Methods of treating nerve injury

Abstract

The present disclosure relates to methods of treating nerve injury. In particular, the present disclosure relates to methods of repairing a severed peripheral nerve in a subject, and methods of reducing pain and increasing protective sensation.

Description

[0001] Cross-references to related applications

[0002] This patent application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 618,213, filed January 5, 2024, which is incorporated herein by reference in its entirety.

[0003] background

[0004] field

[0005] This disclosure relates to methods for treating nerve injuries. Specifically, this disclosure relates to methods for repairing severed nerves in a subject, and methods for reducing pain and increasing protective sensation.

[0006] Related technical descriptions

[0007] Traumatic peripheral nerve transection commonly occurs in civilian and military populations and typically results in long-term or permanent severe loss of sensory and neuromuscular function. Recovery from a peripheral nerve transection requires the surviving proximal stump to extend a process (an innate behavior), with a growth rate limited to approximately 1 mm / day. This usually involves slow, partial, and nonspecific reinnervation of distal target tissue. The regeneration rate can vary depending on the neuron's location, with proximal segments observed to increase at 2–3 mm / day, while more distal segments may develop at a rate of 1–2 mm / day.

[0008] In large mammals (such as humans), nerve reinnervation occurs months to years after surgery. The distal axonal segment that is severed in mammals always degenerates within three days. (Brushart, T. (2011) Nerve Repair. New York, NY: Oxford University Press, Inc.; Bittner et al.) Regeneration Research 2015, 1406-1408; Spaeth et al, Journal of Neuroscience Research (2012, 1-12). Degeneration of the distal nerve stump leads to denervation of the target tissue, which may severely and permanently atrophy before congenital regeneration can occur.

[0009] Improving the rate and quality of axonal regeneration in mammals has become a primary goal for neuroscientists and peripheral nerve repair surgeons. Current repair strategies (e.g., nerve growth guides, nerve conjugation protectors, microsutures) rely on guiding axonal outgrowth to increase the success rate of nerve reinnervation. While such techniques sometimes improve sensory and functional recovery, they do not affect the rate of axonal growth, do not improve the recovery timeline, and do not prevent Wallerian degeneration of severed distal axons. (Riley) et al ., J Neurosci Res. 2015, 572-583; Ghergherehchi et al ., J Neurosci Res. 2016, 231-245; Kalbermatten et al., J Reconstru Microsurg, 2009 27-33; Kawasaki et al., J Hand Surg Am 2000, 104-11.

[0010] Due to the direct costs of acute care, rehabilitation, workforce loss, and long-term functional impairment, the overall economic impact of peripheral nerve injury (PNI) on the U.S. healthcare system is estimated to exceed $150 billion. These staggering statistics, coupled with the current lack of medical technologies to improve the speed and quality of recovery from PNI, underscore the importance of better treatment alternatives. The current standard of care for transverse PNI involves surgical reattachment of the proximal and distal stumps of the injured nerve using microsurgical sutures (“nerve sutures”). Unfortunately, nerve sutures do not address the potential problem of forced degeneration of all distal axonal segments of the severed nerve. More importantly, no technology in clinical practice or development has demonstrated the ability to increase the speed and quality of natural regeneration, which remains the only possible pathway to sustained recovery. Long-term clinical outcomes of PNI include partial to near-complete loss of sensation and / or function, manifesting as a degree of functional impairment that is often permanent in nature. Therefore, there is a need for methods to improve clinical outcomes for patients with PNI. Summary of the Invention

[0011] In a first aspect of this disclosure, a method for repairing a severed nerve is provided, the method comprising: applying at least 5 mL of hypotonic saline solution to a first and a second severed end of the nerve, wherein the calcium concentration of the hypotonic saline solution is less than 500 ppm; suturing the first and second severed ends together to form a sutured nerve region; placing the sutured nerve region in a cavity that is at least partially closed; applying no more than 2.5 mL of a PEG solution to the severed nerve region within the cavity, wherein the PEG solution is an aqueous solution of 50% PEG 3350 Da w / w; aspirating the PEG solution from the cavity; removing the sutured nerve region from the cavity; and rinsing the sutured nerve region with at least 10 mL of lactated Ringer's solution.

[0012] In a second aspect of this disclosure, a method is provided for repairing severed nerves in subjects who report a digital pain score of 2 to 6 on a scale of 0 to 10, the method comprising: applying hypotonic saline to a first and a second severed end of the nerve, wherein the calcium concentration of the hypotonic saline is less than 500 ppm; suturing the first and second severed ends together to form a sutured nerve region; placing the sutured nerve region in a cavity that is at least partially closed; applying a PEG solution to the severed nerve region within the cavity; aspirating the PEG solution from the cavity; removing the sutured nerve region from the cavity; and rinsing the sutured nerve region with isotonic saline containing calcium; wherein the subject exhibits a decrease in digital pain score of at least 0.5 four weeks after nerve repair.

[0013] In a third aspect of this disclosure, a method is provided to increase protective sensation in the hand of a subject having a severed nerve extending from below the distal edge of the brachial plexus to the fingertip, wherein the subject senses SWMT force using a Semmmes-Weinstein Monofilament Test (SWMT) filament with a specification greater than 6.65 g. The method comprises: applying hypotonic saline to a first and a second severed end of the nerve, wherein the calcium concentration of the hypotonic saline is less than 500 ppm; suturing the first and second severed ends together to form a sutured nerve region; placing the sutured nerve region in a cavity that is at least partially closed; applying a PEG solution to the severed nerve region within the cavity; aspirating the PEG solution from the cavity; removing the sutured nerve region from the cavity; and rinsing the sutured nerve region with a calcium-containing isotonic saline solution; wherein the subject senses SWMT force using an SWMT filament with a specification less than 4.56 g 12 weeks after nerve repair.

[0014] In a fourth aspect of this disclosure, a PEG solution is provided for use in treating nerve damage in a subject, wherein the treatment comprises: Apply at least 5 mL of hypotonic saline solution to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; Apply no more than 2.5 mL of PEG solution to the severed nerve region within the device; Aspirate the PEG solution from the device; and Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of lactated Ringer's solution.

[0015] In some embodiments of the fourth aspect, the calcium concentration of the hypotonic saline is less than 500 ppm. In some embodiments, the PEG solution is an aqueous solution of 50% PEG 3350 Da w / w.

[0016] In some implementations of the fourth aspect, the PEG solution is applied in combination with hypotonic saline solution and lactated Ringer's solution.

[0017] In a fifth aspect of this disclosure, a hypotonic saline solution is provided for use in treating nerve injury in a subject, wherein the treatment comprises: Apply at least 5 mL of hypotonic saline solution to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; Apply no more than 2.5 mL of PEG solution to the severed nerve region within the device; Aspirate the PEG solution from the device; and Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of lactated Ringer's solution.

[0018] In some embodiments of the fifth aspect, the calcium concentration of the hypotonic saline is less than 500 ppm. In some embodiments, the PEG solution is an aqueous solution of 50% PEG 3350 Da w / w.

[0019] In some implementations of the fifth aspect, a hypotonic saline solution is applied in combination with a PEG solution and lactated Ringer's solution.

[0020] In a sixth aspect of this disclosure, a lactated Ringer's solution is provided for use in treating nerve damage in a subject, wherein the treatment comprises: Apply at least 5 mL of hypotonic saline solution to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; Apply no more than 2.5 mL of PEG solution to the severed nerve region within the device; Aspirate the PEG solution from the device; and Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of lactated Ringer's solution.

