Search

Peripheral nerve allografting is limited by the need for long-term systemic immunosuppression. The purpose of this study was to determine if nerve allograft preservation reduced the requirements for systemic Cyclosporin A (CsA) immunosuppression. One hundred twenty Lewis rats were randomized to one of seven experimental groups. Group 1 received a 2-cm Lewis posterior tibial nerve autograft. Groups 2-7 received 2-cm ACI posterior tibial nerve allografts. The allograft group was then further subdivided into three groups of two receiving daily subcutaneous injections of 0, 2.5, or 5.0 mg/kg of CsA for 12 weeks. Within each CsA dose, one group received a fresh while the other received a preserved allograft. Preserved grafts were stored in University of Wisconsin solution for 7 days at 5 degrees C prior to implantation. Animals from each group were sacrificed at 6, 12, and 20 weeks postoperatively. Evaluations included histomorphometry, electrophysiology, and serial walking track analysis. Histology revealed varying degrees of nerve regeneration in all groups at 6, 12, and 20 weeks. For a given CsA dose, the group receiving the preserved graft revealed evidence of better nerve regeneration by all histomorphometric parameters including fiber width and density, percentage neural tissue, and total fiber number. There was no statistical difference in walking track analysis between groups at 4 weeks. By 20 weeks, functional recovery statistically poorer than autograft was seen only in the fresh allograft groups receiving 0 or 2.5 mg/kg of CsA. Identical electrophysiologic findings were seen at 20 weeks. These results suggest that nerve graft preservation may decrease systemic immunosuppression requirements while improving functional recovery. As well, storage of nerve grafts is feasible and would facilitate elective surgery and less costly reconstructive repair.

Donor-specific immunosuppression using anti-intercellular adhesion molecule-1 (ICAM-1) and anti-lymphocyte function-associated antigen-1 (LFA-1) has been shown to inhibit nerve allograft rejection without side effects. This dose-response study evaluated several dosing regimens using a 2-week course of three monoclonal antibodies (mAbs) against ICAM-1 and LFA-1 in combination on peripheral nerve allograft rejection in a rat model. Assessments of regeneration included walking track, electrophysiological, and histomorphologic analyses. Donor (ACI)-specific tolerance induction was assessed. Toxicity and mAb serum levels were monitored. At 18 weeks post engraftment, intermediate and high-dose groups were histologically indistinguishable from isograft controls, and superior to the untreated allograft group which demonstrated a significantly lower percent nerve tissue than all other groups. There were no differences in print length factor after 12 weeks or conduction velocity at sacrifice between any groups. Tolerance induction was not demonstrated. During mAb administration, animals in higher dose groups experienced temporary systemic side effects. This study demonstrated that a short course of mAb therapy directed against ICAM-1/LFA-1 inhibits rejection in rat peripheral nerve allografts by an unknown mechanism. The use of immune modulation in nerve transplantation may eliminate the need for systemic immunosuppression.

Lymphocyte migration into nerve allografts was measured to estimate the cyclosporine A (CsA) dose required to suppress rejection. Twelve outbred sheep received daily subcutaneous CsA at 0, 5, 10, or 15 mg/kg/day for 2 weeks prior to implantation of multiple heterotopic subcutaneous nerve grafts. Lymphocyte migration was determined after 7 days by an intravenous pulse of autologous 111indium-labeled lymphocytes and subsequent quantitation of gamma radioactivity in nerve tissue (CPM/g, mean +/- SEM). Measurement by radioimmunoassay revealed a dose-dependent increase in blood cyclosporine levels. Lymphocyte migration into autografts (404+/-44) was significantly less than migration into allografts (16,554+/-2,049), in control animals (P < 0.01). A dose-dependent inhibition of lymphocyte migration into nerve allografts was observed with counts of 7,662+/-1,692, 4,083+/-1,112, and 1,561+/-232 in sheep receiving 5, 10, or 15 mg/kg/day of CsA, respectively. Daily CsA administration produced effective blood levels and immunosuppression sufficient to inhibit lymphocyte migration into nerve allografts.

