Covering the proximal nerve stump with chondroitin sulfate proteoglycans prevents traumatic painful neuroma formation by blocking axon regeneration after neurotomy in Sprague Dawley rats.

OBJECTIVE: Neuropathic pain caused by traumatic neuromas is an extremely intractable clinical problem. Disorderly scar tissue accumulation and irregular and immature axon regeneration around the injury site mainly contribute to traumatic painful neuroma formation. Therefore, successfully preventing traumatic painful neuroma formation requires the effective inhibition of irregular axon regeneration and disorderly accumulation of scar tissue. Considering that chondroitin sulfate proteoglycans (CSPGs) can act on the growth cone and effectively inhibit axon regeneration, the authors designed and manufactured a CSPG-gelatin blocker to regulate the CSPGs' spatial distribution artificially and applied it in a rat model after sciatic nerve neurectomy to evaluate its effects in preventing traumatic painful neuroma formation. METHODS: Sixty female Sprague Dawley rats were randomly divided into three groups (positive group: no covering; blank group: covering with gelatin blocker; and CSPG group: covering with the CSPG-gelatin blocker). Pain-related factors were evaluated 2 and 8 weeks postoperatively (n = 30). Neuroma growth, autotomy behavior, and histological features of the neuromas were assessed 8 weeks postoperatively (n = 30). RESULTS: Eight weeks postoperatively, typical bulb-shaped neuromas did not form in the CSPG group, and autotomy behavior was obviously better in the CSPG group (p < 0.01) than in the other two groups. Also, in the CSPG group the regenerated axons showed a lower density and more regular and improved myelination (p < 0.01). Additionally, the distribution and density of collagenous fibers and the expression of α-smooth muscle actin were significantly lower in the CSPG group than in the positive group (p < 0.01). Regarding pain-related factors, c-fos, substance P, interleukin (IL)-17, and IL-1ß levels were significantly lower in the CSPG group than those in the positive and blank groups 2 weeks postoperatively (p < 0.05), while substance P and IL-17 remained lower in the CSPG group 8 weeks postoperatively (p < 0.05). CONCLUSIONS: The authors found that CSPGs loaded in a gelatin blocker can prevent traumatic neuroma formation and effectively relieve pain symptoms after sciatic nerve neurotomy by blocking irregular axon regeneration and disorderly collagenous fiber accumulation in the proximal nerve stump. These results indicate that covering the proximal nerve stump with CSPGs may be a new and promising strategy to prevent traumatic painful neuroma formation in the clinical setting.

Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.

NF-κB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, neural-tumor co-culture in vitro invasion, and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

Preventing neurovascular invasion in desmoid tumors.

Desmoid tumors or aggressive fibromatoses are rare, non-encapsulated, infiltrative and locally aggressive tumors originating from deep musculo-aponeurotic structures. Traditionally, preferred treatment method for desmoid tumors is wide local excision. Depending on the side and type of resection, the reported local recurrence rates range from 15 to 77%. Similarly, in our institution there is a significant recurrence rate (24%) in patients who underwent surgery for desmoid tumor. After several recurrences, amputation may be inevitable following repeating vascular and nerve reconstructions. There is a need for a nonviable barrier in order to prevent the invasion of the viable tumor to the neurovascular structures which are also viable tissues. Depending on this need, we present two cases that we used synthetic vascular graft in their operations to cover neurovascular structures in order to prevent tumor invasion. For patients who are not suitable for radiotherapy and the neurovascular structures need to be secured because of the risk of local recurrence, this method can prevent possible future invasion of vessels and nerves.

The role of different methods of nerve ablation in prevention of neuroma.