[0021] In some embodiments of the sixth aspect, the calcium concentration of the hypotonic saline is less than 500 ppm. In some embodiments, the PEG solution is an aqueous solution of 50% PEG 3350 Da w / w.

[0022] In some implementations of the sixth aspect, lactated Ringer's solution is applied in combination with hypotonic saline solution and PEG solution.

[0023] In a seventh aspect of this disclosure, a combination of hypotonic saline solution, PEG solution, and lactated Ringer's solution is provided for use in treating nerve injury in a subject, wherein the treatment comprises: Apply at least 5 mL of hypotonic saline solution to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; Apply no more than 2.5 mL of PEG solution to the severed nerve region within the device; Aspirate the PEG solution from the device; and Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of lactated Ringer's solution.

[0024] In some implementations of the seventh aspect, lactated Ringer's solution is applied in combination with hypotonic saline solution and PEG solution.

[0025] In some of the embodiments described herein, the PEG solution, hypotonic saline solution, and lactated Ringer's solution are applied in the following order: a) Hypotonic saline solution; b) PEG solution; and c) Lactated Ringer's solution; The order of the sequence is a), b), then c).

[0026] In some embodiments described herein, the treatment further includes trimming the first and second severed ends of the nerve prior to the application of a calcium-free hypotonic solution. In some embodiments, the hypotonic saline is calcium-free.

[0027] In some embodiments, the nerve is a peripheral nerve. In some embodiments, the nerve injury is a severed nerve. In some embodiments, the nerve is severed from below the distal edge of the brachial plexus to the fingertip.

[0028] In some implementations, subjects reported a numerical pain score of 2 to 6 on a scale of 0 to 10. In some implementations, subjects showed a decrease in their numerical pain score of at least 0.5 four weeks after nerve repair.

[0029] In some implementations, subjects used Sams-Weinstein monofilament test (SWMT) filaments with a specification greater than 6.65 g to sense SWMT force. In some implementations, subjects used SWMT filaments with a specification less than 4.56 g to sense SWMT force 12 weeks after neural repair.

[0030] In some implementations, subjects showed a decrease of at least 1 in their numerical pain score 12 weeks after nerve repair.

[0031] In some embodiments, the neurotherapy device includes at least a partially enclosed chamber, and a PEG solution is applied into the chamber.

[0032] In the eighth aspect of this disclosure, a packaged product is provided, comprising: First solution; Second solution; The third solution; and Instructions for use that describe the order in which the first solution, the second solution, and the third solution are applied to the nerve repair site; wherein The first solution is a hypotonic saline solution with a calcium concentration of less than 500 ppm; The second solution is a 50% aqueous solution of PEG 3350 Da w / w; The third solution is lactated Ringer's solution; and The instruction manual describes the following method steps: a) Apply at least 5 mL of the first solution to the first and second severed ends of the severed nerve; b) Suture the first and second severed ends together to form a sutured nerve region; c) Place the sutured nerve region within the nerve treatment device; d) Apply no more than 2.5 mL of the second solution to the severed nerve region within the device; e) Aspirate the second solution from the device; f) Remove the sutured nerve region from the device; and g) Rinse the sutured nerve area with at least 10 mL of the third solution; The method steps are in the following order: a), b), c), d), e), f), and then g).

[0033] In the ninth aspect of this disclosure, a packaged product is provided, comprising: First solution; Second solution; Third solution; Neurotherapy devices; and Instructions for use that describe the order in which the first solution, the second solution, and the third solution are applied to the nerve repair site; wherein The first solution is a hypotonic saline solution with a calcium concentration of less than 500 ppm; The second solution is a 50% aqueous solution of PEG 3350 Da w / w; The third solution is lactated Ringer's solution; and The instruction manual describes the following method steps: a) Apply at least 5 mL of the first solution to the first and second severed ends of the severed nerve; b) Suture the first and second severed ends together to form a sutured nerve region; c) Place the sutured nerve region within the nerve treatment device; d) Apply no more than 2.5 mL of the second solution to the severed nerve region within the device; e) Aspirate the second solution from the device; f) Remove the sutured nerve region from the device; and g) Rinse the sutured nerve area with at least 10 mL of the third solution; The method steps are in the following order: a), b), c), d), e), f), and then g).

[0034] In some embodiments of the kit products described herein, the instructions also specify trimming the first and second severed ends of the nerve before applying a calcium-free hypotonic solution. In some embodiments, the first solution is calcium-free hypotonic saline.

[0035] In some implementations, the kit products described herein are used to treat nerve injuries in a subject, optionally, wherein the nerve injury is a peripheral nerve injury. Brief description of the attached diagram

[0037] Figure 1A-1E A multi-view schematic diagram illustrates an example of a neurotherapy device for delivering a therapeutic solution to an isolated segment of a nerve for nerve repair as described herein. The treatment device has opposing slits positioned along their intersection with the anterior wall to form a flanged end wall. Figure 1A A perspective view of the treatment device is depicted. Figure 1B A top view of the treatment device is depicted. Figure 1C A right-side view of the treatment device is depicted. Figure 1D A rear view depicting a portion of the handle of the treatment device is shown from above. Figure 1E A cross-sectional view depicting a section taken along the midline between the left and right sides of the treatment device, which is transverse to the longitudinal axis.

[0038] Figure 2A The changes in the total MHQ score are shown for all subjects, in those receiving the treatment methods described in this article (treatment group A) and those receiving standard treatment (treatment group B).

[0039] Figure 2B The changes in the total MHQ score are shown in subjects with severed nerves extending from below the distal edge of the brachial plexus to the wrist crease, comparing those receiving the treatment methods described herein (treatment group A) and those receiving standard treatment (treatment group B).

[0040] Figure 2C The changes in the total MHQ score are shown in subjects with severed nerves from below the distal edge of the wrist to the fingertips, in subjects receiving the treatment methods described herein (treatment group A) and subjects receiving standard treatment (treatment group B).

[0041] Figure 2D The total MHQ score over time is displayed for subjects receiving the treatment methods described in this article and those receiving standard treatment.

[0042] Figure 3A The static two-point discrimination measurement is shown in subjects receiving the treatment methods described in this article and subjects receiving standard treatment.

[0043] Figure 3B Dynamic two-point discrimination measurements are shown in subjects receiving the treatment methods described in this article and subjects receiving standard treatment.

[0044] Figure 4A The results of the Sams-Weinstein monofilament test (SWMT) are shown for subjects who received the treatment described in this article and those who received standard treatment after 12 weeks.

[0045] Figure 4B The results of the Sams-Weinstein monofilament test (SWMT) are shown at different time points throughout the 48 weeks for subjects receiving the treatment described in this article and those receiving standard treatment.

[0046] Figure 5 The results of MRCC motor function tests are shown in subjects who received the treatment methods described in this article and those who received standard treatment after 48 weeks.

[0047] Figure 6 The percentage of respondents who received the treatment methods described in this article and those who received standard treatment is shown based on their PGIC score at 48 weeks.

[0048] Figure 7A The baseline NPRS scores of subjects who received the treatment methods described in this article and those who received standard treatment are displayed across all subjects.