The potential to store nerve grafts for a prolonged period of time was assessed in a rat sciatic nerve model. Three-centimeter syngeneic nerve grafts were stored in Belzer/University of Wisconsin cold storage solution at different temperatures (5 degrees C, 22 degrees C, or 37 degrees C) for varying time periods (6 h, 24 h, or 3 weeks) prior to transplantation. Functional assessment using serial walking track analyses revealed no difference between storage times and temperatures. At 14 months postengraftment, the conduction velocities and the number of myelinated fibers that had regenerated across all grafts stored at 5 degrees C for all time periods tested were superior to grafts stored at either 22 degrees C or 37 degrees C. Nerve grafts stored for up to 3 weeks at 5 degrees C acted as effective conduits for proximal regenerating fibers and resulted in histologic, electrophysiologic, and functional results equivalent to fresh nerve grafts. Nerve graft storage may be applicable to nerve allografts and potentially provide allograft material that requires reduced or no associated host immunosuppression.

This study evaluated the immunosuppressive effect of monoclonal antibodies against cell surface molecules in a murine peripheral nerve allograft model. After nerve allografting, 18 recipients were treated with both anti-intercellular adhesion molecule-1 (ICAM-1) and anti-lymphocyte function-associated molecule-1 (LFA-1) monoclonal antibodies in low or high dose. Nerve allografts were harvested at 8 weeks for histologic and morphometric evaluation. Recipients were subsequently challenged with skin grafts at 9 weeks and a cytotoxic assay at 12 weeks. The majority of the antibody-treated allografts (13 of 18) showed excellent regeneration comparable to the autografts with preservation of the normal nerve architecture and scant cellular infiltrate. All untreated allografts demonstrated severe structural disorganization with cellular infiltrate consistent with acute rejection. In the high dose group, the mean skin graft survival time from nerve donor mice, but not third-party mice, was significantly prolonged. (17.5 vs. 11.3 days). Similarly, the cytotoxic activity against nerve donor alloantigen was significantly suppressed. These preliminary findings suggest that antibody therapy alone can facilitate nerve regeneration in a murine nerve allograft model.

In a rat nerve allograft model, specific immunosuppression was approached with monoclonal antibodies (MAbs) against cell-surface molecules. After engraftment, recipients were treated with antiintercellular adhesion molecule-1 (ICAM-1) and antilymphocyte function-associated antigen-1 (LFA-1) MAbs for 14 days. Functional recovery was evaluated biweekly. Electrophysiological and histological assessments were performed at 6 and 16 weeks. Immunologic responsiveness in the recipients was assessed with a cytotoxic T lymphocyte (CTL) assay at 16 weeks and skin grafts at 18 weeks. The untreated allograft group demonstrated complete disruption of fascicular architecture with poor nerve regeneration. The MAb-treated allografts maintained well-organized nerve architecture with a dense population of well-myelinated fibers. These animals showed functional and electrophysiological recovery. Suppression of CTL activity was nerve donor specific and the survival time of nerve donor skin grafts was prolonged, suggesting induction of alloantigen-specific tolerance. MAbs therapy directed against ICAM-1/LFA-1 presents a new approach for the management of the peripheral nerve allograft response.

The deposition of collagen in fetal skin wounds has been shown in several animal models. The authors used a radiolabeled RNA antisense probe, complementary to the mRNA for the alpha-1 chain of human procollagen type I, to assess regulation of this collagen species in fetal and adult rabbit wounds. Dorsal skin wounds were placed on fetal and maternal animals at the beginning of the third trimester, and were harvested 3, 5, and 7 days later. In situ RNA/RNA hybridization was performed on suitable specimens, and morphometric analysis was carried out with a computerized LECO image analyzer. Fetal wounds exhibited an inflow of mesenchymal cells that produced collagen type I at levels higher than the surrounding tissue; this activity was highest on days 3 and 5 after wounding. Adult wounds had increased fibroblast presence by day 7, producing collagen type I at levels higher than those of adjacent unwounded tissue. Morphometric analysis of the signal produced by in situ hybridization and of the number of cells producing the signal in a given field showed that fetal wounds appear to produce collagen type I by an increase in the number of cells in the area of the wound--not by induction of the gene for procollagen type I. In contrast, adult wounds had both fibroblast migration and induction of procollagen type I mRNA synthesis. These findings imply multilevel regulation of collagen production in the adult and posttranslational regulation in the fetus.

Nerve crush is a commonly used experimental model in the rat; however, a standard method of inducing this injury has not been defined. This study examined six crush techniques that are frequently used and characterized the subsequent nerve injury. Five types of nerve crush using a No. 5 jeweler's forceps and a sixth using a 30-s single crush with a serrated hemostat were studied in the posterior tibial nerve of the Lewis rat. Regeneration was evaluated using serial walking track assessments at 1, 2, 4, 6, and 8 weeks postoperatively. Nerve conduction studies and histological examination were performed at 2 days, 2 weeks, and 8 weeks. Blood-nerve barrier breakdown was observed at 2 days and recovered by 2 weeks. By 4 weeks normal walking track patterns were obtained in all groups. A pattern of Wallerian degeneration and axonal regeneration was noted at 2 weeks, with histological recovery in all groups by 8 weeks. Nerve crush, induced by any of the six methods tested, was similar and provides a reliable model of axonotmesis.