BACKGROUND: The aim of this study was to compare the incidence of neuroma formation and neuropathic pain following different techniques of nerve ablation in a rat sural nerve model. METHODS: Rat sural nerve was subjected to four different techniques of ablation with standardized creation of a 1-cm gap (n = 15 in each group). These included nerve avulsion, transection and burying in muscle, transection and folding of nerve, and transection alone. Animals were killed after 3 months. Explanted nerves were sectioned and stained with Masson trichrome and S-100 stain against neural tissue. The maximal neural cross-sectional area and neural-to-connective tissue ratio was quantified. Quantitative reverse-transcriptase polymerase chain reaction (n = 5) was used to analyze relative mRNA expression of ciliary neurotrophic factor and calcitonin gene-related peptide. RESULTS: Neural cross-sectional area was statistically increased (p < 0.05) compared with controls in folded, muscle buried, and transected specimens but decreased in avulsed specimens. The neural-to-connective tissue ratio was statistically decreased in the avulsed group. Relative mRNA expression of ciliary neurotrophic factor was lowest in muscle buried (4 percent of control) (p < 0.05) and avulsed specimens (15 percent of control) (p < 0.05) and higher in folded (52 percent of control) and transected specimens (75 percent of control). Relative mRNA expression of calcitonin gene-related peptide was highest in folded specimens (302 percent of control) (p < 0.05). CONCLUSIONS: Folding and transection lead to increased histologic evidence of neuroma formation, whereas folding leads to neuropathic pain, assayed by calcitonin gene-related peptide expression. Avulsion and muscle burying are preferable techniques for nerve ablation and inhibit nerve regeneration, evidenced by decreased ciliary neurotrophic factor expression. Avulsion offers an alternative to muscle burying when there is no muscle in the vicinity to bury the transected nerve.

A free vein graft cap influences neuroma formation after nerve transection.

INTRODUCTION: : Neuroma formation is a major problem in nerve surgery and consensus about its prevention has not been reached. It has been suggested that vein covering can reduce neuroma formation in transected nerves. In this article, the Authors propose an easy and novel method of covering by nerve stump capping with a free vein graft. METHODS: : Neuroma-like lesions were created on the rat thigh sectioning the femoral nerve above its division in 16 animals. The proximal nerve stump was invaginated into the lumen of a 1.5 cm long femoral free vein graft on the right side, and the vein was closed on itself by microsurgical sutures to form a cap for the nerve stump. On the left side acting as the control neuroma, the nerve was cut and left uncovered. Histological and immunohistochemical assessment was used to quantify the degree of neuroma formation. RESULTS: : Significant differences were found in both neuroma size and axon-glia organization between the treated and control sides indicating that free vein graft capping reduced neuroma formation in comparison to uncovered nerve stumps. CONCLUSIONS: : Our results confirm that vein-covering of a transected nerve stump can be effective in reducing neuroma formation. Moreover, unlike previous works that buried the nerve into an adjacent vein left in place, our experiments showed that also the use of a free vein graft cap can hinder neuroma formation. Although translation of rat experiments to the clinics should be dealt with caution, our data suggest a careful clinical use of the technique. (c) 2009 Wiley-Liss, Inc. Microsurgery, 2009.

Neuroma formation in a rat median nerve model: influence of distal stump and muscular coating.

BACKGROUND: The purpose of this study was to investigate neuroma formation in a rat median nerve model. METHODS: In three groups, the median nerve was exposed and a gap was created. In the first group, a short gap of 1 cm (n = 12) was created; in the second, a long gap of 2 cm (n = 12) was created in the nerve. Another group was used to analyze the development of neuroma formation when the proximal stump was buried in adjacent muscle with an additional gap of 2 cm (n = 12). The use of different lengths should allow one to gain information about dilution effects of distal stump factors that may contribute to neuroma formation. Nine months later, specimens were gathered and histologically analyzed. The cross-sectional areas of neuromas were measured and the neural/connective tissue ratios were estimated. RESULTS: The cross-sectional areas demonstrated that neuroma formation was significantly higher in the short-gap group than in the long-gap group, and smallest in the muscle-covered group. The percentage of neural tissue was highest in the muscle-covered and long-gap groups and lowest in the short-gap group. CONCLUSIONS: These results demonstrate an association between neuroma formation and distal stump distance. This observation may be explained by the factors originating from the distal stump that were blocked when the proximal nerve stump was completely buried in the muscle. For clinical application, the authors recommend not only burying the proximal stump in a muscle but also surgically augmenting the gap between the proximal and distal stumps.