[0049] Figure 7B The changes in NPRS scores relative to baseline are shown for subjects receiving the treatment methods described in this article and subjects receiving standard treatment.

[0050] Figure 7C The changes in NPRS scores relative to baseline are shown in subjects with severed nerves extending from below the distal edge of the brachial plexus to the wrist crease, for those receiving the treatment methods described herein and those receiving standard treatment.

[0051] Figure 7D The changes in NPRS scores relative to baseline are shown for subjects with severed nerves extending from below the distal edge of the wrist to the fingertips, those receiving the treatment methods described herein and those receiving standard treatment.

[0052] Figure 7E The NPRS of subjects receiving the treatment methods described herein and those receiving standard treatment are shown at weeks 4, 8, and 12 postoperatively.

[0053] Figure 8A The baseline CISS scores of subjects receiving the treatment methods described in this article and those receiving standard treatment are shown.

[0054] Figure 8B The changes in CISS scores relative to baseline were shown for subjects receiving the treatment methods described in this article and those receiving standard treatment throughout the 48 weeks.

[0055] Figure 8C CISS is shown at weeks 4, 8, and 12 postoperatively in subjects who received the treatment methods described herein and those who received standard treatment.

[0056] Detailed description of the preferred implementation scheme

[0057] In a first aspect of this disclosure, a method for repairing a severed nerve is provided, the method comprising: applying at least 5 mL of hypotonic saline solution to a first and a second severed end of the nerve, wherein the calcium concentration of the hypotonic saline solution is less than 500 ppm; suturing the first and second severed ends together to form a sutured nerve region; placing the sutured nerve region in a cavity that is at least partially closed; applying no more than 2.5 mL of a PEG solution to the severed nerve region within the cavity, wherein the PEG solution is an aqueous solution of 50% PEG 3350 Da w / w; aspirating the PEG solution from the cavity; removing the sutured nerve region from the cavity; and rinsing the sutured nerve region with at least 10 mL of lactated Ringer's solution.

[0058] In a second aspect of this disclosure, methods for repairing severed nerves in subjects reporting mild to moderate pain due to nerve rupture are also provided. In some embodiments, repairing severed nerves in such patients using the methods described herein results in greater and / or faster pain relief compared to standard treatment. In some embodiments, the pain level is determined using the Numerical Pain Rating Scale (NPRS). The NPRS scale has a numerical rating of 0–10, where 0 represents no pain, 1–3 represents mild pain, 4–6 represents moderate pain, and 7–10 represents severe pain. Subjects are asked to give three pain ratings, corresponding to the mildest and most severe pain experienced currently and in the past 24 hours. The average of the three ratings is used to represent the subject's pain level in the past 24 hours. See McCaffery, M., Beebe, A., et al. (1989). Pain: Clinical manual for nursing practice, Mosby St. Louis, MO, which is incorporated herein by reference in its entirety.

[0059] In some embodiments described herein, the molecular weight of polyethylene glycol (i.e., PEG) is the weight-average molecular weight (M). w In some such embodiments, the polymer's M wThis can be determined using techniques known in the art, such as, but not limited to, size exclusion chromatography (SEC), gel permeation chromatography (GPC), static light scattering (SLS), dynamic light scattering, and ultracentrifugation. In some embodiments described herein, the molecular weight of the poly(ethylene glycol) (i.e., PEG) is number average molecular weight (M). n In some such embodiments, the polymer's M n It can be determined by techniques known in the art, such as, but not limited to, colligative property measurement, osmometry, and freezing point depression.

[0060] In some embodiments, subjects report a digital pain score of 2 to 6 on a scale of 0 to 10, and the method includes: applying hypotonic saline to a first and a second severed end of the nerve, wherein the calcium concentration of the hypotonic saline is less than 500 ppm; suturing the first and second severed ends together to form a sutured nerve region; placing the sutured nerve region in a cavity that is at least partially closed; applying a PEG solution to the severed nerve region within the cavity; aspirating the PEG solution from the cavity; removing the sutured nerve region from the cavity; and rinsing the sutured nerve region with isotonic saline containing calcium. Some embodiments include identifying subjects with a digital pain score of 2 to 6 prior to nerve repair.

[0061] In some implementations, subjects showed a decrease in their digital pain rating of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 four weeks after nerve repair. In some implementations, subjects showed a decrease in their numerical pain rating of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 eight weeks after nerve repair. In some such implementations, subjects showed a decrease in their numerical pain rating of at least 0.5 four weeks after nerve repair. In some implementations, subjects exhibited a decrease in their numerical pain rating of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 12 weeks after nerve repair. In some such implementations, subjects exhibited a decrease in their numerical pain rating of at least 1.0 12 weeks after nerve repair. In some implementations, subjects showed a decrease in their digital pain rating of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 24 weeks after nerve repair.

[0062] In a third aspect of this disclosure, a method for increasing protective sensation in the hand of a subject having a severed nerve extending from below the distal edge of the brachial plexus to the fingertips is also provided. Thus, in some embodiments, the subject exhibits reduced sensation in the hand due to nerve damage, including a reduction to the degree of diminished or lost protective sensation. In some embodiments, the Samms-Weinstein monofilament test (SWMT) is used to determine the reduction in sensation. The Samms-Weinstein monofilament test (SWMT) is a clinical tool used to assess peripheral nerve damage before and / or after recovery. See, for example, McGill et al., Diabet Med, 1998, 15: 615–617, which is incorporated herein by reference in its entirety. Subjects with higher sensitivity perceived SWMT tests using fibers with a specification of 2.83–4.31 g; subjects with lower sensitivity perceived SWMT tests using fibers with a specification of 4.56–6.65 g; and subjects with no sensitivity perceived SWMT tests using fibers with a specification greater than 6.65 g.

[0063] In some embodiments, subjects exhibit a Sams-Weinstein monofilament test (SWMT) using fibers with a specification greater than 6.65 g, and the method includes: applying hypotonic saline to a first and second severed end of the nerve, wherein the calcium concentration of the hypotonic saline is less than 500 ppm; suturing the first and second severed ends together to form a sutured nerve region; placing the sutured nerve region in a cavity that is at least partially closed; applying a PEG solution to the severed nerve region within the cavity; aspirating the PEG solution from the cavity; removing the sutured nerve region from the cavity; and rinsing the sutured nerve region with calcium-containing isotonic saline. Some embodiments include identifying subjects exhibiting SWMT performance using fibers with a specification greater than 6.65 g prior to nerve repair.

[0064] In some embodiments, subjects demonstrated SWMT testing using fibers with a specification of less than 4.56 g at 4, 8, 12, 24, or 48 weeks post-neural repair. In some such embodiments, subjects demonstrated SWMT testing using fibers with a specification of less than 4.56 g at 12 weeks post-neural repair. In some embodiments, subjects demonstrated SWMT testing using fibers with a specification of 2.83–4.31 g at 4, 8, 12, 24, or 48 weeks post-neural repair. In some such embodiments, subjects demonstrated SWMT testing using fibers with a specification of 2.83–4.31 g at 4, 8, 12, 24, or 48 weeks post-neural repair.

[0065] In some embodiments of the methods described herein, the nerve is a peripheral nerve. In some such embodiments, the nerve ruptures below the distal edge of the brachial plexus to the fingertip. In other embodiments, the nerve ruptures below the distal edge of the brachial plexus to the wrist crease. In yet another embodiment, the nerve ruptures below the distal edge of the wrist to the fingertip.

