molecular weight PEG having an average molecular weight of no greater than 5,000 Da or 3,500 Da. The average molecular weight of PEG may be about 3,350 Da.

[0040] The method may include flushing or incubating the anastomosis of the reconnected nerve in the priming solution prior to fusing the axons. Flushing or incubating the reconnected nerve in the priming solution may be performed after positioning the delivery device around the reconnected nerve.

[0041] The delivery device may include a port in fluid communication with the holding chamber. Introducing the fusion solution may include introducing the fusion into the holding chamber through the port. The port may be configured to connect to a syringe for injecting the solution into the holding chamber.

[0042] The nerve may be exposed to the fusing solution for no more than 2 minutes. The nerve may be exposed to the priming solution for no more than 2 minutes. The nerve may be exposed to the sealing solution for no more than 2 minutes.

[0043] In another aspect of the present invention, a method for repairing severed nerves is disclosed. The method comprises: 2+The ends of the severed axons are rinsed in a saline priming solution and, in the presence of the priming solution, the severed nerve is physically reconnected by suturing the proximal and distal ends of the severed nerve together to restore axon-to-axon contact. The method also 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 chamber within the elongated body for receiving the reconnected nerve. The 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, the elongated opening being used to introduce the reconnected nerve into the chamber. Placing the delivery device around the reconnected nerve includes introducing the reconnected nerve into the chamber through the longitudinal opening. The method also includes inducing fusion of the severed axons within the reconnected nerve by introducing a fusion solution into the chamber and incubating the reconnected nerve in the fusion solution. The fusion solution comprises approximately 50% (w / w) low molecular weight PEG. The method further comprises removing the fusion solution from the holding chamber by suction and removing the delivery device from around the nerve. 2+ The reconnected nerve is flushed with a saline sealing solution to seal any remaining membrane discontinuities of the fused axonal membranes.

[0044] In another aspect of the present invention, disclosed herein is a kit comprising a neurotherapy device and one or more solutions from any of the above solutions. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 A perspective view of an example of a nerve treatment device that can be used to deliver a therapeutic solution to an isolated segment of a nerve for nerve repair is shown. The treatment device includes an open configuration and slits and holes in opposing side walls that are configured to receive and retain the nerve.

[0047] Figure 2 Another example of a neurotherapy device having separable lower and upper bodies and fluid irrigation ports is schematically shown.

[0048] Figure 3A-Figure 3E Schematically illustrated are multiple perspective views of another example of a treatment device comprising an integral upper body and a lower body separated by a cleft for receiving a nerve. Figure 3A A right cross-sectional view of the therapeutic device is depicted. Figure 3B A left cross-sectional view of the therapeutic device is depicted. Figure 3C A posterior view of the treatment device is depicted. Figure 3D A front view of the therapeutic device is depicted. Figure 3E A perspective view of a therapeutic device is depicted.

[0049] Figures 4A-4D Schematically shows a similar Figures 3A-3E Multiple perspective views of another example of a therapeutic device are shown in FIG. Figure 4A A perspective view of a therapeutic device is depicted. Figure 4B A front view of the therapeutic device is depicted. Figure 4C Depicts Figure 4B A cross-sectional view of section AA is shown. Figure 4D A view from the left side of the treatment device is depicted.

[0050] Figures 5A-5C Schematically illustrated are multiple perspective views of another example of a therapeutic device having an open configuration and a slot configured to receive a nerve. Figure 5A A perspective view of a therapeutic device is depicted. Figure 5B A top view of the therapeutic device is depicted. Figure 5C A left side view of the therapeutic device is depicted.

[0051] Figure 6A-6G Schematically illustrated are multiple perspective views of another example of a therapeutic device including an articulated upper body and a lower body shown in an open configuration. Figure 6A A perspective view of a therapeutic device is depicted. Figure 6B A top view of the therapeutic device is depicted. Figure 6C A front view of the therapeutic device is depicted. Figure 6D Depicts Figure 6C A cross-sectional view of section BB is shown in FIG. Figure 6E A right side view of the treatment device is depicted. Figure 6F Depicts Figure 6E A close-up view of insert A is shown in FIG. Figure 6G Depicts Figure 6A A perspective view of a variation of the treatment device shown in .

[0052] Figure 7 Depicted is a perspective view of another example of a therapeutic device including an open configuration and a curved body having a variable width and an open slot configured to receive a nerve.

[0053] Figures 8A-8E Schematically illustrated are multiple perspective views of another example of a treatment device including an open configuration and slits in opposing end walls configured to receive and retain a nerve. Figure 8AA perspective view of therapeutic device 800 is depicted. Figure 8B A top view of the therapeutic device is depicted. Figure 8C Depicted are left or right side views of the treatment device. Figure 8D Depicts a front or back view of the treatment device. Figure 8E Depicts Figure 8D A cross-sectional view of section AA is shown in FIG.

[0054] Figure 9 A perspective view of another example of a therapeutic device is shown. The therapeutic device includes an upper body hinged to the lower body and configured to be inserted into a receiving chamber to fluidically seal the chamber.

[0055] Figure 10 A perspective view of another example of a therapeutic device is shown. The therapeutic device is similar to Figure 1 The treatment device shown in , but includes a long-handled scoop-style handle.

[0056] Figures 11A-11E Schematically shows a similar Figure 1 1 and 2. Multiple perspective views of another example of a therapeutic device of a therapeutic device shown in FIG. The therapeutic device has opposing slits disposed along an intersection with a front wall to create a flanged end wall. Figure 11A A perspective view of a therapeutic device is depicted. Figure 11B A top view of the therapeutic device is depicted. Figure 11C A right side view of the treatment device is depicted. Figure 11D Depicted is a rear view looking down from a portion of the handle of the treatment device. Figure 11E Depicted is a cross-sectional view of a section taken along a midline transverse to the longitudinal axis between the left and right sides of the therapeutic device.

[0057] Detailed description

[0058] The device, method and test kit planned herein are designed to quickly repair and improve the recovery of damaged peripheral nerves in acute surgical environments. In some embodiments, the test kit for neurotherapy (for example, peripheral nerve treatment) can include three kinds of sterile solutions, and optionally, a device for local application (directly to the affected nerve) of the focus of the solution. When applied according to the instructions sequence, the solution can include therapeutic addition to acute peripheral nerve injury (PNI) patient surgical repair. The device can be used independently of the test kit and / or solution and method for other therapeutic agents delivered to nerve and / or for isolating nerve for other therapeutic treatments as described herein. The solution can be used independently of the device, and can be used for treating nerve injury according to methods and / or sequences except those described herein. The method and / or sequence described herein can be used together with the modification of solution as described herein, and / or can be used independently of the device as described herein.

[0059] Components

[0060] equipment

[0061] The neurotherapy device can be used in a surgical setting to effectively isolate a segment of a nerve for treatment. The therapy device can be used to uniformly and accurately apply a PEG fusion solution to an isolated segment of a nerve at a nerve repair site (e.g., where the nerves are sutured together to form an anastomosis). Thus, the therapy device can be a delivery device. The therapy device can be included in a kit for nerve repair (e.g., a set of solutions such as for nerve fusion described elsewhere herein), or can be provided as a stand-alone device. The therapy device can allow for the application of a PEG fusion protocol as described elsewhere herein in a reproducible manner.

[0062] The therapeutic device can be made of any suitable material, including polymers, plastics and / or rubber. For example, the therapeutic device can be made of one or more silicones (e.g., polydimethylsiloxane (PDMS)) and / or plastics (such as polyether ether keytone (PEEK), polyurethane, polyethylene, polyolefin, polypropylene, polyether block amide, 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 inspection of the treated nerve within the device. The device can be disposable (e.g., configured for single use) or can be reusable. The device can be sterilizable by conventional methods (e.g., ozone, UV, high pressure sterilization, 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 into a single integral unit. In other embodiments, the device can include separately manufactured components that are subsequently connected together (e.g., bonded together, molded together, and / or mechanically fixed together). In some embodiments, some components can be reversibly connectable / detachable. Some components may be reusable, while others may be disposable.

[0063] In various embodiments, the device or portions of the device may have a hardness of approximately 20-40D. The hardness may be relatively low to prevent damage to the nerve being treated. In some embodiments, the hardness may vary in different portions of the device. For example, the portion of the device that makes physical contact with and / or holds the nerve may be softer than other portions of the device. In some embodiments, the hardness of the device may be adjusted by varying the concentration of the polymer and / or cross-linking agent during the manufacturing process. In some embodiments, the concentration may be variable across different portions of the device to produce variable hardness. The flexibility of the device in different portions may depend on a combination of the hardness of the material and the size of the portion.

[0064] In various embodiments, the therapeutic device can be a solid, non-articular device that creates a temporary fluid containment field around the anastomosis between the proximal and distal ends of the nerve after suturing. The therapeutic device can be configured to prevent unnecessary exposure of surrounding tissue to the therapeutic agent (such as PEG solution) during the administration of the agent to the nerve, so that the device makes local drug delivery possible. In some embodiments, the therapeutic device can be configured not to perform any therapeutic measures and can only have the function of temporarily containing the therapeutic solution around the nerve. The therapeutic device can allow the delivery and removal of a series of therapeutic solutions to be controlled according to the order of administration. The therapeutic device can only be in contact with the treated tissue (nerve). The device can be placed in contact with the treated tissue for only a short time (e.g., 1-10 minutes). The device can be used only for part of a surgical or therapeutic procedure. The device does not need to remain in the body. The device can be used to protect uninjured nerve segments and surrounding tissue from being exposed to PEG during a fusion procedure. The device design can provide ease of use and can minimize interference with the nerve before and after PEG fusion during the surgical operation.