Ineffectiveness of dietary folic acid supplementation on the incidence of lipomyelomeningocele: pathogenetic implications.

OBJECT: Periconceptual folic acid supplementation is effective in myelomeningocele prevention. The relationship between folic acid and lipomyelomeningocele (LMM) and the overall incidence of this occult form of spina bifida has never been studied. The objectives of this study were to determine the impact of dietary folic acid supplementation on the incidence of LMM and to measure its overall incidence. METHODS: In a retrospective population-based study the authors calculated the incidence of LMM in Nova Scotia between 1985 and 2001. Because of changes in public policy during this period, there are three intervals defined in relation to the treatment of the food supply with folic acid: 1) prior to folic acid fortification (1985-1994); 2) postsupplementation but prefortification (1995-1998); and 3) postfortification. The overall incidence of LMM in Nova Scotia between 1985 and 2001 was 16 per 100,000 live births or one case per 6121 live births. Its incidence between 1985 and 1994 was 15 per 100,000 live births, and between 1995 and 1998 it was 12 per 100.000 live births (relative risk [RR] 0.82, 95% confidence interval [CI] 0.31-2.22; p = 0.7). Between 1999 and 2001, the incidence of LMM was 29 per 100,000 live births, which was not significantly different from that between 1995 and 1998 (RR 2.41. 95% CI 0.79-7.36; p = 0.11) or between 1985 and 1994 (RR 1.98, 95% CI 0.86-4.56; p = 0.1). CONCLUSIONS: The overall incidence of LMM between 1985 and 2001 in Nova Scotia was 16 per 100,000 live births and has not been reduced by dietary folic acid supplementation. This finding provides epidemiological evidence that the embryogenesis of LMM is fundamentally different from that of myelomeningocele.

Influence of nerve stump transplantation into a vein on neuroma formation.

The objective of this animal study was to investigate the influence of nerve stump transposition into a vein on neuroma formation. In 24 rats the femoral nerve was severed and the proximal nerve stump was transposed into the lumen of the femoral vein on one side. On the other side, the nerve was severed and left in place. The distal nerve stump was shortened to knee level on both sides. In group 1, the bloodstream was released; in group 2, the segment of the femoral vein containing the nerve stump was excluded from circulation. Histological assessment was performed 8 months later. There were significant differences between the treatment and control sides with respect to neuroma size, endoneural architecture, neural-tissue-to-connective-tissue ratio, and myelination of axons. These data suggest that nerve transposition into a vein could inhibit the formation of classic neuroma.

Perineural invasion of cutaneous malignancies.

BACKGROUND: Perineural invasion is an important mode of tumor spread and is associated with increased aggressiveness and a propensity for recurrence among cutaneous malignancies. OBJECTIVE: To review the pathogenesis, diagnosis, and treatment of cutaneous tumors exhibiting perineural invasion. METHODS: This article is based on a review of the medical literature concerning tumors with perineural involvement. RESULTS: This article describes the clinical signs and histologic features of cutaneous malignancies exhibiting perineural involvement. CONCLUSION: Appropriate patient care mandates consideration of perineural invasion in the evaluation of cutaneous tumors. As the majority of patients present without symptoms of neural involvement, physicians must be vigilant in the search for this type of tumor spread.

Prevention and treatment of painful neuromas of the superficial radial nerve by the end-to-side nerve repair concept: an experimental study and preliminary clinical experience.