[0066] In some embodiments, the method described herein includes placing the sutured nerve region within a cavity that is at least partially closed. Non-limiting examples of such partially closed cavities are described in International Patent Publication No. WO 2019 / 023274, which is incorporated herein by reference in its entirety. For example, in some embodiments, the partially closed cavity may be as follows: Figure 1A-1E The illustrated neurotherapy device.

[0067] Figure 1A-1E The multi-view view of the treatment device 1100 is shown schematically. Figure 1A-1E Examples of suitable but non-restrictive dimensions (in mm) for the various parts of the treatment device 1100. Figure 1A A perspective view of the treatment device 1100 is depicted. Figure 1B A top view of the treatment device 1100 is depicted. Figure 1C A right-side view of the treatment device 1100 is depicted. Figure 1D A rear view of a portion of the handle 1132 of the treatment device 1100 is depicted from above. Figure 1EA cross-sectional view is depicted, taken along the midline between the left and right sides of the treatment device 1100, which is transverse to the longitudinal axis. A slit 1128 may be provided along the right end wall 1108 and the left end wall 1110, located at the junction between the front portion 1105 of the side wall 1104 and the left and right portions 1109 and 1111 of the side wall 1104. The front portion 1105 of the side wall 1104 forms the front inner surface of the receiving chamber 1106, and the left and right portions 1109 and 1111 of the side wall 1104 form the left and right inner surfaces of the receiving chamber 1106. A single flange 1130 may be defined on each end wall 1108, 1110. The flange 1130 may form a large portion of the surface area of ​​the end walls 1108, 1110 and may form the entire inner surface of the receiving chamber 1106. The distal edge of flange 1130 may be opposite anterior sidewall 1105, which forms an intermediate body 1112 along the anterior surface of treatment device 1100. The distal edge of the unbiased flange 1130 may be positioned close to the anterior sidewall 1105, either in contact with it or overlapping its left and right edges, similar to the distal edge of flange 130 described elsewhere herein. The positioning of slit 1128, which more clearly divides sidewall 1104 into anterior sidewall 1105 and left and right sidewalls 1109 and 1111 respectively, as described, allows for greater plasticity of the anterior sidewall 1105. The anterior sidewall 1105 can be easily bent forward distally from flange 1130, which advantageously facilitates nerve insertion through slit 1128 for reception in aperture 1136. The top edge of the front sidewall 1105 may be angled or tilted downward along the direction of the receiving chamber 1106, which may advantageously help guide the nerve into the slit 1128 during the introduction of the nerve into the treatment device 1100.

[0068] The hole 1136 of the treatment device 1100 can be disposed off-center on the end walls 1108 and 1110 in a direction transverse to the longitudinal axis. For example, the hole 1136 can be disposed at the junction of the front side wall 1105 and the left side wall 1109 and the right side wall 1111. Figure 1A and Figure 1C As shown, slit 1128 may intersect the circumference of hole 1126 at a point at the foremost end of the circumference. Front wall 1105 may typically merge with left side wall 1109 and right side wall 1111 along the bottom and / or rear of the circumference of hole 1126. The entire hole 1136 is positioned below a single flange 1130, which advantageously allows the flange 1130 to be more flexible because its longer horizontal length can be separated from the rest of the end walls 1108, 1110.

[0069] like Figure 1CAs shown, the receiving chamber 1106 may include a ramp 1150 as described elsewhere herein, which connects the front, rear, left, and / or right inner surfaces of the receiving chamber 1106 to the bottom surface of the receiving chamber 1106. The positioning of the slit 1128 and the hole 1126 more biased towards the front wall 1105 allows the bottom surface of the receiving chamber 1106 to be moved more towards the front of the body 1102 of the treatment device 1100.

[0070] like Figure 1C As shown, the treatment device 1100 may include a handle 1132 having a downward angle. The handle 1132 may 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 may extend to a vertical position above the bottom of the body 1102 and to a horizontal position approximately the same as the bottom of the body 1102 (e.g.,...). Figure 1C (as shown) or below the bottom of the main body 1102.

[0071] In some embodiments, the method described herein further includes pruning the first and second severed ends of the nerve prior to the application of a hypotonic solution.

[0072] In the method described herein, hypotonic saline is applied to the severed ends of the nerve prior to suturing to pre-prime them. Due to osmosis, the application of the hypotonic fluid allows fluid to enter the cells. Furthermore, the application of calcium-free hypotonic saline prevents calcium inflow into the severed axons after injury, thus preventing further damage. In some embodiments, the calcium concentration of the hypotonic saline is less than 1 ppm (parts per million), 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, 20 ppm, 30 ppm, 40 ppm, 50 ppm, 60 ppm, 70 ppm, 80 ppm, 90 ppm, 100 ppm, 125 ppm, 150 ppm, 175 ppm, 200 ppm, 225 ppm, 250 ppm, 275 ppm, 300 ppm, 325 ppm, 350 ppm, 375 ppm, 400 ppm, 425 ppm, 450 ppm, 475 ppm, 500 ppm, 550 ppm, 600 ppm, 700 ppm, 800 ppm, 900 ppm, or 1000 ppm. In some embodiments, the hypotonic saline is calcium-free. In some embodiments, at least 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, or 20 mL of hypotonic saline is applied to the first and second ruptured ends of the nerve. In some specific embodiments, at least 5 mL of hypotonic saline is applied to both the first and second ruptured ends of the nerve.

[0073] In some embodiments, the methods described herein involve applying a poly(ethylene glycol) (“PEG”) solution to the severed nerve region within the cavity. Application of the PEG solution can improve the speed and quality of nerve injury recovery. In some embodiments, the PEG is a low molecular weight PEG. For example, the molecular weight of the PEG may be no greater than about 1 kDa, 2 kDa, 3 kDa, 4 kDa, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, 10 kDa, 11 kDa, 12 kDa, 13 kDa, 14 kDa, or 15 kDa, or within the range defined by any two of the aforementioned molecular weights. In some embodiments, the molecular weight of the PEG may be about 1 kDa to about 15 kDa, about 2 kDa to about 13 kDa, about 3 kDa to about 5 kDa, about 3 kDa to about 10 kDa, or about 5 kDa to about 15 kDa. In some embodiments, the molecular weight of the PEG may be about 3.35 kDa (i.e., 3,350 Da). In some embodiments, no more than about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 is applied to the severed nerve area. mL, 1.8 mL, 1.9 mL, 2.0 mL, 2.1 mL, 2.2 mL, 2.3 mL, 2.4 mL, 2.5 mL, 2.6 mL, 2.7 mL, 2.8 mL, 2.9 mL, 3.0 mL, 3.1 mL, 3.2 mL, 3.3 mL, 3.4 mL, 3.5 mL, 3.6 mL, 3.7 mL, 3.8 mL, 3.9 mL, 4.0 mL, 4.1 mL, 4.2 mL, 4.3 mL, 4.4 mL, 4.5 mL, 4.6 mL, 4.7 4.8 mL, 4.9 mL, or 5.0 mL of PEG solution. In some specific embodiments, no more than 2.5 mL of PEG solution is applied to the severed nerve region within the cavity. In some embodiments, the PEG solution is an aqueous solution of 50% PEG 3350 Da (w / w). In some embodiments, the PEG solution is applied for approximately 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180 seconds or longer, or within the range defined by any two of the foregoing values, before aspiration.In some implementations, the PEG solution is applied for approximately 30-180 seconds, 60-150 seconds, or 90-120 seconds or longer before aspiration.