[0065] Figure 1 A perspective view of an example of a neural treatment device 100 is shown, which can be configured as a delivery device for delivering a therapeutic solution (eg, a PEG fusion solution) to a nerve. Figure 1Examples of suitable, but non-limiting, dimensions (in mm) for various portions of the therapeutic device 100 are included. The therapeutic device 100 may generally include a body 102 having a sidewall 104. The sidewall 104 may be integral throughout the body 102, or may include multiple components connected (e.g., attached) to one another. The sidewall 104 may define a containment chamber 106 having a void volume formed within the body 102. The containment chamber 106 may be configured to enclose or partially enclose a length or segment of the nerve 50 ("enclose" may be used herein to refer to any degree of enclosed). For example, the containment chamber may circumferentially surround the nerve by approximately 180 degrees, 270 degrees, 360 degrees, or any number of degrees within the range defined therein. The containment chamber 106 may be configured to hold a volume of a solution (e.g., a therapeutic solution) that surrounds or partially surrounds the enclosed segment of the nerve 50. The body 102 may be configured to surround or partially enclose a segment of the nerve 50 and to create a containment chamber 106 having a sufficient or precise volume to hold a desired amount of solution. The body 102 and the receiving chamber 106 can include dimensions configured to enclose a nerve 50 of a specific length and / or can be configured to enclose a nerve 50 having a specific diameter. The shape, size, and / or material properties of the body 102 can be configured to stably enclose the desired nerve length and size while generally minimizing the outer profile of the body 102, thereby facilitating easy insertion, removal, and / or manipulation of the device 100 within the subject's body space. For example, the body 102 can 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) can select from a variety of device 100 sizes depending on the specific nerve to be treated. In some embodiments, a kit can provide multiple devices 100 to select from that can be of different sizes and / or designated for treating a specific nerve.

[0066] The body 102 can generally include 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 can define a longitudinal axis extending from the left end wall 108 to the right end wall 110, generally along the direction in which the nerve 50 to be treated is to be aligned. The body 102 can include a lower body 114 having a top surface 116. The top surface 116 includes an entry area 118 through which a segment of the nerve 50, or at least a portion thereof, can be received into the receiving chamber 106. The entry area 118 can 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 can be greatest or maximized at the entry 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 entry area 124. In some embodiments, for example, Figure 1In the embodiment shown in FIG, body 102 can be configured as an open bath in which treatment device 100 is configured for use with lower body 114 generally oriented so that top surface 116 faces upward and gravity substantially maintains the solution within the holding chamber. Holding chamber 106 can be configured so that the segment of nerve 50 can be completely disposed within the void volume of holding chamber 106 (e.g., the segment can be completely submerged in the solution), or the segment can be configured to be only partially disposed within holding chamber 106 so that the top of nerve 50 extends upward beyond top surface 116. The volume within holding chamber 106 can be configured to submerge the segment of nerve 50 without filling to top surface 116. An open bath configuration can be particularly advantageous for easily placing and removing nerve 50 from the treatment device.

[0067] In other embodiments, the body 102 can 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 the upper body 120 can cooperate to form a containment chamber 106 that substantially surrounds the entire circumference of the segment of the nerve 50. In some embodiments, the closed bath embodiment can be oriented in any direction during use (e.g., the lower body 114 can be oriented partially or completely above the upper body 120). The lower body 114 and the upper body 120 can form a fluid-tight seal that retains the solution within the containment chamber 106.

[0068] like Figure 1 As shown in FIG, the left end wall 108 and / or the right end wall 110 of the body 102 can include a substantially flat outer surface. The left end wall 108 and the right end wall 110 can 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, which defines the receiving chamber 106. The aperture 126 can include a generally circular cross-section or cross-section of any suitable shape. The aperture 126 can be configured to receive the nerve 50 into the receiving chamber 106. In some embodiments, the aperture 126 can be positioned within the side wall 104 such that the circumference or periphery of the aperture 126 does not intersect the top surface 116. The left end wall 108 and the right end wall 110 can each include a slit 128 extending from the circumference of the aperture 126 to the top surface 116. The slit 128 can extend in a substantially vertical direction. The slit 128 can allow the sidewalls 104 of the body 102 to be offset from one another (eg, 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 .

[0069] In some embodiments, the sidewall 104 may include a tapered or decreasing thickness toward the slit 128. For example, Figure 1, the thickness of the sidewall 104 may decrease as the sidewall 104 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 the sidewall 104 extends from the back side of the intermediate body 112 to the slit 128, wherein both the front and back sides of the slit 128 include portions of the sidewall 104 having a tapered diameter. The end walls 108, 110 of the receiving chamber 106 can be designed to have focusing blades or flanges 130 that allow nerves of a range of diameters to be placed within the device. One or more flanges 130 can be formed by the sidewall 104. The flanges 130 can be configured to curve inwardly toward the receiving chamber 106 and / or outwardly away from the receiving chamber 106. Each flange 130 can have a distal edge that forms an edge of the slit 130 and can have a proximal end that begins to curve near the sidewall 104. When present, the taper can be constant, forming a Figure 1 106 . In some embodiments, the flange 130 may be substantially triangular in shape, or may be higher near the proximal end. In some embodiments, the sidewall 104 may be formed 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 the bending of the flange 130. The flange 130 may have a constant diameter or a reduced diameter at the distal end of the hinge. In some embodiments, the flange 130 may be configured to bend only in one direction or to bend more easily in one direction than in the opposite direction. For example, the flange 130 may be configured to bend inwardly toward the receiving chamber 106, but may be configured not to bend or to be less inclined to bend outwardly away from the receiving chamber 106.

[0070] In some embodiments, the hole 126 can function as a hinge, and the portion of the body 102 on a first side (e.g., the front) of the hinge can be configured to bend away from the portion of the body 102 on a second, opposite side (e.g., the back) of the hinge. Figure 1 , the front portion can bend away from the back portion such that the width of the slit 130 increases the most where it intersects the top surface 116 and increases the least where the slit 130 intersects the hole 126. The strain can be distributed throughout the 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 motions described herein.

[0071] The slit 128 can include opposing edges (e.g., a front edge and a rear edge) that, when biased apart, allow the nerve 50 to pass through the opposing edges. The distal edges of the opposing flanges 130 can form opposing edges of the slit 128. In some embodiments, the opposing edges of the slit 128 can 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 the opposing edges can be no greater than 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 holding chamber 106 prevents leakage of the solution through slit 128 in an unbiased configuration, or such that leakage is minimized and / or negligible. In some embodiments, the opposing edges of slit 128 can overlap in an unbiased configuration. For example, rear flange 130 can be located inside front flange 130, or vice versa. The edges can 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. The overlap can prevent or inhibit fluid from leaking from holding chamber 106. The slit 130 may comprise 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.

[0072] In some embodiments, a user can use a tool (e.g., forceps, pliers, or other surgical instrument) and / or a finger to insert the target segment of nerve 50 into treatment device 100 (into aperture 126) to bias the opposing edges of slit 128 apart in a manner as described elsewhere herein. In some embodiments, slit 128 can be sufficiently biased so that a sufficient gap or space can be established to allow nerve 50 to be received through slit 128 without contacting the edges of slit 128 or with only inadvertent contact, such that the edges do not exert any significant friction or other forces on nerve 50 during insertion. In some embodiments, body 102 can be sufficiently soft and flexible, particularly along the edges of slit 130, so that the forces imparted to slit 130 by contact with nerve 50 bias or facilitate biasing the edges apart without causing damage or injury to the nerve and / or without loosening or disturbing the anastomosis in nerve 50. During insertion, a tool (e.g., forceps, pliers, or other surgical instrument) and / or a finger can be used to grasp nerve 50. In some embodiments, the nerve 50 can be inserted into the left and right holes 126 sequentially in any order. In some embodiments, the nerve 50 can be inserted into the left and right holes 126 substantially simultaneously. In various embodiments, such as Figure 1 In the device 100 shown in FIG, the therapeutic device 100 can be designed to not require any articulated components. The lack or minimization of articulated components avoids any areas during surgery where nerves or other sensitive tissue could become trapped between parts, which could damage or injure the tissue. The use of a flexible body 102 (e.g., made of relatively low durometer silicone) can advantageously provide dynamic properties to the therapeutic device 100 without the need for articulation.

[0073] The aperture 126 can comprise a diameter approximately equal to the diameter of the target nerve 50. The aperture 126 can be configured to form a fluid-tight seal around the circumference of the nerve 50. In some embodiments, the diameter of the aperture 126 can be slightly smaller than the diameter of the nerve 50. For example, the diameter can be at least approximately 90%, 95%, 96%, 97%, 98%, or 99% of the nerve diameter. At least the sidewall 104 surrounding the aperture 126 can be sufficiently compliant so that the aperture 126 is configured to accommodate a slightly larger nerve 50. Offsetting the opposing edges of the slit 130 can increase the effective diameter of the aperture 126. In some embodiments, the flange 130 can be biased inwardly or outwardly to increase the effective diameter of the aperture 126. In some embodiments, the aperture 126 or a portion thereof (e.g., a portion proximal to the slit 128) can be disposed on the flexible flange 130, thereby allowing for greater expansion of the diameter of the aperture 126. The body 102 can be sufficiently soft and flexible so that the aperture 126 does not exert sufficiently high pressure on the nerve 50 to damage or injure the nerve 50 or loosen or disturb the anastomosis in the nerve 50. The flange 130 can be configured to apply a gentle compressive pressure to the nerve 50 to form a compressed fluid seal around a circumferential portion of the nerve 50. In some embodiments, the diameter of the aperture 126 can be slightly larger than the diameter of the target nerve 50. For example, the diameter can be no greater than approximately 101%, 102%, 103%, 104%, 105%, or 110% of the diameter of the target nerve. The surface tension of the solution contained within the containment chamber 106 can prevent the solution from leaking through the aperture 126 in the unbiased configuration, or inhibit leakage, minimizing it and / or rendering it negligible.

[0074] In some embodiments, the nerve diameter can range from 1-4 mm, 4-8 mm, 8-12 mm, or overlapping ranges or ranges. The therapeutic device 100 can be manufactured in several different sizes to accommodate different nerve diameter ranges. The therapeutic device 100 can be applied to any suitable nerve. For example, the therapeutic device 100 can be applied to the digital nerve (approximately 1-2 mm). In another example, the device can be applied to the median nerve in the wrist (approximately 5-7 mm).