This article studies the utilization of the end-to-side neurorrhaphy concept in the prevention and treatment of painful neuromas. A total of 20 rats were divided into 2 groups (10 rats per group). In group A, the tibial nerve was divided and left lying in the subcutaneous tissue. In group B, the cut ends of the tibial nerve were sutured to the adjacent peroneal nerve in an end-to-side fashion. Evaluation was performed 90 days after nerve injury. For group A, the proximal end of the tibial nerve formed a "classic" neuroma and the distal end showed a degenerated nerve. In group B, the proximal end of the tibial nerve formed a "non-classic" neuroma and the nerve healed into the peroneal nerve with continuity of the epineurium of the 2 nerves. The distal end of the tibial nerve in group B showed evidence of axonal regeneration. Preliminary clinical experience utilizing the same technique in the prevention and treatment of painful neuromas of the superficial radial nerve is presented and other techniques of nerve-to-nerve implantation are discussed.

End-to-side anastomosis of transected nerves to prevent neuroma formation.

Neuroma can be painful and physically and psychologically disabling. Among the many methods of treatment available, one of the more successful is centrocentral nerve union with an autologous graft. However, it cannot be used in small nerves that lack two fascicles. This study evaluated neuroma prevention in an end-to-side anastomosis, a new technique applicable to all nerves. The lateral branch of the right sciatic nerve in 20 rats was transected at the midthigh level. The proximal segment was looped back to the main nerve and an end-to-side epineural anastomosis was performed. The lateral branch of the left sciatic nerve was transected to serve as a control, and the proximal nerve stump was closed by interrupted epineural sutures. The animals were sacrificed 12 weeks after the operation. Histologic analysis of specimens from the 12 controls showed neuroma formation. Specimens from 12 side-to-end anastomoses contained regenerated nerve tissues and formed smaller masses compared with that of the controls. The regenerated tissues at the anastomoses were orientated more orderly than were tissues from the controls in 75% of cases. The differences were statistically significant. Electron microscopic study on specimens from the remaining eight controls showed the presence of abundant large abnormal myelinated fibers (10-15 microns) with thick irregular myelin sheaths scattered among smaller myelinated fibers (2-10 microns) that had thin myelin sheaths. In the remaining eight end-to-side anastomoses, large abnormal myelinated fibers were absent. The myelinated fibers were 2 to 10 microns in diameters and had a normal appearance with thin myelin sheaths. End-to-side anastomosis formed a smaller mass of regenerated nerve tissues. Ultrastructurally they were formed better and orientated more orderly resembling normal nerve.

Effect of a modified Nd:YAG laser technique on neuroma formation: An experimental study in rat sciatic nerve.

BACKGROUND AND OBJECTIVES: Traumatic transection of a peripheral nerve is inherently associated with the development of neuroma at the end of the proximal stump, often leading to therapy-resistant pain. This study was designed to evaluate whether the neodymium:yttrium aluminum garnet (Nd:YAG) laser could prevent neuroma formation after neurectomy. STUDY DESIGN/MATERIALS AND METHODS: The sciatic nerves of 14 rats were diffuse coagulated by defocused Nd:YAG laser (12 W power), and subsequently transected with additional focused laser energy. The control group consisted of contralateral nerves transected by microscissors. The nerves were reexposed at different time intervals up to 9 weeks after surgery, and evaluation consisted of macroscopy, and light and transmission electron microscopy. RESULTS: True neuroma formation could not be observed after laser transection, and only five nerves formed a neuromatous bulb, with minimal adhesions to surrounding tissue. Microscissor transection resulted in widespread amputation neuromas, consisting of regenerating axons and connective tissue, and nervous tissue regenerating into surrounding tissue. Laser-transected nerves showed degenerative changes of the axons and myelin, while proliferation of Schwann cells could not be observed. No outgrowth of axons could be observed outside the coagulated proximal stump. An epi/perineurial layer was present, covering the nerve stumps. Microscissor-transected nerves showed proliferation of fibroblasts and Schwann cells, forming minifascicles, and vigorous outgrowth of axons into the tissue and even into the distal nerve stump. CONCLUSIONS: Within the limitations of this study it is concluded that the formation of amputation neuromas is suppressed by Nd:YAG laser application by thermal coagulation of the nerve and suppression of Schwann-cell proliferation.