[0074] In some embodiments, the method described herein requires rinsing the sutured nerve region with a calcium-containing isotonic saline solution. Rinsing the sutured nerve region with an excess of calcium-containing isotonic solution dilutes residual PEG and restores transmembrane osmotic balance of the axon. In some embodiments, at least 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, or 20 mL of calcium-containing isotonic saline solution is applied to the sutured nerve region. In some specific embodiments, at least 10 mL of calcium-free hypotonic saline solution is applied to the sutured nerve region. In some embodiments, the calcium-containing isotonic saline solution is lactated Ringer's solution. Lactated Ringer's solution is a solution commonly used to treat dehydration and restore fluid balance. This solution contains an aqueous solution of sodium chloride, sodium lactate, potassium chloride, and calcium chloride. One liter of lactated Ringer's solution contains approximately 130 mmol of Na. + Approximately 109 mmol Cl - Approximately 28 mmol lactate ions and approximately 4 mmol K+ ions. + and approximately 1.5 mmol Ca 2+ .

[0075] Example

[0076] Some aspects of the embodiments discussed above are further disclosed in detail in the following examples, which are not intended to limit the scope of this disclosure in any way. Those skilled in the art will understand that many other embodiments also fall within the scope of the methods of this application, as described above and in the claims.

[0077] Example 1: Acute single transverse peripheral nerve injury occurring below the distal edge of the brachial plexus, requiring surgical repair. The therapeutic effects of wounds

[0078] A randomized, patient- and assessor-blinded controlled study using a hybrid model of in-person and remote visits evaluated the safety and efficacy of the method described herein compared to standard treatment in treating acute, single-root transverse peripheral nerve injuries requiring surgical repair that occur below the distal margin of the brachial plexus. Subjects in the study suffered confirmed single-root transverse peripheral nerve injuries, including motor and / or sensory impairments of the radial, median, or ulnar nerves, with the injury located distal to the fingertips at the level of the brachial plexus bundle. The nerve injuries were classified as Sunderland grade IV and V (Class III), suitable for direct end-to-end repair with minimal or acceptable tension. Surgical repair occurred within 48 hours of injury. Subjects were at least 16 years old and no older than 80 years. Subjects were assessed at baseline and at weeks 4, 8, 12, 24, 36, and 48 post-operatively.

[0079] Subjects in treatment group B (Tx-B) served as the control group and received standard treatment (SOC) consisting of standard suture nerve repair. Subjects in treatment group A (Tx-A) received the following treatment: 1. Trim nerve stumps as needed; 2. Immediately apply solution #1 to pretreat the damaged nerve stump for fusion; 3. Suture immediately; 4. Place an isolation chamber below the sutured nerve site; 5. Apply solution #2 through the isolation chamber and continue exposure for approximately 90-120 seconds; 6. Draw solution #2 from the isolation chamber as needed; 7. Remove the isolation chamber; 8. Apply solution #3 to rinse, dilute, and irrigate the surgical area; 9. Suture the wound Solution #1 is 5 mL of sterile, calcium-free, hypotonic saline (pretreatment); Solution #2 is 2.5 mL of 3.35 kDa polyethylene glycol (fusion accelerator), 50% aqueous solution; and Solution #3 is 10 mL of sterile lactated Ringer's solution for injection (rinsing). The isolation chamber is an isolation chamber medical device for the local application of Solution #2, substantially similar to the reference [device / device / etc.]. Figure 1A-1E The aforementioned isolation chamber medical device.

[0080] Michigan Hand Outcomes Questionnaire (MHQ)

[0081] The subjects were assessed using the total score of the Michigan Hand Outcomes Questionnaire (MHQ). Chung et al ., J Hand Surg Am.1998; 23(4):575-87, which is incorporated herein by reference in its entirety. The MHQ is a 37-item self-assessment tool that measures functional impairment in six areas: function, activities of daily living, pain, hand appearance, patient satisfaction, and work impairment. Screening assessments of the MHQ should reflect the subject’s perception of functional capacity 7 days prior to injury. Baseline assessments were performed 4 weeks post-injury. A score quantifying the change in the amount of improvement in each area was calculated for each participant by subtracting the score from the second administration of the MHQ from the score of the first administration. The total MHQ score ranged from 0 to 100, with 100 being the best score. Figure 2A The study showed that at weeks 8, 12, 24, and 48, subjects in treatment group A had greater changes in total MHQ score relative to baseline compared to subjects in control group B. Figure 2B and Figure 2C The total MHQ scores of subjects with nerve ruptures extending from the distal edge of the brachial plexus to the wrist crease and from the distal edge of the wrist to the fingertips are displayed separately. Similarly, Figure 2D The results show that subjects in treatment group A had higher total MHQ scores compared to subjects in control group B. Data on changes in total MHQ scores at different time points post-surgery are shown in Table 1, which displays the total MHQ scores, with changes relative to baseline in parentheses.

[0082] Table 1. Total MHQ in the treatment group Comments Results of the changes.

[0083]

[0084] Two-point discrimination (2PD) test

[0085] The Medical Research Council Grade (MRCC) two-point discrimination (2PD) test was also used to assess subjects. These tests typically use neurosensory assessments to evaluate mechanosensory perception in a clinical setting and measure innervation density by testing the ability to identify differences between one to two pressure points. Assessments were performed based on the site of injury. Static and dynamic assessments were performed only on the ulnar and radial sides of the affected fingers (from the palmar crease to the fingertip). Neurosensory endpoints included changes in MRCC sensory scale scores relative to baseline at visits at weeks 4, 8, 12, 24, 36, and 48. Assessments were performed by blinded assessors. The scale is typically used to grade sensory outcomes after peripheral nerve surgery. The scale is divided into S0–S4: S0 is sensory loss; S1 is recovery of deep skin pain; S2 is superficial skin pain and some degree of tactile sensation recovery; S3 is superficial skin pain and tactile sensation recovery without overreaction; and S4 is complete recovery. (MacKinnon et al.,) Plast Reconstr Surg85:419-424, 1990, which is incorporated herein by reference in its entirety.

[0086] Static two-point discrimination (2PD) measures innervation density (the number of nerves present in a region) by testing the ability to identify differences between one or two static pressure points. Dynamic two-point discrimination recovery precedes static two-point discrimination. Dynamic 2PD is used to determine the progression of sensory recovery. A two-point discrimination test disk (2-point disk-criminator) is used to determine the shortest distance (in millimeters) at which a subject can perceive two points (instead of one). Each discrimination test disk measures eight calibrated, fixed two-point intervals within a different range, from 1 mm to 25 mm. Respondents are categorized as subjects with a sensory scale score of S3 or S4. Figure 3A The static 2PD results for subjects in treatment group A and control treatment group B at week 48 are shown. Figure 3B The dynamic 2PD results are shown up to week 12 for subjects in treatment group A and control group B. Except for the dynamic 2PD measurement at week 12, subjects in treatment group A showed a higher response rate compared to subjects in control group B. At week 24, the response rates for the static and dynamic 2PD tests in treatment group A were 77.8% and 62.8%, respectively, while those in treatment group B were 64.3% and 61.5%, respectively. At week 36, the response rates for the static and dynamic 2PD tests in treatment group A were 66.7% and 85.7%, respectively, while the response rate for each of the static and dynamic 2PD tests in treatment group B was 36.4%. At week 48, the response rates for the static and dynamic 2PD tests in treatment group A were 62.5% and 66.7%, respectively, while those in treatment group B were 50.0% and 54.5%, respectively. The data for the 2PD results can be found in Table 2.