The pattern and temporal sequence of histopathological events in a rat nerve allograft model were evaluated. Following grafting and varying survival periods (from 1 to 30 weeks), the host and donor nerve were removed and assessed by light and electron microscopy. Nerve allografts underwent Wallerian degeneration and rejection. Wallerian degeneration was the dominant pathologic process at weeks 1 and 2 after engraftment. Histologic rejection started as an epineurial process at weeks I and 2, became progressively endoneurial and was most prominent at 4 and 6 weeks after engraftment. Rejection was accompanied by evidence of graft Schwann cell and endoneurial tube loss. The rejection process delayed, but did not prevent, nerve regeneration by the host. Regeneration of fine neurofilament-positive axonal sprouts into the proximal portions of the graft was observed as early as week 2. Subsequently, regeneration occurred through the periphery and around the exterior of the rejected nerve allograft fascicle. Regenerating axons were accompanied by S100 protein reactive Schwann cells and newly synthesized laminin-positive endoneurial tubes. Regenerating axons reinnervated the distal host segment at week 8 and increased in number and myelination thereafter. The observations of rejection and regeneration through nerve allograft segments are discussed in reference to previous studies.

The ability of small nerve segments interposed between synthetic conduits to increase the total nerve gap distance across which successful nerve regeneration would occur was studied. Fifty adult male Lewis rats were randomized into five groups. In Group I a segment of resected sciatic nerve was repaired by a nerve graft. Group II had alternating silicone tubing/nerve graft/silicone tubing replacement of the resected nerve segment (single stepping stone group). Group III had silicone tubing/nerve graft/silicone tubing/nerve graft/silicone tubing repair of the nerve deficit (double stepping stone). Group IV had a single long silicone conduit repair. Group V control underwent a sham operation. Nerve regeneration was evaluated using walking track pattern analysis, electrophysiologic assessment and histomorphological evaluation. 'Stepping stone nerve grafts' enhanced regeneration across nerve gaps in comparison to a single long conduit, but were inferior to a single long nerve graft. In the repair of long nerve gaps, the use of multiple short conduits with interposed short nerve segments could provide a source of trophic factors to enhance regeneration.

Lymphocyte migration into fresh and preserved peripheral nerve allografts was quantitated to assess the effect of cold preservation and freeze-thawing pretreatment on the local immunological response to nerve allografts. Out-bred ewes received multiple 1.5-cm subcutaneous heterotopic peroneal nerve autografts, fresh allografts, and pretreated allografts, implanted within the same recipient. Lymphocyte migration was studied at 7 days by injecting autologous 111indium-labeled lymphocytes intravenously. After 3 hr of recirculation, lymphocyte migration into graft tissue was quantitated by a gamma counter (epm/g, mean +/- SEM). Lymphocyte traffic into fresh nerve allografts (21,623 +/- 3783) increased an average 9.4-fold over the autograft value (2918 +/- 377, P < 0.04). Histologic studies illustrated a marked lymphocytic infiltrate of CD4+ and CD8+ cells and enhanced class I and II MHC expression in fresh allografts, but not in autografts. Short-term cold preservation, for 6 and 12 hr (5 degrees C), enhanced lymphocyte entry into pretreated allograft tissue. Conversely, cold preservation for longer periods (1 and 3 weeks) dramatically reduced lymphocyte migration to values below corresponding autograft levels (783 +/- 100 and 1,252 +/- 120, respectively, P < 0.01). A comparable reduction in lymphocyte migration into nerve allografts was observed after freeze-thawing pretreatment (P < 0.01). Cold preservation of donor allogeneic lymphocytes inhibited their capacity to induce intradermal host lymphocyte migration, implicating passenger lymphocytes as a potential cold-sensitive allogeneic component of the nerve allograft. Assessment of the local response to ovine peripheral nerve allografts, utilizing radiolabeled autologous lymphocytes, demonstrated that cold preservation and freeze-thawing pretreatment significantly reduced lymphocyte migration into nerve allografts. The mechanism(s) of reduced lymphocyte migration may involve inactivation or death of antigen-presenting cells, including passenger lymphocytes.