Treatment with field bean protease inhibitor can effectively repress ethylnitrosourea (ENU)-induced neoplasms of the nervous system in Sprague-Dawley rats.

The ability of field bean protease inhibitor (FBPI) to inhibit ethylnitrosourea (ENU)-induced tumours of the nervous system of Sprague-Dawley rats was investigated. Groups of 1-day-old rats were injected intraperitoneally (i.p.) with neurocarcinogenic amounts of ENU and a few hours later, one group was treated i.p. with 80 mg of FBPI per kg body weight. This treatment was carried out three times a week for the first month and five times a week for the next month. Animals were killed when they were neurologically ill and their neural tissues were assessed for lesions. Those FBPI-treated rats which showed no illness were also killed to terminate the experiment about 8 weeks after the last rat of the control group was affected with paralysis. The neural tumours induced in all groups were predominantly large tumours found in the cerebrum of the rats. ENU-treated rats showed a 100% incidence of nervous system tumours with a mean time of manifestation of neurological symptoms of 282 days, which was significantly shorter in comparison to that noted in the FBPI-treated group. The latter group showed an incidence of 58.3%, i.e. a significant reduction of 41% in the incidence of neural tumours, as well as a lower mean value for the number of tumours per rat. All these aspects indicated that FBPI is a potential neurooncopreventive agent. A neural tumour incidence of 100% in the rats treated with heat-inactivated FBPI confirmed that the tumour suppressive activity of FBPI is related to its protease inhibitory activity.

[Clinical applyeation of neural stump buried into muscle for the prevention and treatment of neuroma].

In order to verify the effectiveness of neural stump buried into the muscle in the prevention and treatment of neuroma, 17 cases were reported, in which 8 cases having 19 painful neuromas and 9 cases having 13 amputated meural stumps, buried into muscle. They wese followed up for 6 months to 40 months, It was shown that good and excellent results were obtained and no evidence of neuroma was observed in all cases except in one which had painful neuroma occurred from the failure of embedment of the neural stump into the muscle. The conclusion was that the neural stump buried into muscle was an effective method for the prevention and treatment of neuroma.

Study of the post-natal effects of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. II. Influence of low-molecular-weight polypeptide factors from the thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex and brain white substance.

The influence of the polypeptide factors extracted from thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex or brain white substance on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day of gestation. The polypeptide factors were given to the offspring as a series of s.c. injections, at a dose of 0.5 mg/rat/day, starting at one or 2.5 months of age and continuing throughout the whole of post-natal life. ENU induced tumors of the brain, spinal cord, peripheral nerves and kidneys in 94-98% of the offspring exposed to the carcinogen, with an average number of 2.3-2.6 tumors per rat, and an average survival time of 294 days. Post-natal thymus factor or pineal gland factor administration was followed by an increase in mean lifespan of approximately 2 months and a significant decrease (P < 0.05) in the total tumor number per tumor-bearing rat, as well as the incidence and multiplicity of spinal cord tumors. Pineal gland factor also decreased the incidence of peripheral nerve and kidney tumors and their number per tumor-bearing rat. Brain cortex factor and brain white substance factor treatment was followed by a decrease in total tumor multiplicity of 1.2- to 3.3-fold, and a decrease in incidence of brain tumors of 10 to 33% per rat in comparison to the controls. Brain cortex factor also decreased the total tumor incidence. At the same time, brain white substance factor administration increased the incidence of peripheral nerve tumors and decreased the mean lifespan. Both bone marrow factor and anterior hypothalamus factor did not have any modifying effects on any of the ENU-induced tumors and mean lifespan. Thus, our results show the possibility of attenuation of transplacental ENU-induced carcinogenesis with post-natal administration of some polypeptide substances.

Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and epsilon-aminocaproic acid.

