Warren C. Breidenbach

A randomized prospective study of polyglycolic acid conduits for digital nerve reconstruction in humans.

This article reports the first randomized prospective multicenter evaluation of a bioabsorbable conduit for nerve repair. The study enrolled 98 subjects with 136 nerve transections in the hand and prospectively randomized the repair to two groups: standard repair, either end-to-end or with a nerve graft, or repair using a polyglycolic acid conduit. Two-point discrimination was measured by a blinded observer at 3, 6, 9, and 12 months after repair. There were 56 nerves repaired in the control group and 46 nerves repaired with a conduit available for follow-up. Three patients had a partial conduit extrusion as a result of loss of the initially crushed skin flap. The overall results showed no significant difference between the two groups as a whole. In the control group, excellent results were obtained in 43 percent of repairs, good results in 43 percent, and poor results in 14 percent. In those nerves repaired with a conduit, excellent results were obtained in 44 percent, good results in 30 percent, and poor results in 26 percent (p = 0.46). When the sensory recovery was examined with regard to length of nerve gap, however, nerves with gaps of 4 mm or less had better sensation when repaired with a conduit; the mean moving two-point discrimination was 3.7 ± 1.4 mm for polyglycolic acid tube repair and 6.1 ± 3.3 mm for end-to-end repairs (p = 0.03). All injured nerves with deficits of 8 mm or greater were reconstructed with either a nerve graft or a conduit. This subgroup also demonstrated a significant difference in favor of the polyglycolic acid tube. The mean moving two-point discrimination for the conduit was 6.8 ± 3.8 mm, with excellent results obtained in 7 of 17 nerves, whereas the mean moving two-point discrimination for the graft repair was 12.9 ± 2.4 mm, with excellent results obtained in none of the eight nerves (p < 0.001 and p = 0.06, respectively). This investigation demonstrates improved sensation when a conduit repair is used for nerve gaps of 4 mm or less, compared with end-to-end repair of digital nerves. Polyglycolic acid conduit repair also produces results superior to those of a nerve graft for larger nerve gaps and eliminates the donor-site morbidity associated with nerve-graft harvesting.

Successful Hand Transplantation — One-Year Follow-up

Background On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite-tissue transplantation, we developed a protocol for human hand transplantation. Methods After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. Results The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus...

HAND TRANSPLANTATION: COMPARISONS AND OBSERVATIONS OF THE FIRST FOUR CLINICAL CASES

Twenty, 15, and 8 months after the first four successful human hand transplant procedures were performed in Lyon (France), Louisville (U.S.), and Guangzhou (China), the transplant teams convened in Louisville, Kentucky, to share their experiences at the Second International Symposium on Composite Tissue Allotransplantation. This article presents reconstructive and immunological data from these landmark procedures in tabular format, in an attempt to answer some key questions about early outcomes of clinical hand transplantation. On the basis of these data, the initial outcomes of the first four hand transplants are encouraging and warrant proceeding with additional hand transplantations.

Sciatic Function Index, Nerve Conduction Tests, Muscle Contraction, and Axon Morphometry as Indicators of Regeneration

&NA; The purpose of this study was to determine which parameters were the best measure of nerve regencration, assuming that the sciatic functional index (SFI) represented the “gold standard.” Three different sciatic functional indexes and 11 commonly used electrophysiologic and morphologic indicators of regeneration were all determined in 24 rats 12 weeks after one of three lesions was created in the sciatic nerve. With linear regression analysis, only fiber/axon diameter ratio (D/d) and myelin thickness/axon diameter ratio showed statistically significant correlations with sciatic functional index (r = 0.55 and 0.53, respectively). The other 11 parameters had poorer correlation. Therefore, if sciatic functional index is the best measure of comprehensive nerve function, then other parameters are not. It is probable that each parameter measures some different component of the regeneration process. A stepwise multiple linear regression analysis produced a model that included D/d, nerve conduction velocity, and nerve action potential amplitude that gave a slightly better correlation (r = 0.67). The relatively poor correlation between sciatic functional index and the other parameters of nerve function indicates that all nerve regeneration studies must be interpreted carefully before comparisons are made. Furthermore, the best measure of nerve function remains unproved or undiscovered in the experimental animal.

Major replantation versus revision amputation and prosthetic fitting in the upper extremity: a late functional outcomes study.

The functional outcomes of amputated arms that were either replanted or had a prosthesis were compared. In addition, factors that influenced the functional outcome of replants were evaluated. The Carroll test was used to evaluate functional capacity of 22 successful upper extremity replantations at or proximal to the wrist as well as 22 amputees (at similar levels) fitted with a variety of prosthetic devices. The outcome was excellent or good in 8 (36%) replanted limbs. This proportion was statistically higher than those grades in the prosthetic group. When the groups were more closely matched (adults with below elbow injuries), the replantation group had 6 (50%) good or excellent outcomes and the prosthetic group had none. An analysis of covariance of the replantations demonstrated a statistical association between a better outcome in younger patients with more distal injuries. This study indicates that replantation produces superior functional results compared with amputation and a prosthesis.