[0075] In some embodiments, body 102, or even the entire therapeutic device 100, can be symmetrical about a midline separating the left and right halves of body 102 or device 100. In some embodiments, left end wall 108 can be a mirror image of right end wall 110. For example, aperture 126 can be aligned along the longitudinal axis of device 100. Extending from left end wall 108 to right end wall 110, aperture 126 allows nerve 50 to be placed within aperture 126, with the distribution of void volume of containment chamber 106 surrounding the segment of nerve 50 being uniform as nerve 50 extends from left end wall 108 to right end wall 110. Slit 128 can be aligned along the longitudinal axis of device 100. In some embodiments, aperture 126 can be aligned without exerting any significant tension on nerve 50, allowing nerve 50 to freely move (e.g., translate and / or rotate in a left or right direction) when positioned within aperture 126. Aperture 126 can generally retain the isolated segment of nerve 50 within containment chamber 106. In some embodiments, aperture 126 can be configured in an unbiased configuration to apply a nominal amount of tension to the segment of nerve 50 positioned within receiving chamber 106. The tension can be sufficient to hold or secure nerve 50 within therapeutic device 100. For example, the tension can be configured to prevent or inhibit nerve 50 from sliding in a rightward or leftward direction through aperture 126 of the device. The tension can be configured to remove any slack from the segment of nerve 50 positioned within receiving chamber 106. The tension can prevent nerve 50 from freely rotating within aperture 126.

[0076] In some embodiments, therapeutic device 100 can be configured to position nerve 50 within containment chamber 106 such that nerve 50 is suspended between right and left apertures 126, and the contained solution can fill a portion of the void volume between the bottom surface of containment chamber 106 and the isolated segment of nerve 50. In some embodiments, the contained solution can fill containment chamber 106 to a level such that it surrounds the entire circumference of the isolated segment of nerve 50 between left and right apertures 126. In other embodiments, apertures 126 can be located in sidewalls 104 of left and right end walls 108, 110 such that a portion of the edge or circumference of aperture 126 is coplanar with a portion of a surface of containment chamber 106. In such embodiments, the isolated segment of nerve 50 can be positioned against a surface of containment chamber 106 (e.g., along the bottom surface of containment chamber 106) along the length of central body 112. In such embodiments, body 102 can be used to support the weight of nerve 50 between right and left apertures 126, which can allow body 102 to be configured to apply less frictional forces to nerve 50 via apertures 126. In some embodiments, the contained solution may or may not wet the surface of nerve 50 that is configured to be positioned against the interior surface of containment chamber 106 .

[0077] In some embodiments, hole 126 can be positioned above the bottom surface or floor of holding chamber 106 (proximate to top surface 116) such that the lowest point of hole 126 is higher than the lowest point of the floor. The inner floor of holding chamber 106 can be beveled or curved so that nerve 50 is not subjected to tension when placed in treatment device 100. The floor can rise to meet hole 126 so that nerve 50 can be positioned in a somewhat curved orientation (e.g., a subtle U-shaped orientation) when resting against the floor of holding chamber 106. A variable depth floor can fully support an isolated segment of nerve 50 along the length of middle body 112 but can be configured to position the middle portion of nerve 50 (e.g., anastomosis) in the lower portion of holding chamber 106. The variable depth can allow the contained solution to cover, immerse, and / or be more concentrated near the middle portion while simultaneously directing the contained solution away from hole 126 and / or slit 128 or minimizing the amount of solution disposed adjacent to hole 126 and / or slit 128. Such a configuration can allow the aperture 126 and / or slit 128 to include larger dimensions, exerting less friction, tension, or other forces on the nerve 50, as fluid containment may not be an issue. In some embodiments, the intermediate body 112 and / or the inner chamber 106 can include a length along the longitudinal axis that is at least approximately 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm.

[0078] In some embodiments, the body 102 may include a cross-sectional profile transverse to the longitudinal axis that is circular, semicircular, round, rectangular, square, polygonal, or any other suitable shape. Figure 1 As shown in , the shape can be a partial stadium-shaped or oblong shape. In some embodiments, the outer perimeter of the cross section can substantially match the shape of the inner perimeter, which defines the receiving chamber 106. The sidewall 104 can have a substantially uniform thickness along at least the length of the central body 112. The cross-sectional shape of the receiving chamber 106 can be configured to minimize the surface area to volume ratio of the receiving chamber. In some embodiments, the bottom surface or floor of the receiving chamber can be rounded along the transverse axis. The floor can slope downward or deepen toward the center of the floor in the transverse direction, which may facilitate placement of an isolated segment of the nerve 50 and / or can at least partially cradle the nerve 50 to provide additional support. The contour of the outer surface of the body 102 can be generally rounded or have rounded edges to enable relatively atraumatic engagement of the therapeutic device 100 with the host tissue. 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 positioned on another flat surface. In some embodiments, the body 102 can be symmetrical about a midline extending between the front and back portions of the body 102.

[0079] In various embodiments, the therapeutic device 100 can include a handle 132 for manipulating and / or positioning the device 100. The handle 132 can extend from the body 102. In some embodiments, such as Figure 1 As shown in FIG, a handle 132 may extend from the central body 112. The handle 132 may 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 connected to or integral with the body 102. Figure 1 As shown in , the distal end of the handle 132 can be aligned vertically with the proximal end, or can be located above or below the proximal end as described elsewhere herein. Figure 1 As shown in , the distal end of the handle 132 can 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 can be transverse to the longitudinal axis of the body 102. The top surface of the handle 132 can be flush with the top surface 116 of the body. In some embodiments, the length of the handle can be at least about 5mm, 10mm, 15mm, 20mm, 25mm or 30mm. The placement handle 132 can be designed for grasping with standard pliers, forceps or other surgical tools. In some embodiments, the handle 132 is configured to be grasped by the user's fingers and / or hands. In some embodiments, the handle 132 includes a textured surface that is easy to grasp. The surface of the handle 132 can be textured on any one or more of its surfaces (e.g., top, bottom, left, right). For example, the handle 132 can include a Figure 1 , grooves, bumps, knurled surfaces, etc. shown in . In some embodiments, the handle 132 may include indentations or depressions specifically configured to correspond to specific surgical tools. In some embodiments, the handle 132 is integrally formed with the body 102. In some embodiments, the handle 132 is connected to the body 102 (e.g., glued or mechanically connected). The handle 132 may include the same or different material as the body 102. In some embodiments, the handle 132 may be harder than the body 102 and / or may include a harder material than the body 02. 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 therapeutic device described herein are generally interchangeable with each other and / or the various features of the handles may be interchangeable.

[0080] Figure 2-11E Other examples of various embodiments of the therapeutic device 100 are shown. The various features of the disclosed examples of the therapeutic device 100 may be combined or transformed, unless it is not possible to do so. For example, in some embodiments, the therapeutic device 100 may wrap around the nerve at the anastomosis site with a wiper seal at each end, as described with respect to Figure 1In some embodiments, as described elsewhere herein, the wiper seal can be formed by more than one flange 130 or flexible wiper blade. Corresponding numbers (e.g., 130, 230, and 330) can refer to corresponding features of another figure or embodiment described elsewhere.

[0081] In various embodiments, as described elsewhere herein, the body can include a lower body and an upper body. Figure 2 An example of a therapeutic device 200 is schematically shown including a lower body 214 and an upper body 220. Figure 2 , the lower body 214 and the upper body 220 can fit around the entire circumference of the isolated segment of the nerve 50. The lower body 214 and the upper body 220 can each include approximately half the circumference and half the volume of the containment chamber 206. In some embodiments, the upper body 220 may not include any portion of the void volume of the container chamber 206, but can be used to seal against the top surface 216 of the lower body 214 to completely enclose the containment chamber 206. In some embodiments, as Figure 2 , the upper body 220 can be 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 significantly away from the body 232 to avoid pinching the nerve or any surrounding tissue. A control rod 238 can extend from the hinge 236 and allow the user to hinge the upper body 220 between a closed (e.g., sealed) and an open configuration. In some embodiments, the control rod 238 can be an extension of the connecting arm 234. The control rod 238 can extend in a generally distal direction of the handle 232. The control rod 232 can be driven by one or more fingers of the user or by a tool.

[0082] In various embodiments, the body 202 of the therapeutic device 200 can be configured to deliver a fluid (e.g., a therapeutic solution) into the holding chamber 206, particularly in embodiments comprising a closed bath design. The therapeutic device 200 can include one or more internal fluid channels extending through the body 202, and optionally a handle 232. The device 200 can include one or more fluid ports 240 extending from the body 202 or handle 232, the fluid ports 240 being configured to introduce fluid into and / or withdraw fluid from the holding chamber 206. In some embodiments, the fluid ports 240 can include or be connected to a Luer lock connector. The Luer lock connector can be configured to easily engage and disengage a syringe.

[0083] Figure 2 The treatment device 200 shown schematically in FIG. 2 includes a fluid port 240 extending from a distal end of a handle 232 . Figure 2 The fluid port 240 shown in the figure includes a Luer lock connector that can be easily connected to a continuous syringe loaded with an appropriate solution, such as according to the PEG fusion protocol described elsewhere herein. Thus, the therapeutic device 200 can minimize or remove variability (e.g., volume) in delivering the solution to the holding chamber. Figure 2 The therapeutic device 200 shown in FIG includes a fluid channel that extends 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 can be hollow and can have a fluid channel formed therein. The lower body 214 includes one or more flushing holes 242 that fluidically connect the fluid channel and the holding chamber 206. In some embodiments, the upper body 220 can include an internal fluid channel and one or more flushing holes 242 that fluidically connect the fluid channel and the holding chamber 206, at least when in a closed configuration. When the upper body 220 is in the closed configuration, the fluid channel of the upper body 220 can be placed in fluid communication with the fluid channel in the lower body 214 and / or the handle 232, so that fluid can flow from the lower body 214 and / or the handle 232 into the upper body 220.