[0087] Table 2. Responses of the treatment group to the two-point discrimination test.

[0088]

[0089] Sams-Weinstein Monofilament Test (SWMT)

[0090] The Sams-Weinstein Monofilament Test (SWMT) assesses nerve damage based on its location. SWMT evaluates the perception of skin pressure thresholds, reflecting the reinnervation of surrounding targets. Sensory testing is performed only on the ulnar and radial sides of the affected fingers (from the palmar crease to the fingertip) (finger injury). For motor or mixed motor injuries, testing is performed on the hand region affected by ulnar, radial, or median nerve damage. This assessment is conducted at baseline. Subsequent assessments are performed at weeks 4, 8, 12, 24, 36, and 48. Assessments are performed by blind evaluators. Subjects use left and right sides as self-controls. SWMT provides information about protective sensation; a rigorous system detects relatively small differences in sensory function, and these changes appear early in nerve damage. The assessment tool consists of a set of monofilaments of varying thickness and diameter, with gradient forces ranging from 0.086 gm to 448 gm. Sensory evaluators are individually calibrated to output target forces with a standard deviation within 5%. Normal values ​​for the hand are within the range of green filaments (1.65 mN to 2.83 mN). Figure 4A The results of SWMT on the affected nerve are shown at 12 weeks post-surgery. A significantly higher percentage of subjects in treatment group A had greater sensation in the affected finger compared to subjects in control group B. Furthermore, a significantly higher percentage of subjects in control group B had no sensation at 12 weeks compared to subjects in treatment group A. At week 48, no subjects in treatment group A had sensory loss, compared to 5.3% of subjects in treatment group B. Figure 4B This was also observed at 24 and 36 weeks post-surgery. SWMT data are shown in Table 3.

[0091] Table 3. SWMT Respondents at Selected Time Points

[0092] MRCC Motion Function Test

[0093] The MRCC motor scale score is assessed based on the location of the injury. This assessment is only for motor and mixed motor nerve injuries. MRCC motor assessment is performed at baseline. Subsequent assessments are performed at weeks 4, 8, and 12. Additional assessments are performed at weeks 24, 36, and 48. Assessments are performed by blind evaluators. Muscle strength is best assessed by isolating individual muscle groups and comparing their strength to the patient's. It can be used to assess larger muscles or muscle groups, as well as intrinsic muscles of the hand. The assessment is on a 5-point scale, where 0 / 5 indicates no muscle activation; 1 / 5 indicates muscle activation but no limb movement; 2 / 5 indicates limb movement only when the effects of gravity are eliminated; 3 / 5 indicates the subject can overcome gravity but not resistance; 4 / 5 (or 4+ or 4-) indicates weakened muscle strength, but sufficient to overcome varying degrees of physical resistance; and 5 / 5 indicates intact muscle strength. Figure 5 The study provided motor function test results, showing the number of patients with a score of 3 / 5 or higher at week 48.

[0094] Changes in Patient Overall Impression (PGIC)

[0095] Changes in patient overall impression were determined using a questionnaire and assessed at baseline. Subsequent assessments were performed at weeks 4, 8, 12, 24, 36, and 48. The PGIC assessed all aspects of patient health and evaluated whether clinical status had improved or declined. The percentage of subjects in both treatment groups who responded based on their PGIC scores is shown in the figure. Figure 6 At week 4 post-surgery, both treatment groups A and B had similar percentages of respondents. However, at week 8 post-surgery, the percentage of respondents in treatment group A (76.5%) was higher than that in treatment group B (47.8%). Similar observations were observed at week 12 post-surgery, with the percentage of respondents in treatment group A (70.6%) higher than that in treatment group B (37.5%). At week 24 post-surgery, the percentage of respondents in treatment group A (80.0%) was higher than that in treatment group B (52.4%), and at week 48 post-surgery, the percentage of respondents in treatment group A (86.7%) was higher than that in treatment group B (80.0%).

[0096] Numerical Pain Rating Scale (NPRS)

[0097] The NPRS was reported by the subjects and assessed at baseline. Subsequent assessments were performed at weeks 4, 8, 12, 24, 36, and 48. The NPRS was used to assess pain and determine pain intensity. This test measures a single dimension of overall pain intensity at rest or activity. Patients were asked to rate their pain three times, corresponding to the mildest and most severe pain experienced in the past 24 hours. The mean of the three ratings was used to represent the subject's pain level in the past 24 hours. The NPRS scale is numbered from 0 to 10, where 0 is no pain, 1-3 is mild pain, 4-6 is moderate pain, and 7-10 is severe pain. Baseline pain was similar in both treatment groups. Figure 7A However, compared to the standard treatment group B, subjects in treatment group A showed a greater decrease in NPRS scores relative to baseline at weeks 4, 8, and 12 throughout the 12 weeks. Figure 7B This trend was also observed in weeks 24, 36, and 48. Figure 7B Compared to treatment group B (standard treatment), subjects in treatment group A showed a greater degree of decline relative to baseline at each of these time points. This was true for the entire subject population, as well as for those with severed nerves extending from below the distal edge of the brachial plexus to the wrist crease. Figure 7C ), and objects with severed nerves extending from below the distal edge of the wrist to the fingertips ( Figure 7D This trend was observed throughout the 24 weeks. At weeks 4, 8, and 12, the overall NPRS pain scores of subjects in treatment group A were also lower than those in treatment group B receiving standard treatment. Figure 7E This trend was also observed at week 24, where the mean NPRS score for subjects in treatment group A was 1.70, compared to a mean NPRS score of 3.03 for subjects in control treatment group B. At week 48, the mean NPRS score for subjects in treatment group A was 1.63, compared to a mean NPRS score of 3.03 for subjects in control treatment group B.

[0098] Severity of cold intolerance symptoms (CISS)

[0099] Cold sensitivity is a complex symptom that can manifest as pain, numbness, stiffness, weakness, swelling, and changes in skin color. The CISS (Cold Intolerance Spectroscopy) is used to assess sensitivity to cold in daily life. Cold sensitivity, described as "an excessive or abnormal response to exposure of the injured area to cold, resulting in discomfort or cold avoidance behavior," is a common complaint following various hand injuries and conditions. Carlsson et al ., BMC Musculoskeletal Disord 2010, 11:89; Tark et al., J Hand Surg[Am]1989, 14(1):17–27, which is incorporated herein by reference in its entirety. Symptom severity of cold intolerance (CISS) is used to assess sensitivity to cold intolerance in daily life. Ruijs et al . J Hand Surg Br 2006; 31:533–6, which is incorporated herein by reference in its entirety. The CISS questionnaire was administered at baseline and self-assessed. Subsequent assessments were conducted at weeks 4, 8, 12, 24, and 48. The CISS score reflects symptom severity, with 4 being the lowest severity and 100 the highest.