Functional assessment of rat sciatic, tibial, and peroneal nerve injuries was performed using walking track analysis. Individual walking print length (PL), toe spread (TS), and intermediate toe spread (ITS) values were measured up to 24 weeks after specific nerve transection, with or without repair. Sciatic and tibial nerve manipulation initially affected all footprint measurements, consistent with loss of intrinsic and extrinsic motor function. After sciatic repair, TS demonstrated partial recovery without any substantial recovery in PL or ITS, compared with sciatic transection values. By contrast, after tibial repair, PL values recovered dramatically, between 16 and 24 weeks, to levels not significantly different from control subjects. This was not observed after tibial transection without repair. TS recovered partially, whereas ITS recovered to control levels by 20 weeks after tibial repair. Peroneal transection resulted in multiple contractures, rendering this group unmeasurable at 4 weeks. After peroneal repair, only the PL reflected significant loss of function at 2 weeks, recovering to control values by 8 weeks. Manual TS measurements in nonwalking rats did not reflect functional nerve regeneration. Thus, individual PL measurements alone can be used to characterize functional recovery after tibial and peroneal nerve injury, whereas TS reflected recovery after sciatic nerve injury.

The efficacy of short-term immunosuppression in a nerve allograft model was examined by comparing regeneration across peripheral nerve allografts with either temporary (12 weeks) or continuous (30 weeks) cyclosporin A treatment. One-hundred fifty Lewis rats received 2-cm nerve grafts from allogeneic ACI or syngeneic Lewis rat donors and were allocated to the following groups: allogeneic grafts and continuous cyclosporin A, with 18 weeks (20 rats) or 30 weeks (20 rats) of survival after graft placement; allogeneic grafts and temporary cyclosporin A, with 12 weeks (10 rats), 18 weeks (20 rats), or 30 weeks (20 rats) of survival; and control rats with allogeneic and syngeneic grafts, no cyclosporin A, with 12, 18, or 30 weeks (10 rats each) of survival. Functional regeneration across the nerve grafts was serially assessed with walking-track analysis. Endpoint evaluations included electrophysiological, histological, and morphometric studies. Both walking-track and electrophysiological function reached a plateau at a significantly worse level in nonimmunosuppressed allograft recipients than in syngeneic or treated allograft recipients. The group with temporary therapy experienced significant worsening in both motor and electrophysiological function at Week 18, 6 weeks after cyclosporin A withdrawal, compared to the group with continuous treatment. At Week 30, motor and electrophysiological function in the temporary-treatment group recovered to levels similar to those of the syngeneic and continuous cyclosporin A groups. Histological assessment of the graft segments from the temporary cyclosporin A group at 18 weeks showed evidence of rejection, with mononuclear cell infiltration and demyelination; morphometric evaluation demonstrated significantly decreased numbers of nerve fibers in the distal host segment. These histological and morphometric changes were no longer present in the nerves from the temporarily immunosuppressed rats at Week 30. Withdrawal of immunosuppression after successful regeneration through nerve allografts results in short-term graft rejection. Eventual restoration of graft histological and function parameters is comparable to continuously immunosuppressed rats. Temporary immunosuppression of nerve allograft recipients is feasible.

Functional recovery following sciatic, tibial, and peroneal nerve injury was assessed over a 1-year period using walking track analysis in the rat. Internal neurolysis did not affect nerve function. Crush injury induced a temporary, but complete, loss of function that recovered to control levels by 4 weeks. Nerve transection resulted in complete loss of function without any evidence of recovery. After nerve repair, functional recovery occurred, reaching near-optimal recovery by 12 weeks. The degree of functional recovery varied with the specific nerve involved. The sciatic nerve recovered 41 percent of function, whereas the tibial nerve recovered 54 percent of function. The peroneal nerve exhibited the highest degree of recovery, achieving functional levels similar to control values. Assessment of neural regeneration using walking track analysis appears to be a valuable addition to the traditional methods of histology and electrophysiology.