[0084] In some embodiments, the therapeutic device can have a slit extending through the therapeutic device from the edge of the lip or flange along the length of the mid-body to the center of the cylindrical or other shaped mid-portion of the body (e.g., to the receiving chamber) to facilitate placement of the nerve 50 (see, e.g., Figure 4A ). The cleft can be formed by or similar to the slit 130 and can effectively divide the body into portions corresponding to the lower body and the upper body. 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 embedded in 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 lock syringe to allow the nerve to be immersed in a solution (e.g., a fusion solution) and rapidly aspirated with saline after treatment is completed.

[0085] Figure 3A-Figure 3E Several perspective views of another example therapeutic device 300 are schematically shown. Figure 3A-Figure 3E Examples of suitable but non-limiting dimensions (in mm) for various portions of therapeutic device 300 are included. Figure 3A A right cross-sectional view of therapeutic device 300 is depicted. Figure 3B A left cross-sectional view of therapeutic device 300 is depicted. Figure 3C A rear view of treatment device 300 is depicted. Figure 3DA front view of treatment device 300 is depicted. Figure 3E A perspective view of a therapeutic device 300 is depicted. The therapeutic 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, connected by a generally cylindrical middle body 312. The body 302 may enclose 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 middle body 312. The slit 329 may be coplanar with the longitudinal axis (it may not extend circumferentially along the middle body 312). The slit may extend from an outer surface of the body 302 to the receiving chamber 306 and may effectively divide or proportionately separate the body 302 into a lower body 314 and an upper body 320. The lower body 314 and the upper body 320 can be connected (e.g., integral with each other) at a point on the circumference of the body 302 opposite the slit 329. The upper body 314 and the lower body can be offset from each other about this point. The slit 329 can extend (e.g., in a radial direction) through each of the end walls 308, 310 to merge with the aperture 326. The slit 329 can 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 opposing edge of the upper body 320 can place the treatment device 300 in an open configuration configured to receive the target nerve 50 through the slit into the receiving chamber 306, such that the nerve 50 extends through the right and left apertures 326. In some embodiments, opposing edges along the length of slit 329 (e.g., an upper edge and a lower edge) can contact one another, placing therapeutic device 300 in a closed configuration in which body 302 is configured to enclose the entire circumference of the isolated segment of nerve 50 within containment chamber 306. In other embodiments, opposing edges of slit 329 can be brought into proximity with one another 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 nerve 50 is enclosed.

[0086] In some embodiments, therapeutic device 300 may include one or more inserts 344 configured to be positioned within containment chamber 306 at the left and right ends of containment chamber 306. Inserts 344 may be generally annular or washer-shaped, including a central aperture. Inserts 344 may generally include substantially flat left and right surfaces. The thickness of insert 344 may be less than the width of the annular flat surface from the outer circumference to the inner circumference. Inserts 344 may be comprised of the same material as body 302 and / or a different material. Inserts 344 may have a hardness that is the same as or less than the hardness of body 302. Inserts 344 may be grouped into pairs, each pair including identical inserts 344 configured to be positioned at the right and left ends of containment chamber 306. At least one of inserts 344 may be configured to form at least a portion of left end wall 308. At least one of inserts 344 may be configured to form at least a portion of right end wall 310. The inserts 344 can each include a slit through its circumference that is configured to align with the slits 328 in the adjacent end walls 308, 310. Each pair of inserts 344 can include an outer diameter approximately equal to the diameter of the receiving chamber 306 and an inner diameter configured to accommodate nerves 200 of different sizes (e.g., 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, etc.).

[0087] In some embodiments, selecting appropriately sized inserts 344 can adapt the therapeutic device 300 to treat different nerves (e.g., nerves of varying diameters). In some embodiments, the inserts 344 can be inserted into and attached to the inner diameter of the containment chamber 306 (e.g., via an adhesive). In some embodiments, the inserts 344 can be manufactured integrally with the body 302. The inserts 344 can be arranged from the outside in (from the inner walls 308, 310 inward) in order of increasing central bore diameter of the inserts 344. In some embodiments, all inserts 344 (e.g., two, three, four, five, etc. pairs) can remain in the containment chamber 306, and inserts 344 having a smaller diameter than the isolated nerve 50 can conform to (e.g., curve around) the size of the nerve 50. Smaller nerves will encounter less resistance than larger nerves because the smaller the nerve, the fewer inserts 344 are likely to deform it. Increasing the number of circumferentially overlapping inserts 344 around the nerve 50 can strengthen the fluid seal around the nerve 50. In some embodiments, the inserts 344 can be independently removed from the receiving chamber 306. For example, the inserts 344 can include a frangible connection to the receiving chamber 306 or can be cut away by a surgical instrument. In some embodiments, a user can selectively remove inserts 344 that include holes that are too small to receive the target nerve 50, leaving only inserts 344 that are large enough to receive the nerve 50.

[0088] In some embodiments, the therapeutic device 300 may include one or more lips 346 extending longitudinally along all or part of the length of the central body 312. The lips 346 may be coplanar with the longitudinal axis (and may not extend circumferentially along the central body 312). The lips 346 may be positioned circumferentially proximate to the slit 329. For example, Figures 3A-3E As shown in FIG, a crack 329 can separate the upper lip 346 from the lower lip 346. One or more lips 346 can each include a groove 348 extending longitudinally along all or part of the length of the lip 346. In some embodiments, the groove 348 can include a groove 348 such as Figures 3A-3E 346. The 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 accommodate, retain and / or frictionally engage a portion of a fixture (e.g., a spring clip) configured to secure the upper lip 346 and the lower lip 346 together. In some embodiments, the groove can abut the outer cylindrical surface of the middle body 312. Securing the upper lip 356 and the lower lip 356 together can place the body 302 in a closed configuration as described above, in which the opposing edges of the crack 329 are brought together or at least the width of the crack 329 is minimized. In some embodiments, the body 302 can be configured so that the lower body 314 and the upper body 320 are in a closed position in an unbiased 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 into the nerve 50. In other embodiments, the lower body 314 and the upper body 320 can be naturally biased to an open configuration, and the securing means can maintain the body 302 in a closed position. The body 302 can 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.

[0089] As described elsewhere herein, the therapeutic device 300 may include one or more fluid ports 340 configured to deliver fluid to and / or remove fluid from the containment chamber 306. The fluid ports 340 may be generally cylindrical. Figures 3A-3E As shown in , the fluid port 340 may include a fluid lumen 341 that extends directly into the receiving chamber 306. The fluid lumen 341 may be substantially linear. The fluid lumen 341 may be generally cylindrical. In some embodiments, as Figure 3A-Figure 3EAs shown in , the therapeutic 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 can be used to deliver fluid into the holding chamber 306 (e.g., via a syringe), and the other fluid port 340 can be used to remove or aspirate fluid from the holding chamber 306 (e.g., via a syringe or a vacuum line). Delivery and removal can occur sequentially and / or simultaneously. In some embodiments, both fluid ports 340 can be used for delivery and / or removal. For example, two components of a therapeutic solution can be delivered to the holding chamber 306 sequentially and / or simultaneously, respectively, via the fluid ports 340. One or more fluid ports 340 can be circumferentially aligned along the outer circumference of the intermediate body 312 or can be offset circumferentially. The fluid ports 340 can be circumferentially offset from the lips 346 by any number from 0 to 360 degrees (e.g., 30, 45, 60, 90, 120, 135, 165, 180, etc.). In some embodiments, the fluid ports 340 can be formed in and / or can extend from one or more lips 346.

[0090] In some embodiments, as respectively with respect to Figure 1 and Figure 2 As described, the treatment device 300 can include one or more handles similar to handles 132 or 232. In some embodiments, the one or more lips 346 and / or the one or more fluid ports 340 can effectively serve as handles and can be configured to be grasped by surgical tools and / or fingers as described elsewhere herein.

[0091] Figures 4A-4D Several perspective views of another example therapeutic device 400 are schematically shown. Figures 4A-4D Examples of suitable but non-limiting dimensions (in mm) for various portions of therapeutic device 400 are included. Figure 4A A perspective view of treatment device 400 is depicted. Figure 4B A front view of treatment device 400 is depicted. Figure 4C Depicts Figure 4B A cross-sectional view of section AA is shown. Figure 4D A left side view of therapeutic device 400 is depicted. Therapeutic device 400 may include the same or similar features as therapeutic device 300.

[0092] Figures 5A-5C Several perspective views of another example therapeutic device 500 are schematically shown. Figures 5A-5C Examples of suitable but non-limiting dimensions (in mm) for various portions of therapeutic device 500 are included. Figure 5AA perspective view of therapeutic device 500 is depicted. Figure 5B A top view of therapeutic device 500 is depicted. Figure 5C A left side view of the treatment device 500 is depicted. The treatment device 500 can include an open bath design similar to the treatment device 100. The treatment device 500 can include a generally rectangular body 502. One or more edges and / or corners of the rectangular body 502 can be beveled and / or rounded. The body 502 can include left and right end walls 508, 510 interconnected by a rectangular middle body 512. The body 502 can include a top surface 516 having an entry area 525 that leads to the holding chamber 506. The introduction and / or removal of fluid from the holding chamber 106 (e.g., flushing and / or aspiration) can be easily accomplished through the entry area 525 in a device that includes an open bath configuration. The holding chamber 506 can have a generally rectangular configuration. In some embodiments, as Figure 5C As shown in FIG, one or more bottom edges (e.g., front edge, back edge, left edge, right edge) along the floor of the receiving chamber 506 may include a beveled surface 550 and / or a rounded 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 downwardly from the top surface 516. The slot 528 may open into the receiving chamber 506 and may be configured to receive and retain 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, with the nerve 50 configured to be positioned within the slot 528. The bottom of the slot 516 may include a rounded (e.g., semicircular) 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 may effectively perform the combined functions provided by the aperture 126 and the slit 128 of the treatment device 100. The body 502 of the treatment device 500 may not include any compliant flanges configured to bend to receive the nerve 50.