[0100] Baseline CISS report in Figure 8A In the middle. At weeks 8, 12, 24, and 48, subjects in treatment group B showed a greater increase relative to baseline compared to subjects in treatment group A. Figure 8B At weeks 4, 8, and 12, subjects in treatment group B also had higher overall CISS scores compared to those in treatment group A (standard treatment). At weeks 24 and 48, subjects in treatment group B also showed higher overall CISS scores compared to those in treatment group A.

[0101] Although this application has been described with reference to specific embodiments, those skilled in the art will understand that various changes and substitutions with equivalents can be made without departing from the spirit and scope of this application. Furthermore, numerous modifications can be made to adapt particular circumstances, materials, composition, processes, process steps, or steps to the objectives, spirit, and scope of this application. All such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for repairing a severed nerve, the method comprising: At least 5 mL of hypotonic saline solution is applied to the first and second ruptured ends of the nerve, wherein the calcium concentration of the hypotonic saline solution is less than 500 ppm. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed within a cavity that is at least partially closed; No more than 2.5 mL of PEG solution is applied to the severed nerve region within the cavity, wherein the PEG solution is an aqueous solution of 50% PEG 3350 Da w / w; The PEG solution is aspirated from the chamber; The sutured nerve region is removed from the chamber; and The sutured nerve area was rinsed with at least 10 mL of lactated Ringer's solution.

2. The method of claim 1, further comprising trimming the first and second severed ends of the nerve prior to applying a calcium-free hypotonic solution.

3. The method according to claim 1 or claim 2, wherein the hypotonic saline solution is calcium-free.

4. The method according to any one of claims 1 to 3, wherein the nerve is a peripheral nerve.

5. The method of claim 4, wherein the nerve is severed from below the distal edge of the brachial plexus to the fingertip.

6. A method for repairing severed nerves in subjects who report a numerical pain score of 2 to 6 on a scale of 0 to 10, the method comprising: Hypotonic saline solution is applied to the first and second ruptured ends of the nerve, wherein the calcium concentration of the hypotonic saline solution is less than 500 ppm. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed within a cavity that is at least partially closed; The PEG solution was applied to the severed nerve region within the cavity; The PEG solution is aspirated from the chamber; The sutured nerve region is removed from the chamber; and The sutured nerve area was rinsed with isotonic saline containing calcium. The subjects described above showed a decrease of at least 0.5 in their digital pain score 4 weeks after nerve repair.

7. The method of claim 6, further comprising trimming the first and second severed ends of the nerve prior to applying a calcium-free hypotonic solution.

8. The method according to claim 6 or 7, wherein the nerve is a peripheral nerve.

9. The method of claim 8, wherein the nerve is severed from below the distal edge of the brachial plexus to the fingertip.

10. The method according to any one of claims 6 to 9, wherein the subject exhibits a decrease of at least 1 in digital pain score 1 12 weeks after nerve repair.

11. The method according to any one of claims 6 to 10, comprising applying at least 5 mL of calcium-free hypotonic saline to the first and second ruptured ends of the nerve.

12. The method according to any one of claims 6 to 11, wherein the hypotonic saline is calcium-free.

13. The method according to any one of claims 6 to 12, wherein no more than 2.5 mL of the PEG solution is applied to the severed nerve region within the cavity.

14. The method according to any one of claims 6 to 13, wherein the PEG solution is an aqueous solution of 50% PEG 3350 Daw / w.

15. The method according to any one of claims 6 to 14, wherein the calcium-containing isotonic saline is lactated Ringer's solution.

16. The method according to any one of claims 6 to 15, wherein the sutured nerve region is rinsed with at least 10 mL of lactated Ringer's solution.

17. A method for increasing protective sensation in the hand of an object having severed nerves extending from below the distal edge of the brachial plexus to the fingertips, wherein the object senses SWMT force using a Sams-Weinstein monofilament test (SWMT) filament with a specification greater than 6.65g, the method comprising: Hypotonic saline solution is applied to the first and second ruptured ends of the nerve, wherein the calcium concentration of the hypotonic saline solution is less than 500 ppm. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed within a cavity that is at least partially closed; The PEG solution was applied to the severed nerve region within the cavity; The PEG solution is aspirated from the chamber; The sutured nerve region is removed from the chamber; and The sutured nerve area was rinsed with isotonic saline containing calcium. The subjects were described as sensing SWMT forces using SWMT filaments with a specification of less than 4.56 g 12 weeks after neural repair.

18. The method of claim 17, further comprising trimming the first and second severed ends of the nerve prior to applying a calcium-free hypotonic solution.

19. The method of claim 17 or 18, wherein the subject exhibits a decrease of at least 1 in digital pain score 1 12 weeks after nerve repair.

20. The method according to any one of claims 17 to 19, comprising applying at least 5 mL of calcium-free hypotonic saline to the first and second ruptured ends of the nerve.

21. The method according to any one of claims 17 to 20, wherein the hypotonic saline is calcium-free.

22. The method according to any one of claims 17 to 21, wherein no more than 2.5 mL of the PEG solution is applied to the severed nerve region within the cavity.

23. The method according to any one of claims 17 to 22, wherein the PEG solution is an aqueous solution of 50% PEG 3350 Daw / w.

24. The method according to any one of claims 17 to 23, wherein the calcium-containing isotonic saline is lactated Ringer's solution.

25. The method according to any one of claims 17 to 24, wherein the sutured nerve region is rinsed with at least 10 mL of lactated Ringer's solution.

26. A PEG solution for use in treating nerve damage in a subject, wherein the treatment includes: Apply at least 5 mL of hypotonic saline solution to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; No more than 2.5 mL of the PEG solution is applied to the severed nerve region within the device; The PEG solution is aspirated from the device; as well as Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of lactated Ringer's solution; The calcium concentration of the hypotonic saline solution is less than 500 ppm; and The PEG solution is a 50% aqueous solution of PEG 3350 Da w / w.

27. The PEG solution for the stated purpose according to claim 26, wherein the PEG solution is administered in combination with the hypotonic saline solution and the lactated Ringer's solution.

28. A hypotonic saline solution for the treatment of nerve injury in a subject, wherein the treatment includes: At least 5 mL of the hypotonic saline solution was applied to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; Apply no more than 2.5 mL of PEG solution to the severed nerve region within the device; The PEG solution is aspirated from the device; as well as Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of lactated Ringer's solution; The calcium concentration of the hypotonic saline solution is less than 500 ppm; and The PEG solution is a 50% aqueous solution of PEG 3350 Da w / w.

29. The hypotonic saline solution for the purpose according to claim 28, wherein the hypotonic saline solution is administered in combination with the PEG solution and the lactated Ringer's solution.

30. Lactated Ringer's solution for the treatment of nerve damage in subjects, wherein the treatment includes: Apply at least 5 mL of hypotonic saline solution to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; Apply no more than 2.5 mL of PEG solution to the severed nerve region within the device; The PEG solution is aspirated from the device; as well as Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of the lactated Ringer's solution; The calcium concentration of the hypotonic saline solution is less than 500 ppm; and The PEG solution is a 50% aqueous solution of PEG 3350 Da w / w.

31. The lactated Ringer's solution for the stated purpose according to claim 30, wherein the lactated Ringer's solution is administered in combination with the hypotonic saline solution and the PEG solution.