The influence of the arachidonic acid metabolism inhibitors, indomethacin and voltaren; an inhibitor of phosphodiesterase activity, theophylline and the protease inhibitor epsilonaminocaproic acid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day after conception. Indomethacin and voltaren (20 p.p.m. in drinking water), theophylline (0.01% in diet) and EACA (1000 p.p.m. in drinking water) were given to the offspring throughout their post-natal life until all survivors were killed at 12 months. In the ENU-only control groups, 100% of the offspring developed tumors of brain, spinal cord, peripheral nervous system or kidneys, with a total average number of 3.1 tumors per rat. The most marked inhibitory effect was exerted by theophylline, which significantly decreased the incidence and multiplicity of total tumors, and at all main sites selectively (brain, spinal cord, peripheral nerves and kidneys). It also prolonged average survival time of the offspring. Indomethacin and voltaren significantly decreased total tumor incidence and multiplicity and brain tumor incidence and multiplicity. Indomethacin also decreased kidney tumor multiplicity and voltaren diminished spinal cord tumor multiplicity. EACA decreased multiplicities of total, brain, peripheral nerve and kidney tumors, and diminished the incidence of brain tumors. These chemopreventive agents decreased tumor incidences 20-33% and tumor multiplicities 1.4-2.7 times, compared with the ENU-only controls.

Effect of the CO2 milliwatt laser on neuroma formation in rats.

BACKGROUND AND OBJECTIVE: The purpose of this study was to determine whether the milliwatt laser can suppress neuroma formation at the end of a divided nerve. STUDY DESIGN/MATERIALS AND METHODS: The peripheral nerves of eight rats were transected with microscissors and the cross-sectional area of their proximal ends was irradiated using the CO2 milliwatt laser. The power ranges used were similar to those applied to weld neural tissue. RESULTS: None of the eight irradiated nerve ends formed a neuromatous bulb and only one of them regenerated into the surrounding tissues. Histologically, these nerve ends did not show the disorganized picture of classic neuromas. On morphometric measurements, they contained less connective tissue than the control nerve ends (P < 0.001) and their nerve fibers were larger in diameter (P < 0.001) and better myelinated (P < 0.001). CONCLUSION: These findings in rats show that the CO2 milliwatt laser has the ability to suppress neuroma formation at the end of a divided nerve.

Implantation of peripheral neural stump into muscle and its effect on the development of posttraumatic neuroma.

Dissection of the peripheral nerve is associated inherently with the development of posttraumatic neuroma on the end of the proximal stump of damaged nerve. It is unfavourable, as it causes pain on the side of dissected nerve and additionally it is an obstacle in case of secondary surgical reconstruction of the nerve. Among many methods of treating stumps of dissected nerves in order to avoid the development of neuromas, it is recommended to sew the proximal stump of dissected nerve into the venter of adjacent skeletal muscle. The present study is an evaluation of histological changes occurring at the borderline between nerve and muscle after implanting the proximal stump of dissected femoral nerve into the venter of skeletal muscle. The experiments were carried out in 30 WAG rats in which sciatic nerves were cut and the proximal end of the nerve was introduced into the venter of the adjacent muscle. The nerves with muscular fragments were obtained for histological analysis at 3, 5, 10, 20 and 40 days. In no specimen signs of developing posttraumatic neuroma were found.

Epineurial capping via Surgitron and the reduction of stump neuromas in the rat.

Stump neuromas and recurrent neuromas are common problems following amputation and neuroma excision, respectively. Epineurial capping by microsuture has been shown to be somewhat effective in the reduction of the size of stump neuromas and in their confinement away from a weightbearing area. The present study shows that epineurial capping by coagulation of the epineurium with a radiofrequency wave Surgitron forms an effective seal around the proximal stumps of severed axons in rats. This seal effectively reduced axon proliferation but did not completely inhibit neuroma formation. Removal of the distal stump did not significantly affect neuroma formation in the proximal stump.