[0093] In some embodiments, the bottom of slot 528 can be positioned at a height above, or at the bottom point of, the floor of containment chamber 506. As described elsewhere herein, therapeutic device 500 can be configured to receive an isolated segment of nerve 50 in a slightly curved or bent orientation, such that the nerve droops downwardly between slots 528. Anastomosis 52 of nerve 50 can be generally located in the center of containment chamber 506. As described elsewhere herein, a beveled or rounded surface 550 interconnecting the bottom edge of slot 528 with the floor of containment chamber 506 can help support nerve 50 and more evenly distribute the weight of the nerve throughout the length of body 502, so that nerve 50 is not overly stressed at the point where it passes through the inner bottom edge of slot 528. In some embodiments, the height difference between the bottom of slot 528 and the bottom of the floor of containment chamber 506 can be sufficiently large that nerve 50 can be fully submerged in the central portion of containment chamber 506 without requiring the level of the contained solution to rise above the bottom of slot 528. In some embodiments, the height difference between the bottom of slot 528 and the bottom of the floor of containment chamber 506 can be sufficiently large that nerve 50 can be completely submerged within the central portion of containment chamber 506 without requiring the level of the contained solution to rise above the top of nerve 50 while the top of nerve 50 is located within slot 528, or without requiring the level of the contained solution to rise above the lower portion of nerve 50 while the bottom of nerve 50 is located within slot 528 (e.g., the lower 1 / 4, 1 / 3, 1 / 2, 2 / 3, or 3 / 4 of nerve 50). In this manner, when nerve 50 is located within slot 528, nerve 50 can serve to at least partially fluidly seal the bottom of slot 528 and, if nerve 50 forms a substantially snug fit with slot 528, nerve 50 can facilitate retention of the contained solution within containment chamber 506 due to the increased volume. For example, the height difference can be at least about 0.5mm, 1.0mm, 1.5mm, 2.0mm, 2.5mm, 3.0mm, 3.5mm, 4.0mm, 4.5mm, 5.0mm, 5.5mm, 6.0mm, 6.0mm, 6.5mm, 7.0mm, 7.5mm, 8.0mm, 8.5mm, 9.0mm, 9.5mm or 10mm.

[0094] The handle 532 of the treatment device 500 may include a finger stop 533 on which the user may place a finger (e.g., thumb) to facilitate the user's use of the finger to operate the treatment device 500. The finger stop 533 may include a generally circular shape. Figure 5BAs shown in , the diameter of the finger stop can be equal to or greater than the length of the body 502 of the therapeutic device 500. The finger stop 533 can be surrounded by a thin edge. In some embodiments, both the upper and lower surfaces of the handle 532 can include the finger stop 533. In some embodiments, the finger stop 533 can include the same or different material as the rest of the handle 532. For example, the finger stop 533 can include a softer material. In some embodiments, the finger stop 533 can be a void space extending from the top surface to the bottom surface of the handle 532.

[0095] In various embodiments, the handle 532 may include one or more bends and / or angles. When the handle 532 extends distally, the handle 532 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 arranged more toward the top of the body 502 rather than the bottom of the body 502. The arrangement of the handle 532 on the body 502 and / or the upward angle of the handle 532 may advantageously elevate the majority of the handle 532 beyond the surgical field of view. In some embodiments, the handle 532 may be arranged more toward the bottom of the body 502. In some embodiments, the handle 532 may be arranged more toward the left or right side of the body 502. In some embodiments, the handle 532 may be arranged toward one of the four common angles of the rear side of the body 502. In some embodiments, the handle 532 may be angled downward, to the right, and / or to the left.

[0096] Figure 6A-6G Several perspective views of another example of a configuration of a treatment device 600 configured to receive an opening of a nerve 50 are schematically shown. Figure 6A-6G Examples of suitable but non-limiting dimensions (in mm) for various portions of therapeutic device 600 are included. Figure 6A A perspective view of therapeutic device 600 is depicted. Figure 6B A top view of therapeutic device 600 is depicted. Figure 6C A front view of therapeutic device 600 is depicted. Figure 6D Depicts Figure 6C A cross-sectional view of section BB is shown in FIG. Figure 6E A right side view of therapeutic device 600 is depicted. Figure 6F Depicts Figure 6E A close-up view of insert A is shown in FIG. Figure 6G Depicts Figure 6A600. Treatment device 600 may include many similar or identical features as treatment device 300. Treatment device 600 may include a lower body 614 and an upper body 620 configured to be positioned in an open configuration configured to contain nerve 50 within containment chamber 606, and a closed configuration (not shown) in which the isolated segment of nerve 50 is completely circumferentially surrounded by body 602 of treatment device 600. Body 602 may include a slit 629 between lower body 614 and upper body 620 in the closed configuration. Body 602 may include a lip 646 that may include a groove 648 as described elsewhere herein. Groove 648 may be configured to retain a fixture configured to secure body 602 in the closed configuration. The body 602 of the therapeutic device 600 may be generally cylindrical. Figure 6D and Figure 6E As shown in , the body 602 can 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 can be generally cylindrical, at least along the length of the intermediate body 612.

[0097] The lower body 614 and the upper body 620 can be connected together at a hinge 652. The hinge 652 can be located circumferentially opposite the lip 646 in the closed configuration. The hinge 652 can form part of or can be part of a flange 653 that extends laterally from the middle body 612 along at least a portion of the length of the middle body 612. The flange 653 can be used similar to a handle in the closed configuration to facilitate operation of the treatment device 600. The flange can connect the lower body 614 to the upper body 620. Figure 3A-Figure 3E Unlike the example shown in Figure 3A-Figure 3E In the embodiment shown in FIG. 6 , the deformation or strain experienced by the body 302 when biased apart from the upper body 314 and the lower body 320 can be generally distributed circumferentially around the body 302, and the body 602 can be configured to isolate the deformation to the hinge 652. Figures 6A-6F , hinge 652 can be a living hinge. Living hinge 652 can be a thinned portion of body 602 that, due to its reduced size, is inherently more flexible than the remainder of body 602, even if hinge 652 comprises the same material as the remainder of body 602. In other embodiments, hinge 652 can be a mechanical hinge that includes a separable hinge assembly.

[0098] The body 602 can 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 can be configured to mate with the groove 656 in an interference fit. The interference fit can help to fluidically seal the containment chamber 606 in a closed configuration and / or can help to secure the lower body 614 to the upper body 620. In some embodiments, the ridge 654 can be provided on the lower body 614 and the groove 656 can be provided on the upper body 620. The ridge 654 and the groove 656 can be provided on the intermediate body 612, on the lip 346, or between the intermediate body 612 and the lip 346 (e.g., with portions provided in both). In some embodiments, the body 602 can include multiple mating interference features (eg, two or more rows of ridges 654 and grooves 656).

[0099] The body 602 of the treatment device may include uneven left and right end walls 608, 610. In some embodiments, such as Figures 6A-6C , the end walls 608, 610 can comprise a generally conical shape in the closed configuration. In the closed configuration, the end walls 608, 610 can be generally frustoconical, with the generally circular aperture 626 forming the apex of the conical structure. A fissure 629 between the lower body 614 and the upper body 620 can evenly divide the frustoconical end walls 608, 610 into two halves. The interior surface of the frustoconical end walls 608, 610 can serve as an inclined surface 650 similar to the inclined surfaces described elsewhere herein that helps support the isolation segment of the nerve 50 across the transition from the aperture 526 to the lower floor of the containment chamber 606. In some embodiments, the frustoconical end walls 608, 610 can include a length extending from the intermediate body 612 to the aperture 626 that is at least about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm. As Figure 6A and Figure 6B, the thickness of the frustoconical end walls 608, 610 can decrease or taper as the end walls 608, 610 extend outward from the central body 612. The end walls can be generally compliant and can function similarly to the flange 130 described elsewhere herein. The end walls 608, 610 can be more compliant toward and proximate the aperture 626 than near the central body 612. The end walls 608, 610 can be somewhat deformable so that the circumference of the aperture can effectively expand to accommodate nerves 50 of varying diameters. The frustoconical configuration of the flange-like structure extending at least partially in the longitudinal direction (as opposed to the radial direction) can promote circumferential flexure of the end wall flanges 608, 610, which allows for accommodation of nerves 50 having a diameter greater than the unbiased diameter of the aperture 626. Similarly, the configuration can promote the formation of a compressive seal circumferentially around the nerve 50 within the aperture 626.

[0100] like Figure 6G As shown in the variation depicted in , the treatment device 600 can include one or more operating tabs 658 extending (e.g., extending laterally) from the body 602. The operating tabs 658 can 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 a closed and an open position). The operating tabs 658 can be generally rectangular in shape. The length of the operating tabs 658 can be no more than 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 operating tabs 658 can extend laterally from the end walls 608, 610. For example, as Figure 6G As shown in FIG, four operating tabs 658 may extend from the body 602. Two operating tabs 658 may extend from the front of the body 602, and two operating tabs 658 may extend from the rear of the body 602. Two operating tabs 658 may extend from the left end wall 608, and two operating tabs 658 may extend from the right end wall 610. The operating tabs 658 may extend in directions that are offset by approximately 90 degrees from each other.

[0101] Figure 7A perspective view of another example therapeutic device 700 is depicted. The therapeutic device 700 includes an open bath configuration as described elsewhere herein. The therapeutic device 700 can include a non-uniform width across the length of the body 702. The receiving chamber 706 can include a non-uniform width across the length of the body 702. In some embodiments, the width profile of the body 702 can mirror the width profile of the receiving chamber 706. In some embodiments, the height profile of the body 702 can mirror the depth profile of the receiving chamber 706. The width can be smallest at the left and right ends of the body 702 and largest at a central portion of the length (e.g., at the center). The body 702 can be symmetrical about a midline separating the left and right sides of the therapeutic device 700. In some embodiments, the left and / or right ends of the body 702 can include a sufficiently narrow width to facilitate manipulation (e.g., grasping by a user's fingers or a tool). The body 702 can be symmetrical about a midline separating the front and back sides of the therapeutic device 700. The body 702 can include a generally curved front surface and a generally curved back surface. The body 702 can include a generally circular bottom. The therapeutic device 700 can include a receiving chamber 702 having a generally uneven floor. The floor of the receiving chamber 702 can include a continuous, smooth surface. The floor of the receiving chamber 702 can be deepest at a central point of the receiving chamber 702, which can be configured to receive the anastomosis 52. The depth of the floor can increase from the left and right sides of the therapeutic device 700 toward the center. The continuously smooth floor can function similarly to the inclined surface 550 described elsewhere herein, as it descends from the left and right sides toward the center. The depth of the floor can increase from the front and back sides of the therapeutic device 700 toward the center. The left and right end walls 708, 710 can include only the thickness of the left and right edges of the sidewalls 704, which form a central body 712 extending from the left end to the right end of the body 702. The sidewall 704 can be shaped on the left and right end walls 708, 710 to define a slot 728, similar to the slot 528 described elsewhere herein, configured to receive the nerve 50. As described elsewhere herein, the treatment device 700 can be configured to receive the nerve 50 such that when the nerve 50 is positioned within the slot 528, the nerve 50 at least partially seals the slot 528. The floor can reach a height at the front center of the containment chamber 706 and / or the back center of the containment chamber 706 that is lower than, approximately equal to, or higher than a height reached near the slot 728. The floor of the containment chamber 706 can be designed to substantially isolate the volume of the contained solution near the central portion of the treatment device 700 (e.g., around the anastomosis 52 of the nerve 50).