32. A combination of hypotonic saline solution, PEG solution, and lactated Ringer's solution for use in the treatment of nerve injury in a subject, wherein the treatment includes: At least 5 mL of the hypotonic saline solution was applied to the first and second ruptured ends of the nerve. The first and second severed ends are sutured together to form a sutured nerve region; The sutured nerve region is placed inside the nerve treatment device; No more than 2.5 mL of the PEG solution is applied to the severed nerve region within the device; The PEG solution is aspirated from the device; as well as Remove the sutured nerve region from the device; and rinse the sutured nerve region with at least 10 mL of lactated Ringer's solution; The calcium concentration of the hypotonic saline solution is less than 500 ppm; and The PEG solution is a 50% aqueous solution of PEG 3350 Da w / w.

33. The PEG solution for the purpose according to any one of claims 26 or 27, the hypotonic saline solution for the purpose according to any one of claims 28 or 29, the lactated Ringer's solution for the purpose according to any one of claims 30 and 31, or the combination for the purpose according to claim 32, wherein the PEG solution, the hypotonic saline solution, and the lactated Ringer's solution are applied in the following order: a) The hypotonic saline solution; b) The PEG solution; and c) The lactated Ringer's solution; The order of the sequence is a), b), then c).

34. A PEG solution for the purpose according to any one of claims 26, 27 or 33, a hypotonic saline solution for the purpose according to any one of claims 28, 29 or 33, a lactated Ringer's solution for the purpose according to any one of claims 30, 31 or 33, or a combination thereof for the purpose according to any one of claims 32 or 33, wherein the treatment further comprises trimming the first and second severed ends of the nerve prior to application of the calcium-free hypotonic solution.

35. A PEG solution for the purpose according to any one of claims 26, 27, 33 or 34; a hypotonic saline solution for the purpose according to any one of claims 28, 29, 33 or 34; a lactated Ringer's solution for the purpose according to any one of claims 30, 31, 33 or 34; or a combination thereof for the purpose according to any one of claims 32-34, wherein the hypotonic saline solution is calcium-free.

36. A PEG solution for the purpose according to any one of claims 26, 27 or 33-35, a hypotonic saline solution for the purpose according to any one of claims 28, 29 or 33-35, a lactated Ringer's solution for the purpose according to any one of claims 30, 31 or 33-35, or a combination thereof for the purpose according to any one of claims 32-35, wherein the nerve is a peripheral nerve.

37. A PEG solution for the purpose according to any one of claims 26, 27 or 33-36, a hypotonic saline solution for the purpose according to any one of claims 28, 29 or 33-36, a lactated Ringer's solution for the purpose according to any one of claims 30, 31 or 33-36, or a combination thereof for the purpose according to any one of claims 32-36, wherein the nerve injury is a severed nerve.

38. The PEG solution for the purpose of claim 37, the hypotonic saline solution for the purpose of claim 37, the lactated Ringer's solution for the purpose of claim 37, or a combination thereof for the purpose of claim 37, wherein the nerve is severed from below the distal edge of the brachial plexus to the fingertip.

39. A PEG solution for the purpose according to any one of claims 26, 27 or 33-38, a hypotonic saline solution for the purpose according to any one of claims 28, 29 or 33-38, a lactated Ringer's solution for the purpose according to any one of claims 30, 31 or 33-38, or a combination thereof for the purpose according to any one of claims 32-38, wherein the subject reports a numerical pain score of 2 to 6 on a scale of 0 to 10.

40. The PEG solution for the purpose of claim 39, the hypotonic saline solution for the purpose of claim 39, the lactated Ringer's solution for the purpose of claim 39, or a combination thereof for the purpose of claim 39, wherein the subject exhibits a decrease in digital pain score of at least 0.5 four weeks after nerve repair.

41. The PEG solution for the stated purpose according to claim 38, the hypotonic saline solution for the stated purpose according to claim 38, the lactated Ringer's solution for the stated purpose according to claim 38, or a combination thereof for the stated purpose according to claim 38, wherein the object is subjected to SWMT force sensing using a Sams-Weinstein monofilament test (SWMT) filament with a specification greater than 6.65 g.

42. The PEG solution for the purpose of claim 41, the hypotonic saline solution for the purpose of claim 41, the lactated Ringer's solution for the purpose of claim 41, or a combination thereof for the purpose of claim 41, wherein the subject senses SWMT force using SWMT filaments with a specification of less than 4.56 g 12 weeks after neural repair.

43. The PEG solution for the purpose according to any one of claims 39-42, the hypotonic saline solution for the purpose according to any one of claims 39-42, the lactated Ringer's solution for the purpose according to any one of claims 39-42, or a combination of the two for the purpose according to any one of claims 39-42, wherein the subject exhibits a decrease in digital pain score of at least 1 1 week after nerve repair.

44. A PEG solution for the purpose according to any one of claims 26, 27 or 33-43, a hypotonic saline solution for the purpose according to any one of claims 28, 29 or 33-43, a lactated Ringer's solution for the purpose according to any one of claims 30, 31 or 33-43, or a combination thereof for the purpose according to any one of claims 32-43, wherein the neurotherapy device comprises at least a partially enclosed chamber, and the PEG solution is applied within the chamber.

45. Package product, which includes: First solution; Second solution; Third solution; and Instructions for use that describe the order in which the first solution, the second solution, and the third solution are applied to the nerve repair site; in The first solution is a hypotonic saline solution with a calcium concentration of less than 500 ppm; The second solution is a 50% aqueous solution of PEG 3350 Da w / w; The third solution is lactated Ringer's solution; and The instruction manual describes the following method steps: h) Apply at least 5 mL of the first solution to the first and second severed ends of the severed nerve; i) Suture the first and second severed ends together to form a sutured nerve region; j) Place the sutured nerve region within the nerve treatment device; k) Apply no more than 2.5 mL of the second solution to the severed nerve region within the device; l) Aspirate the second solution from the device; m) Remove the sutured nerve region from the device; as well as n) Rinse the sutured nerve area with at least 10 mL of the third solution; The method steps are in the following order: a), b), c), d), e), f), and then g).

46. ​​Package product, which includes: First solution; Second solution; Third solution; Neurotherapy device; and Instructions for use that describe the order in which the first solution, the second solution, and the third solution are applied to the nerve repair site; in The first solution is a hypotonic saline solution with a calcium concentration of less than 500 ppm; The second solution is a 50% aqueous solution of PEG 3350 Da w / w; The third solution is lactated Ringer's solution; and The instruction manual describes the following method steps: h) Apply at least 5 mL of the first solution to the first and second severed ends of the severed nerve; i) Suture the first and second severed ends together to form a sutured nerve region; j) Place the sutured nerve region within the nerve treatment device; k) Apply no more than 2.5 mL of the second solution to the severed nerve region within the device; l) Aspirate the second solution from the device; m) Remove the sutured nerve region from the device; as well as n) Rinse the sutured nerve area with at least 10 mL of the third solution; The method steps are in the following order: a), b), c), d), e), f), and then g).

47. The kit product according to any one of claims 45 or 46, wherein the description further illustrates trimming the first and second severed ends of the nerve prior to applying the calcium-free hypotonic solution.

48. The kit product according to any one of claims 45 to 47, wherein the first solution is calcium-free hypotonic saline.

49. The kit product according to any one of claims 45 to 48, which is used to treat a nerve injury in a subject, optionally wherein the nerve injury is a peripheral nerve injury.

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