Selective reinnervation was studied by comparing the regeneration across a conventional neurorraphy versus a conduit nerve repair. Lewis rats underwent right sciatic nerve transection followed by one of four different nerve repairs (n = 8/group). In groups I and II a conventional neurorraphy was performed and in groups III and IV the proximal and distal stumps were coapted by use of a silicone conduit with an interstump gap of 5 mm. The proximal and distal stumps in groups I and III were aligned anatomically correct and the proximal stump was rotated 180 degrees in groups II and IV (i.e. proximal peroneal nerve opposite the distal tibial nerve and the proximal tibial nerve opposite the distal peroneal nerve). By 14 weeks, there was an equivalent, but incomplete return in sciatic function index (SFI) in groups I, III, and IV as measured by walking track analysis. However, the SFI became unmeasurable by 6 weeks in all group II animals. At 14 weeks, the percent innervation of the tibialis anterior and medial gastronemius muscles by the peroneal and tibial nerves respectively was estimated by selective compound muscle action potential amplitude recordings. When fascicular alignment was reversed, there was greater tibial (P = 0.02) and lesser peroneal (P = 0.005) innervation of the gastrocnemius muscle in the conduit (group IV) versus the neurorraphy (group II) group. This suggests that the gastrocnemius muscle may be selectively reinnervated by the tibial nerve. However, there was no evidence of selective reinnervation of the tibialis anterior muscle. Despite these differences, the functional recovery in both conduit repair groups (III and IV) was equivalent to a correctly aligned microsuture repair (group I) and superior to that in the incorrectly aligned microsuture repair (group II).

The inter- and intraobserver reliability of the walking-track analysis of sciatic nerve function in the rat was assessed. Twenty-five walking tracks were assessed on three different occasions by four observers. Whereas the interobserver reliability was found to be excellent (r = 0.92), the intraobserver reliability was only satisfactory (r = 0.53 to r = 0.76). Walking-track analysis provides a noninvasive technique to assess function recovery in the rat, with excellent intraobserver reliability demonstrated. The lower intraobserver reliability suggests limitations to this new measurement technique.

This study investigated the effect of purified bovine collagen (Zyderm collagen implant) on peripheral nerve tissue in rats. Zyderm was injected extrafascicularly and intrafascicularly into the sciatic nerve of adult Wistar rats. The nerves were examined by light and electron microscopy and the integrity of the blood-nerve barrier assessed by protein tracer technique. With light microscopy the precise anatomical location of the injected material could be identified. The purified bovine collagen did not appear to be neurotoxic. After extrafascicular injection, only minimal nerve fiber damage was seen. Intrafascicular injection produced a histological picture compatible with compression neuropathy and was associated with a breakdown in the blood-nerve barrier.

Peripheral compression neuropathy is a common clinical entity but little human nerve material has been available for study. It has been difficult to develop an experimental model of chronic nerve compression which is reliable and reproducible, making it difficult to assess the various treatment modalities currently in use to manage this problem. In a recent study using a rat model, connective tissue and nerve fiber changes associated with chronic nerve compression were described by the authors. The present study expands this same model of chronic nerve compression to the multifascicular median nerve of the cynomolgus monkey, using this model to test whether or not current surgical treatment modalities for nerve entrapment will alter the course of chronic nerve compression. Using histologic and morphometric parameters, there did not appear to be a difference between nerves treated by decompression alone or by decompression and internal neurolysis. Total number of nerve fibers remained constant, as did axon size, but a demyelinating process was demonstrated which is a significant component of chronic nerve compression. Although the small number of experimental animals (7) makes precise evaluation of the clinical modalities impossible, the authors expect that further study of the multifascicular median nerve of the cynomolgus monkey will prove to be a useful source of future experimental evidence and will help to interpret the diverse therapeutic and operative techniques currently in use.

Lewis rats (RT1(1] were the recipients of 3-cm nerve grafts from syngeneic Lewis donors or allogeneic ACI (RT1a) donors. Microneurosurgical repair of the nerve graft to the transected sciatic nerve of the recipient animal was performed with 10-0 epineurial sutures. Recipients were randomly allocated to cyclosporin A (CsA) immunosuppressed or untreated groups. Cyclosporin A was administered in the minimal effective dosage to prevent nerve allograft rejection across this major histocompatibility disparity (5 mg/kg per day). Nerve regeneration across the nerve grafts was assessed by sciatic function index (SFI) and toe spread index (TSI) determinations serially and by electrophysiologic, histologic, and morphologic assessments 14 weeks after engraftment. Sciatic nerve regeneration across allogeneic nerve grafts in cyclosporin A immunosuppressed recipients was significantly superior compared to the untreated controls (p less than 0.008) and not significantly different from that across the syngeneic control animals.