[0102] Figures 8A-8E Several perspective views of another example therapeutic device 800 are schematically shown. Figures 8A-8E Examples of suitable but non-limiting dimensions (in mm) for various portions of therapeutic device 800 are included. Figure 8AA perspective view of therapeutic device 800 is depicted. Figure 8B A top view of therapeutic device 800 is depicted. Figure 8C A left side view or a right side view of the therapeutic device 800 is depicted. Figure 8D A front view or a back view of the therapeutic device 800 is depicted. Figure 8E Depicts Figure 8D The body 802 of the therapeutic device may include a configuration having the same or similar shape as the body 702, the shape of which is shown in FIG. Figure 7 Description. The treatment device 800 may include left and right end walls 808, 810 that extend inwardly in a generally radial direction from left and right edges of a central body 812 to form left and right surfaces of a receiving chamber 806. The left and right end walls 808, 810 may include slits 828 similar to the slits 128 described elsewhere herein. The slits 828 may extend from the upper surface 816 of the body 808. The slits 828 may extend in a substantially vertical direction. Figure 8E As shown in FIG, the slits can extend all the way to the bottom edges of the left and right end walls 808, 810. The slits 828 can separate 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 slits 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 the nerve 50 between the opposing edges of the flanges 830, which can be biased inwardly and / or outwardly to accommodate the diameter of the nerve 50. In some embodiments, the slits include only a single vertical space within the side wall 804, separating the flanges 830 from one another or from a less compliant portion of the side wall 804. In some embodiments, the gaps forming the slits 828 may extend in at least a certain horizontal direction near the bottom of one or both flanges 830, so that the slits 828 extend below at least a portion of one or both flanges 830, allowing greater flexibility of the flanges 830. In the case of two flanges 830, the slits may branch in opposite directions to extend below both flanges 830. For example, the slits 829 may extend at least partially along the left and / or right semicircles of the end walls 808, 810. Figure 8E The bottom plate of the receiving chamber 806 shown in FIG. 8 extends from the intersection.

[0103] The therapeutic device 800 may include one or more manipulation tabs 858, which may include features similar to the manipulation tabs 658 described elsewhere herein. The manipulation tabs 858 may include generally thin, planar surfaces extending laterally from the body 802 of the therapeutic device 800. The planar surfaces of the manipulation tabs 858 may include a larger surface area that is convenient for gripping by a user's fingers or surgical tools. In some embodiments, such as Figures 8A-8E As shown in , 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 remainder of the top surface 816 of the body 802. The left and right edges of the operating tab may not extend further in the longitudinal direction than the left and right end walls 808, 810 of the device. Figures 8A-8E As shown in FIG, the treatment device 800 may include four operating tabs 858. The operating tabs 858 may generally be located at the left front corner, the right front corner, the left rear corner, and the right rear corner of the body 802.

[0104] Figure 9 A perspective view of another example therapeutic device 900 is shown. The therapeutic device 900 may include a lower body 914 having features generally similar to the lower body 614 of the therapeutic device 600. Figure 9 As shown in FIG, each of the left and right end walls 908, 910 can comprise the lower half of a frustoconical shell that continues vertically upward in a linear manner at a certain height. The left and right end walls can define a slot 928, which is similar to the slot 528 described elsewhere herein. As described elsewhere herein, the configuration of the end walls 908, 910 can be configured to apply a compressive force to the nerve 50 received in the slot 528 and form a compressive seal with the nerve 50.

[0105] As described elsewhere herein, the body 902 of the treatment device 900 can include an upper body 920 connected to a lower body 914 via a hinge 952 (e.g., a living hinge). The upper body 920, or at least a portion thereof, can be configured to be at least partially housed within the housing chamber 906 so as to fluidically seal an access area 924 formed in the top surface 916 of the lower body 914 and / or to fluidically seal at least a portion (e.g., an upper portion) of the slot 928 when the treatment device 900 is placed in a closed configuration. Figure 9As shown in , the insert portion 921 of the upper body 920 may include a shape or outer perimeter configured to generally mate with the inner perimeter of the receiving chamber 906. The upper body 920 may or may not include portions other than a hinge 952 that extends beyond or covers a top surface 916 of the lower body 914, which is located outside of the entry area 924 of the receiving chamber 906. The insert portion 921, configured to be received within 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 remainder 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 can include a concave surface that is configured to be pressed into contact with the generally circular nerve 50 to form a fluid-tight seal around the top of the nerve 50 within the slot 928. The concave surface can be generally semicircular (e.g., an upper semicircle or smaller circle) to conform to the generally circular cross-section of the nerve 50. In some embodiments, the vertical extension 927 can 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 can include a different material (e.g., a softer or more compliant material) than the remainder of the upper body 920 and / or the lower body 914.

[0106] The lower body 914 of the therapeutic device 900 may include one or more support ribs 960 disposed within the containment 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 floor of the containment chamber 906. The support ribs 960 may have a generally circular (e.g., semicircular) cross-sectional shape. The support ribs 960 may include 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 containment chamber 906, such as by increasing the rigidity of the containment chamber 906 (particularly in the lateral direction). The support ribs 960 may be configured to frictionally engage an isolated segment of the nerve 50 extending between the left and right slots 928. The support ribs 960 may facilitate lifting or suspending the nerve 50 from the floor of the containment chamber 906, which may advantageously allow for more complete fluid encapsulation of the nerve 50, particularly around the central portion (e.g., where the anastomosis may be placed). In some embodiments, the nerve 50 can be positioned between front and back opposing support ribs 960. By biasing the support ribs 960 apart (e.g., by separating the front and back portions of the lower body 914 (separated by the slot 928)), the nerve 50 is positioned between the support ribs 960 at an appropriate height and allowed to slide or fall into place under gravity before releasing the force separating the support ribs 960. The support ribs 960 can be biased apart by the user's fingers and / or using appropriate surgical tools as described elsewhere herein.

[0107] Figure 10 A perspective view of another example therapeutic device 1000 is shown. The therapeutic device 1000 may include similar features as the therapeutic device 100. The handle 1032 may include a long handle scoop-like configuration. The handle 1032 may include a bend in an upward direction. The bends may be gradually spaced apart over at least a majority of the length of the handle 1032. Figure 10 As shown in , the bend can include an inflection point where the direction of the bend changes. The distal end of the handle can be located above the top surface 1016 of the body 1002 of the treatment device 1000. The distal end of the handle 1032 can be positioned in a substantially horizontal orientation.

[0108] Figures 11A-11E Several perspective views of another example therapeutic device 1100 are schematically shown. Figures 11A-11E Examples of suitable but non-limiting dimensions (in mm) for various portions of therapeutic device 1100 are included. Figure 11A A perspective view of therapeutic device 1100 is depicted. Figure 11B A top view of therapeutic device 1100 is depicted. Figure 11C A right side view of therapeutic device 1100 is depicted. Figure 11DA rear view looking down from a portion of handle 1132 of treatment device 1100 is depicted. Figure 11E A cross-sectional view of a section taken along a midline transverse to the longitudinal axis between the left and right sides of therapeutic device 1100 is depicted. Therapeutic device 1100 may include features similar to those of therapeutic device 100 and / or therapeutic device 1000. Slits 1128 may be provided along left and right end walls 1108, 1110, along the intersection between a front portion 1105 of sidewall 1104, which forms the front inner surface of containment chamber 1106, and left and right portions 1109, 1111 of sidewall 1104, which form the left and right inner surfaces of containment chamber 1106. Slits 1128 may define a single flange 1130 on each end wall 1108, 1110. Flange 1130 may form the majority of the surface area of inner walls 1108, 1110 and may form the entire inner surface of containment chamber 1106. The distal edge of flange 1130 may oppose anterior sidewall 1105, which forms intermediate body 1112 along the front surface of therapeutic device 1100. Similar to the distal edge of the flange 130 described elsewhere herein, the distal edge of the flange 1130, in an unbiased configuration, can be positioned proximate to the anterior sidewall 1105, can be positioned in contact with the anterior sidewall 1105, or can overlap with the left and right edges of the anterior sidewall 1105. As described, the provision of the slit 1128 between the anterior sidewall 1105 and the left and right sidewalls 1109, 1111, which further defines the proportions of the sidewall 1104, can make the anterior sidewall 1105 relatively more compliant. The anterior sidewall 1105 can be easily bent in a forward direction away from the distal end of the flange 1130, which can advantageously facilitate insertion of the nerve 50 through the slit 1128 and its reception in the aperture 1136. The top edge of the front side wall 1105 can be angled or sloped downward in the direction of the receiving chamber 1106, which can advantageously help guide the nerve 50 into the slit 1128 during introduction of the nerve 50 into the treatment device 1100.

[0109] 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, 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, 1111. Figure 11A and Figure 11C , the slit 1128 can target the circumference of the hole 1126 at the most forward point along the circumference. The front wall 1105 can merge with the left and right side walls 1109, 1111 generally along the bottom and / or rear portion of the circumference of the hole 1126. The provision of the entire hole 1136 under a single flange 1130 can advantageously make the flange 1130 more flexible because a longer horizontal length of the flange 1130 can be separated from the remainder of the end walls 1108, 1110.

[0110] like Figure 11C, receiving chamber 1106 can include sloped surfaces 1150, as described elsewhere herein, interconnecting the front, back, left, and / or right interior surfaces of receiving chamber 1106 with the floor of receiving chamber 1106. Positioning slit 1128 and aperture 1126 more toward front wall 1105 can move the floor of receiving chamber 1106 more toward the front of body 1102 of therapeutic device 1100.

[0111] The treatment device 1100 may include Figure 11C The handle 1132 is shown as having 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 downward. The distal end of the handle 1132 can extend to a vertical position above the bottom of the body 1102, approximately aligned with the bottom of the body 1102 (e.g., Figure 11C ) at the same level as shown in, or below the bottom of the body 1102.

[0112] In various embodiments, the therapeutic device can be configured to facilitate measuring action potentials (e.g., compound action potentials) and / or applying electrical stimulation to isolated segments of nerve 50. In some embodiments, the device's electrodes can be configured to receive electrodes and place them in contact with the nerve. For example, in some embodiments, a needle electrode can be received through fluid port 340 of therapeutic device 300. The electrodes can be located at the left and right ends of nerve 50 on opposite sides of anastomosis 52. In other embodiments, the therapeutic device can include specific access ports or windows configured to receive and / or secure electrodes to the device. In some embodiments, the electrodes can be embedded in the device. For example, the electrodes can be located within the inner surface of a receiving chamber and configured to contact nerve 50 (e.g., on the left and / or right sides of the device). In some embodiments, there can be an electrode configured to serve as a positive terminal and an electrode configured to serve as a negative terminal. In some embodiments, the device can include a ground terminal and / or the negative terminal can be grounded. In some embodiments, the electrodes can be embedded in a polymeric device. The electrodes can be connected to electrical contacts located on the outer surface of the device via electrical leads. The body of the therapeutic device can generally be made of a non-conductive material.

[0113] In some embodiments, the therapeutic device can be used for clinical and / or academic research purposes. The therapeutic device can be used only to isolate nerves for in situ studies or experiments, such as pharmacological studies 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 fusogenic agent other than PEG. In some embodiments, the therapeutic device can be used during an electrofusion (e-fusion) protocol, in which electric shocks are applied to the nerves to stimulate cell fusion (similar to an electroporation protocol). The electrodes described elsewhere herein may be useful for performing an electrofusion protocol. In some methods, the nerve treatment device can be used to maintain and stably hold severed nerve ends in a parallel position during their physical reconnection (e.g., suturing).

[0114] solution

[0115] In various embodiments, the solution applied to the nerve may include commonly used USP grade reagents. The solution may not contain new chemical entities and / or non-USP components. When applied in the appropriate order, the reagents in the solution are responsible for the primary 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 the treatment process may not exceed approximately 1, 2, 3, 4, or 5 minutes each. In preferred embodiments, exposure may be no longer than 2 minutes.

[0116] In some embodiments, the components of the kit may include three solutions and a therapeutic device as described elsewhere herein. The priming solution (Solution 1) may include methylene blue, which may be the active agent. The priming solution may be hypotonic. The priming solution may be a calcium-free solution (e.g., without divalent calcium ions, Ca 2+ ). The presence of calcium may interfere with cellular biochemical processes and / or may induce large cell aggregation and potential premature fusion). The priming solution may comprise a saline solution. The priming solution may be sterile. The priming solution may be pyrogen-free. In some embodiments, the priming solution may comprise methylene blue. Without being limited by theory, methylene blue may act as an antioxidant, provide protection to cells, inhibit or delay Wallerian degeneration of damaged axons, and / or prevent sealing of damaged cell membranes.

[0117] In some embodiments, a 100 mL volume of priming solution may contain approximately: 526 mg sodium chloride, USP (NaCl); 502 mg sodium gluconate, USP (C6H 11NaO7); 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 priming solution may be prepared in ddi-H2O at a pH of approximately 7.4. In some embodiments, the pH may be approximately 6.5-8.0. In some embodiments, the priming solution may be or include Plasma-Lyte TM (Baxter International Inc., Deerfield, IL).

[0118] 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 of no more than 1,000Da, 1,500Da, 2,000Da, 2,500Da, 3,000Da, 3,500Da, 4,000Da, 4,500Da, or 5,000Da. In some embodiments, PEG may include a linear chain molecule. In some embodiments, the chain may include a branched molecule (e.g., a star molecule with 4 arms, 6 arms, or 8 arms). The fusion solution may be sterile. The fusion solution may be pyrogen-free. In some embodiments, a 100mL volume of fusion solution may include approximately 100mg of PEG 3350 (e.g., USP PEG-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 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.

[0119] The sealing solution (Solution 3) may comprise a saline solution. The sealing solution may be isotonic. The sealing solution may comprise 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 comprise 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 may be prepared in ddi-H2O at a pH of approximately 5.0. In some embodiments, the pH may be between approximately 4.0 and 6.5. In some embodiments, the sealing solution may be or may comprise lactated Ringer's solution.

[0120] PEG fusion solution

[0121] The methods of using the kits and / or solutions described elsewhere herein can include sequential delivery of the pharmaceutical agents in solution. In preferred embodiments, delivery of the therapeutic PEG fusion solution can be combined with neurosurgery to repair severed nerves. The method can include a multi-step process as described herein. In various embodiments, one or more steps can be removed or altered where unnecessary for the results. In various embodiments, one or more steps can be added to the method.

[0122] Modern surgical repair of severed peripheral nerves is an open surgical procedure that consists of reconnecting the proximal and distal ends of the severed nerve with microscopic sutures (neurorrhaphy). The therapeutic devices disclosed elsewhere herein can be configured for use in conjunction with neurorhaphy to surgically repair severed peripheral nerves.

[0123] In the first step, the surgical field for nerve repair can be prepared. The mechanism of nerve damage may be important. The treatment device and / or regimen can be configured to treat the stenosis or injury indication. In most cases, a neurolysis procedure can be used to allow for a nearly tension-free repair. Neurolysis can temporarily degenerate nerve fibers and / or relieve pain in the patient. In some embodiments, a clean cut nerve stump may be desirable. Preparation may include trimming if necessary. A calcium-free hypotonic saline solution can be used for irrigation.

[0124] In a second step, the ends of the severed axons can be rinsed. As described elsewhere herein, the ends can be rinsed in a priming solution (Solution 1). The priming solution can contain a hypotonic, Ca-free solution containing 1% methylene blue. 2+ In some embodiments, the terminal end can be rinsed for about 1-2 minutes. Flushing can advantageously increase axoplasm volume, cut open axon terminals, expel intracellular membrane-bound vesicles, and / or prevent the formation of new intracellular vesicles. These various effects of the priming solution can prepare axonal stumps for cell fusion, such as by promoting axon-axon contact in an optimal configuration of cell membranes for cell aggregation and / or fusion.

[0125] In the third step, the severed nerve can be physically reconnected to create an anastomosis. Reconnection can be performed using an operating microscope. Reconnection can include suturing the proximal and distal ends of the nerve together ("neurorrhaphy," which is the standard of care in clinical repair of severed nerves). Reconnection can be performed in the presence of a priming solution. The priming solution can be the same as the solution used in the second step (Solution 1). Reconnection can establish axon-axon contact within the epineurial sheath. In some cases, if the axons are not in direct contact with the repair site, fusion may not occur. In some embodiments, the nerve can be sutured using 8-0 nylon suture or another appropriate suture.

[0126] In a fourth step, as described elsewhere herein, the treatment device can be placed (e.g., gently positioned) so that the sutured nerve remains within the holding chamber of the device. In various embodiments, the anastomosis 52 of the nerve can be roughly centrally located within the holding chamber of the treatment device and / or the deepest portion of the holding chamber, which is configured to maximize exposure of the anastomosis to the applied solution. The delivery device can provide a fluid containment field for isolating the application of the fusion solution and effectively removing the fusion solution. In some embodiments, in addition to or in lieu of the earlier priming step, the reconnected nerve can be rinsed in the priming solution after being placed within the treatment device. The priming solution can be the same solution from the second step (Solution 1).

[0127] In the fifth step, fusion of the closely adjacent 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 comprise approximately 50% w / w PEG / distilled water. The exposure time may be approximately 1-2 minutes. The fusion solution may 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 a decrease in PEG concentration, or decrease with an increase in PEG concentration. In some embodiments, the PEG solution may not comprise more than approximately 50% (w / w) to prevent or minimize any harmful effects of PEG on the treated neurons.

[0128] In a sixth step, the fusion solution can be removed. The fusion solution can be removed from the delivery device holding chamber by aspiration. Aspiration can be performed by a pipette, vacuum, syringe, or any other suitable fluid removal technique.

[0129] In a seventh step, the delivery device can be removed (eg, gently) from around the nerve.

[0130] In step eight, any remaining membrane discontinuities of the fused axonal membrane can be sealed. The discontinuities can be sealed by flushing with an excess volume of sealing solution (Solution 3). The sealing solution can comprise an isotonic Ca-containing solution as described elsewhere herein. 2+ Saline solution. The sealing solution can be applied for about 1-2 minutes. The sealing solution can induce the formation of vesicles that seal any remaining axonal membrane pores. In some embodiments, the sealing solution can be applied to the nerve before removing the therapeutic device from the nerve, in addition to or alternatively after the therapeutic device has been removed.

[0131] In step nine, routine wound closure and incision care can be performed as necessary.

[0132] 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 sequentially reapplied after the previous volume of solution is removed. In some embodiments, the nerve may be rinsed between steps and / or solution reapplications. The rinsing solution may be a saline solution, such as a hypotonic Ca-free solution. 2+ Saline solution or any other suitable solution. In some embodiments, the procedure can be performed without the use of a therapeutic device, or a device other than the devices described herein can be used.