This study reports the degree of spontaneous regeneration that will occur in the sciatic nerve of a rat 5 months after complete resection of the nerve. In 30 animals, the sciatic nerve was excised. Histological assessment at 5 months revealed evidence of regeneration for a variable distance (mean 23.7 mm +/- 6.4 mm). Histological sections were studied at 1-cm intervals along the length of the nerve. Evidence of compartmentation with "minifascicle" formation was noted. The orientation of the nerve fibers was parallel to the long axis of the nerve. This study assessing spontaneous regeneration is meant to serve as a control for other studies evaluating the effect of factors that may influence nerve regeneration in the rat model.

This article describes a model of chronic nerve compression in the rat. The sciatic nerve of adult male Sprague Dawley rats was banded with a 1-cm Silastic tube for varying periods of time. Morphometric analysis, electrodiagnostic studies, and histological evaluation were carried out 3, 5, 8, and 12 months after banding. Histological evaluation at 3 months was normal. At 5 months perineurial thickening was demonstrated. In the periphery of the fascicles, segmental demyelination was noted; central fibers appeared normal. At 8 months there was further epineurial and perineurial thickening. Marked thinning of the myelin was noted in all fibers and evidence of Wallerian degeneration was apparent. Progressive connective tissue and nerve fiber changes were noted at 12 months. Nerve conduction studies after 3 months of compression demonstrated an increase in conduction velocity compared to the normal unbanded control nerves. Progressive slowing of conduction velocity was noted from 5 through 12 months.

Chymopapain injected into the intervertebral disc space (chemonucleolysis) has been used clinically in patients with disc disease with success. Neurosurgical complications secondary to the procedure have, however, been reported. In this study, the authors have investigated the possible neurotoxic effect of chymopapain on the peripheral nerve in rat and primate models. While the extrafascicular injection caused no nerve fiber damage, the intrafascicular injection caused dose-related nerve fiber damage in both species.

A primate model was developed to study the effect of submuscular versus intramuscular placement upon the development of ulnar nerve fibrosis. No significant adherence was found in either location between the ulnar nerve and the flexor-pronator muscle mass. There was no significant difference in the mean nerve fibre diameter or in the percent neural tissue between the ulnar nerves in the two different locations. It is suggested that it is the interaction of the transposed ulnar nerve with other fibrous anatomical structures proximal to, across, and distal to the elbow that causes failure in ulnar nerve transposition procedures, rather than an adverse reaction between the incised flexor-pronator muscle mass and the ulnar nerve.

Recovery of function is of prime importance after peripheral nerve injury and repair. This paper describes a method of obtaining and measuring walking-tracks and generating a Sciatic Function Index (SFI) to quantify functional sciatic nerve recovery in the rat. The reader is provided with a series of walking-tracks to measure, analyze and compare to those analyzed by experienced observers.

The traditional teaching that "nerve fibers are lost at the suture line" after a nerve repair was investigated by asking the question, "Can the number of nerve fibers distal to a nerve repair site be increased by increasing the number of nerve fibers proximally?" Ratios of proximal to distal nerve fibers were increased from 1:1 to 2.5:1 to 3.5:1 by suturing peroneal or posterior tibial or sciatic nerve proximally to peroneal nerve distally. At one year following the repair, distal nerve fiber numbers increased to twice normal as the ratio increased to 2.5:1, and then nerve fiber numbers plateaued. Nerve function, as judged by walking track analysis, was best in the peroneal:peroneal group (1:1 ratio), suggesting that appropriateness rather than number of proximal fibers was more critical in this nerve repair model.

This study investigated nerve regeneration through a pseudosynovial sheath in a primate. After resecting a 3-cm segment of the ulnar nerve at the elbow, the two ends of the divided nerve were placed at either end of the pseudosynovial tube, positioning the nerve ends such that they were separated by a 3-cm gap. Histologic evaluation at 3, 5, 7, and 9 months demonstrated evidence of nerve regeneration across this gap. Nerve fiber diameter and density assessment demonstrated a maturation of the fiber pattern with time. The overall morphologic pattern of the regenerating nerve within the pseudosheath was that of multiple small fascicles, each within its own perineurial compartment. This pattern resembled neither the proximal nor distal nerve fascicular pattern.