[0133] Compared with traditional nerve repair technology, animal studies of nerve-PEG fusion technology have demonstrated better recovery speed and better functional recovery. PEG fusion schemes can include a clearly defined order of bioengineered chemicals that may not be easily available on the shelf (e.g., PEG 3,350kD). A kit of solutions (and in some embodiments, therapeutic devices) can provide great convenience for surgeons. In some embodiments, the shelf life of the kit can be at least 1-2 years (e.g., the shelf life of the PEG fusion solution). In various embodiments, one or more solutions can be stored in a container under vacuum or an inert gas (e.g., nitrogen or argon) to prevent oxidation. The solution may be contained in a container that protects the solution from radiation. The kit may include instructions for use and / or a recommended amount. The kit may include enough reagents for multiple surgeries, or may be configured for single-use operations. As described elsewhere herein, the kit may optionally include one or more surgical tools or other tools, such as tools configured for manipulating and / or operating a therapeutic device.

Claims

1. A nerve treatment device for forming a fluid containment field around at least a portion of an isolated segment of a nerve, the nerve treatment device comprising: an elongated body extending from a first end wall to a second end wall substantially opposite the first end wall, the elongated body including a top surface and having a longitudinal axis extending from the first end wall to the second end wall; a containment chamber formed within the elongated body and extending from the first end wall to the second end wall, the containment chamber including a void volume intersecting the top surface to form an entry region, the entry region configured to receive the isolated segment of the nerve into the containment chamber, and the containment chamber configured to substantially maintain a volume of fluid within the void volume surrounding at least a portion of the isolated segment of the nerve; and a handle extending laterally from the elongated body; wherein the first end wall includes a first hole leading to the receiving chamber, and the second end wall includes a second hole leading to the receiving chamber, the first hole and the second hole being horizontally disposed more toward the front end of the elongated body and configured to respectively retain the first end and the second end of the isolated segment of the nerve, and configured to respectively form a fluid seal around the first end and the second end of the isolated segment of the nerve, wherein the first end wall includes a first slit extending from the top surface through the first end wall to the first hole, and the second end wall includes a second slit extending from the top surface through the second end wall to the second hole, wherein at least a portion of the first end wall is flexible and configured to be biased in a manner that increases a first width between opposing edges of the first slit such that the nerve can be received into the first aperture through the first slit, and wherein at least a portion of the second end wall is flexible and configured to be biased in a manner that increases a second width between opposing edges of the second slit such that the nerve can be received into the second aperture through the second slit, and The first slit separates the inner front surface of the accommodating chamber from the inner surface of the first end wall, and the second slit separates the inner front surface of the accommodating chamber from the inner surface of the second end wall, so that the front wall of the elongated body formed between the first slit and the second slit is configured to be biased in a forward direction in a manner that increases the first width and the second width.

2. The nerve treatment device according to claim 1, wherein the flexible portion of the first end wall includes a first flange, the thickness of the first flange gradually decreases in the distal direction of the first flange, and the distal edge of the first flange is defined by the first slit.

3. A neurotherapy device according to claim 2, wherein the flexible portion of the first end wall includes a second flange, the thickness of the second flange gradually decreases in the distal direction of the second flange, and the distal edge of the second flange is defined by the first slit, so that the distal edge of the first flange and the distal edge of the second flange form opposite edges of the first slit.

4. A neurotherapy device according to claim 1, wherein the first hole and the second hole are located in the first end wall and the second end wall so that the bottom of the first hole and the bottom of the second hole opposite to the top surface are elevated above the floor of the receiving chamber.

5. A nerve treatment device according to claim 4, wherein the receiving chamber includes 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, and the inclined surface and / or the curved surface are configured to help support the weight of the isolated segment of the nerve.

6. The nerve treatment device of claim 1 , wherein the containment chamber is configured to maintain a 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.

7. The nerve treatment device of claim 1, wherein a width of the access area is greater than a width of the first aperture and greater than a width of the second aperture.

8. The nerve treatment device of claim 1, wherein the first hole and the second hole are circular.

9. A nerve treatment device according to claim 1, wherein the first hole and the second hole include a diameter in an unbiased configuration that is slightly smaller than the diameter of the nerve, such that the first hole and the second hole are configured to form a compression seal around the nerve when received within the first hole and the second hole.

10. The nerve treatment device of claim 1, wherein the first aperture and the second aperture are longitudinally aligned.

11. The nerve treatment device of claim 1 , wherein the bottom surface of the elongated body is generally circular.

12. The nerve treatment device of claim 1, wherein at least a portion of the bottom surface of the elongated body is flat so that the device can be stably maintained on a flat surface.

13. The nerve treatment device of claim 1, wherein the first end wall comprises a contour shape corresponding to a portion of an oblong.

14. The nerve treatment device of claim 1, wherein the depth of the receiving chamber increases between a front end and a rear end of the receiving chamber, the front end and the rear end extending from the first end wall to the second end wall.

15. The neurotherapy device of claim 1, wherein the floor of the receiving chamber is uneven.

16. The nerve treatment device of claim 1, wherein the elongated body and the end wall are integrally formed from the same material.

17. The nerve treatment device of claim 1, wherein the elongate body comprises silicone.

18. The neural treatment device of claim 17, wherein the silicone comprises medical grade polydimethylsiloxane (PDMS).

19. The nerve treatment device of claim 1, wherein the handle extends from a rear side of the device to between the first end wall and the second end wall.

20. The nerve treatment device of claim 1, wherein the handle comprises an elongated body.

21. The nerve treatment device of claim 1, wherein the handle comprises a textured surface.

22. The nerve treatment device of claim 1, wherein the handle includes a top surface that is flush with a top surface of the elongated body.

23. The nerve treatment device of claim 1, wherein the handle extends horizontally in a rearward direction.

24. The nerve treatment device of claim 1, wherein the handle is bent or angled in an upward direction.

25. The nerve treatment device of claim 1, wherein the handle is bent or angled in a downward direction.

26. The nerve treatment device of claim 1, wherein the handle includes a proximal end connected to the elongated body and a distal end opposite the proximal end, the distal end being located above a top surface of the elongated body.

27. The nerve treatment device of claim 1, wherein the handle includes a proximal end connected to the elongated body and a distal end opposite the proximal end, the distal end being located below a top surface of the elongated body.

28. The nerve treatment device of claim 1, wherein the handle includes a bend having an inflection point.

29. The nerve treatment device of claim 1, wherein the first slit bisects the first aperture and the second slit bisects the second aperture.

30. The nerve treatment device of claim 1, wherein the first and second apertures are horizontally centered within the first and second end walls, respectively, between the front and rear ends of the elongated body.

31. The nerve treatment device of claim 1, wherein the first slit intersects a front edge of the first aperture, and wherein the second slit intersects a front edge of the second aperture.

32. The neurotherapy device of claim 1, wherein the front wall of the elongated body includes an angled edge on the top surface that slopes downwardly toward the receiving chamber.

33. A neurotherapy device according to claim 1, further comprising a closed fluid channel formed within the elongated body, the fluid channel comprising a first opening engaged with the receiving chamber and a second opening on the outer surface of the device not engaged with the receiving chamber, wherein fluid can be introduced into and / or removed from the receiving chamber via the fluid channel.

34. The nerve treatment device of claim 33, wherein the second opening is formed on a fluid port extending from the elongate body.

35. The neurotherapy device of claim 33, wherein the fluid port comprises a luer connector configured to connect to a syringe.

36. The nerve treatment device of claim 33, wherein the fluid port extends from a distal end of a handle extending from the elongate body.

37. A neurotherapy device according to claim 33, further comprising a second closed fluid channel formed within the elongated body, the second closed fluid channel comprising a third opening engaged with the receiving chamber and a fourth opening on the outer surface of the device not engaged with the receiving chamber, wherein fluid can be introduced into and / or removed from the receiving chamber via the second closed fluid channel.

38. A neural treatment device for forming a fluid containment field around at least a portion of an isolated segment of a nerve, the neural treatment device comprising: an elongated body extending from a first end wall to a second end wall substantially opposite the first end wall, the elongated body including a top surface and having a longitudinal axis extending from the first end wall to the second end wall; and a containment chamber formed within the elongated body and extending from the first end wall to the second end wall, the containment chamber including a void volume intersecting the top surface to form an entry region, the entry region configured to receive the isolated segment of the nerve into the containment chamber, and the containment chamber configured to substantially maintain a volume of fluid within the void volume surrounding at least a portion of the isolated segment of the nerve; wherein the first end wall includes a first slit extending downwardly from the top surface through the first end wall, and the second end wall includes a second slit extending downwardly from the top surface through the second end wall, wherein at least a portion of the first end wall is flexible and configured to be biased in a manner that increases a first width between opposing edges of the first slit such that the nerve can be received through the first slit, and wherein at least a portion of the second end wall is flexible and configured to be biased in a manner that increases a second width between opposing edges of the second slit such that the nerve can be received through the second slit, and The first slit separates the inner front surface of the accommodating chamber from the inner surface of the first end wall, and the second slit separates the inner front surface of the accommodating chamber from the inner surface of the second end wall, so that the front wall of the elongated body formed between the first slit and the second slit is configured to be biased in a forward direction in a manner that increases the first width and the second width.

39. The nerve treatment device of claim 38, wherein the first slit extends to a bottom of a portion of the receiving chamber adjacent to the first end wall.

40. The nerve treatment device of claim 38, wherein the first slit bisects the first end wall.

41. The nerve treatment device of claim 38, wherein the flexible portion of the first end wall comprises a first flange having a thickness that gradually decreases in a distal direction of the first flange, the distal edge of the first flange being defined by the first slit.

42. A neurotherapy device according to claim 41, wherein the flexible portion of the first end wall includes a second flange, the thickness of the second flange gradually decreases in the distal direction of the second flange, and the distal edge of the second flange is defined by the first slit, so that the distal edge of the first flange and the distal edge of the second flange form opposite edges of the first slit.

43. The nerve treatment device of claim 38, wherein the first slit extends along at least a portion of an intersection between the first end wall and a bottom portion of the receiving chamber adjacent the first end wall.

44. A kit comprising the neurotherapy device of claim 1 and one or more solutions for use with the neurotherapy device.

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