The potential use of peripheral nerve allografts would significantly improve the reconstructive potential for patients with major peripheral nerve deficits. This study evaluated the response of the nerve allograft recipient treated with varying dosages of cyclosporin A (CsA) to determine the minimal effective dosage necessary to prevent nerve graft rejection. Lewis rats (RT1l) were the recipients of syngeneic nerve grafts from identical Lewis donors or allogeneic nerve grafts from ACI (RT1a) donors. Nerve grafts were inlaid next to the intact sciatic nerve of the recipient. The immunologic responsiveness of the recipient animal's lymphocytes to a donor-specific antigenic challenge was assessed by the mixed lymphocyte reaction (MLR). In addition, nerve grafts were evaluated histologically. Animals were monitored for cyclosporin A toxicity. It was found that cyclosporin A (5 mg/kg per day) was effective in rendering the recipient animals unresponsive by mixed lymphocyte reaction at 10, 20, and 40 days after engraftment. This dosage was similarly effective in preventing histologic changes characteristic of nerve allograft rejection. This dosage regimen was nontoxic to the animals. Our study ascertained a minimal nontoxic dosage of cyclosporin A that effectively prevented nerve allograft rejection across a major histocompatibility disparity in rats.

This study investigated the existence of neurotrophism in a primate model. In eight adult cynomolgus monkeys the sensory component of the femoral nerve was sectioned and introduced into the proximal channel of a silicone Y chamber. The proximal stump was given distal choices of various tissues inserted into the remaining arms of the silicone Y chamber. The targets presented were combinations of tendon, muscle, intact distal nerve, distal nerve graft, or an empty silicone channel. After 6 weeks, ultrastructural analysis confirmed axonal growth toward distal nerve tissue, while minimal or no nerve regeneration was directed toward tendon, muscle, or the empty silicone channel. The results showed that either a distal nerve stump or a nerve graft will act as a specific target to the regenerating primate proximal nerve stump.

The nerve allograft response in a rat model is presented. The Lewis rat (RTI1) served as the recipient animal while Fischer rats (RTI1) and ACI rats (RTIa) provided the donor nerve allografts. A Lewis/Lewis autograft group was used as the control group. Histological and electrophysiological measurements of nerve regeneration were assessed at five months. While good regeneration was noted in the autograft and matched allograft groups, regeneration across the unmatched allograft was poor. The degree of nerve regeneration (as measured with histological and electrophysiological values) correlated well with previous immunological studies and would support the use of this model for future investigation of the nerve allograft response in the rat.

While compression neuropathy is a common clinical problem, the opportunity to study human nerve material is rare. A histological assessment of the superficial radial nerve of four human cases with entrapment syndrome is reported. Changes in the perineurium and the endoneurial microvessels as well as the presence of Renaut bodies were the earliest histological abnormalities noted. Connective tissue changes included epineurial and perineurial fibrosis. Nerve fibre pathology varied from fascicle to fascicle. The myelinated and unmyelinated fibre populations responded differently to this compression. In the myelinated fibre population, marked thinning of the myelin was noted. In the unmyelinated fibre population, a shift in the fibre histogram due to a new population of very small fibres was observed suggesting degeneration with subsequent regeneration of this fibre population.

A histological and functional comparison of regeneration across a vascularized and conventional nerve graft was carried out in a clinical case. The two branches of the medial antebrachial cutaneous nerve were used to neurotize the median nerve at the wrist. The superficial branch of the radial nerve (vascularized nerve graft) and a conventional sural nerve graft were used as the interposition grafts between the two branches of the medial antebrachial cutaneous nerve and the median nerve. This nerve grafting procedure was carried out in two stages. The proximal neurorrhaphy was carried out 7 months prior to the distal nerve repair. Biopsies were taken from the distal portions of the vascularized radial sensory nerve and the conventional sural nerve at the time of the second procedure. Histological evaluation demonstrated superior regeneration across the vascularized nerve graft. Subjectively, the patient described better sensory recovery in the territory innervated by the vascularized nerve graft. Sensory testing in the two territories demonstrated better sensibility in the territory innervated by the vascularized nerve graft.

A histologic assessment of the radial sensory nerve from a patient with nerve compression is reported. Histologic changes were confined to the region of the nerve compression. Connective tissue changes consisted of an increased thickness of the epineurium and perineurium. Nerve fiber changes consisted of Schwann cell pathology with marked thinning of the myelin noted in the myelinated fibers and evidence of degeneration and regeneration noted in the unmyelinated fiber population. Nerve fiber pathology was not uniform but varied from fascicle to fascicle in the compressed area.

Quantification of peripheral nerve regeneration in animal studies of nerve injury and repair by histologic, morphologic, and electrophysiologic parameters has been controversial because such studies may not necessarily correlate with actual nerve function. This study modifies the previously described sciatic functional index (SFI), tibial functional index (TFI), and peroneal functional index (PFI) based on multiple linear regression analysis of factors derived from measurements of walking tracks in rats with defined nerve injuries. The factors that contributed to these formulas were print-length factor (PLF), toe-spread factor (TSF), and intermediary toe-spread factor (ITF). It was shown that animals with selective nerve injuries gave walking tracks that were consistent, predictable, and based on known neuromuscular deficits. The new formula for sciatic functional index was compared with previously described indices. The sciatic functional index, tibial functional index, and peroneal functional index offer the peripheral nerve investigator a noninvasive quantitative assessment of hindlimb motor function in the rat with selective hindlimb nerve injury.

Regeneration across the nerve allograft in the immunosuppressed host was assessed using electrical and histologic parameters. The Lewis rat (RTIl) served as the recipient animal, and ACI rats (RTIa) provided the donor nerve allografts. Hydrocortisone and azathioprine were used in various dose schedules as the immunosuppressive agents. Animals were immunosuppressed for either 30 or 100 days. Histologic and electrophysiologic measurements of nerve regeneration were assessed at 30, 100, and 180 days. The degree of nerve regeneration was similar in all experimental groups. Short-term, low-dose immunosuppression was as successful as longer-term, higher-dose immunosuppression therapy. The degree of nerve regeneration in all experimental groups was significantly better than that in the fresh, untreated nerve allograft control group (Lewis/ACI) but was not as good as that seen in the autograft control group (Lewis/Lewis).

This study reports a rat model of chronic nerve compression. The sciatic nerves of adult male Sprague Dawley rats were bonded with 1-cm lengths of tubing with varying internal diameters. Histological and electrical studies as well as studies to assess the blood-nerve barrier function were carried out at one through six months. With marked compression of the sciatic nerve, profound electrical changes were noted as early as one month, and histological findings were those of degeneration and regeneration. In the rats with minimal compression, nerve conduction studies remained normal. The earliest findings were alterations in the blood-nerve barrier, followed by histological changes in the large myelinated fibers at the periphery of the fascicles and changes about the nodes of Ranvier. This model appears to be a valid one with which to study other aspects of both the pathophysiology and treatment of chronic nerve compression.

Irregular galaxies can be viewed as laboratories for studying the processes of star formation. This class of galaxy, unlike the more familiar spiral galaxies, forms stars without spiral arms and does so from a chemically less-evolved interstellar medium. In this article the problems associated with star formation in irregular galaxies are outlined and their relevance to our understanding of star formaton as a general astrophysical process is discussed.

Chronically compressed nerves were treated with three surgical modalities. Simple decompression was compared to internal neurolysis with and without the addition of extrafascicular steroid. Electrophysiologic, histologic, and morphometric assessments were performed. Compressed control nerves demonstrated changes compatible with severe nerve compression (Wallerian degeneration). With simple decompression, improvement in histologic and electrophysiologic parameters occurred. When internal neurolysis was added to the decompression, further improvement in histologic and electrophysiologic parameters was noted. There was no added improvement with the addition of steroids.

Loss of cutaneous sensation predisposes paraplegics to ulceration in pressure-bearing areas. We have previously described a method of restoring sensation to anesthetic trochanteric or ischial areas by neurotizing the cutaneous territory of the lateral femoral cutaneous nerve with the medial antebrachial cutaneous nerve of the forearm. After reinnervation of the anterior skin, a musculocutaneous flap is rotated to the desired anesthetic area. A four-year follow-up evaluation has shown good recovery of the quickly and slowly adapting fiber receptor system, mediated through innervated hair follicles and resulting in excellent protective sensation.

In a primate model a histologic assessment of neuroma formation is reported. Three experimental groups were defined. Transected sensory nerves left adjacent to the incisional wound in an area of movement (wrist) were considered the control group. In the "proximally cut" group the same sensory nerves were positioned well proximal to the incisional wound. In the "muscle-implantation" group these nerves were placed in adjacent muscles. At 6 months a histologic assessment of the neuroma formation in the three experimental groups was carried out. Implantation of the sensory nerve into muscle significantly altered the regenerative potential of that nerve. The muscle completely surrounded the sensory nerve. The minimal neuroma that formed had significantly less scar tissue and contained nerve fibers that were of a smaller diameter and decreased density than either the control or the proximally cut group. There were no histologic differences between these latter two groups. However, regeneration into the overlying skin that was noted in the control neuromas was not seen in those nerves which had been proximally cut.