Human coccidiosis--a possible cause of malabsorption.

Abstract Nineteen biopsies of the small-bowel mucosa obtained from six patients infected with coccidia (Isospora belli) revealed a spectrum of abnormalities. All the patients had coccidia in their specimens. All the forms of the endogenous life cycle of the organism were identified within the epithelium. Detection of any of these stages of development is diagnostic of coccidiosis. Oocysts were found in the intestinal contents of one patient, and schizonts in another. All the patients had diarrhea and steatorrhea. Three died, one from pulmonary embolism. The therapy given was ineffective. Coccidia may be etiologic in patients with undiagnosed and obscure diarrhea and malabsorption. By careful examination of serially sectioned suction biopsies of small-bowel mucosa and of intestinal contents, additional cases are likely to be detected.

Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy.

BACKGROUND High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. METHODS Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. RESULTS In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. CONCLUSIONS Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Long-term composite tissue allograft survival, in a porcine model with cyclosporine/mycophenolate mofetil therapy

BACKGROUND Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment. METHODS Radial forelimb osteomyocutaneous flap transplants were performed between size-matched, outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression, and 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin biopsies. RESULTS In all control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving treatment, one died from pneumonia and an another from an anesthetic complication on days 19 and 30, respectively, without signs of rejection. Two flaps were lost on days 25 and 29 from severe rejection. Three pigs were free of rejection at the end of the 90-day follow-up period, and three had stable mild-to-moderate rejection at 90 days (P= 0.0007 vs. controls). White blood cell and platelet counts, serum creatinine values, and liver function tests remained normal in all animals receiving immunosuppressive therapy. CONCLUSIONS Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tissue allograft model including skin using only orally administered agents dosed according to clinically relevant strategies without significant drug-specific systemic side effects.

Outcomes of the First 2 American Hand Transplants at 8 and 6 Years Posttransplant

PURPOSE The feasibility of hand allotransplantation has been demonstrated. The purpose of the article is to report the (1) functional return, (2) psychosocial outcomes, (3) clinical and histological assessment for rejection, (4) complications, and (5) graft survival in the 2 American hand transplant recipients. METHODS We present 2 patients 106 and 81 months, respectively, after unilateral transplantation of an allogeneic hand and forearm. We analyzed clinical course, number of rejection episodes, adverse events, function of the allograft, and quality of life. Clinical laboratory results, biopsy histology, and patient clinical examinations were used to compare the clinical course. Standard hand function tests were used to evaluate function. Psychological interviews were used to assess acceptance and quality of life. RESULTS Our patients have allograft survival with improvements in intrinsic muscle activity, total active motion and return of functional grip, pinch strength, and sensibility. Rejection episodes were restricted primarily to the first 6 months after transplantation, and all responded to treatment. The major posttransplantation complications were a cytomegalovirus infection in patient 1 and osteonecrosis of the hip requiring both hips to be replaced, 1 at year 4 and the other at year 6, as well as transient immunosuppression-related diabetes in patient 2. Recently we have weaned both patients off maintenance steroids. Current Carroll scores are fair for patient 1 (72/99) and fair for patient 2 (55/99), although patient 2 has not had good recovery of intrinsic function. Both patients are back at work and report an excellent quality of life at nearly 9 and 7 years, respectively, after transplantation. CONCLUSIONS Our intermediate long-term results of hand transplants have demonstrated functional return similar to that of replants. Graft survival and quality of life after hand transplantation has far exceeded initial expectations. We conclude that allogeneic hand transplant is feasible and holds promise as a treatment modality for catastrophic upper extremity loss. TYPE OF STUDY/LEVEL OF EVIDENCE Therapeutic IV.

Science of composite tissue allotransplantation.

The science of composite tissue allotransplantation (CTA) is rooted in progressive thinking by surgeons, fueled by innovative solutions, and aided by understanding the immunology of tolerance and rejection. These three factors have allowed CTA to progress from science fiction to science fact. Research using preclinical animal models has allowed an understanding of the antigenicity of complex tissue transplants and mechanisms to promote graft acceptance. As a result, translation to the clinic has shown that CTA is a viable treatment option well on the way of becoming a standard of care for those who have lost extremities and suffered large tissue defects. The field of CTA has been progressing exponentially over the past decade. Transplantation of hands, larynx, vascularized knee, trachea, face, and abdominal wall has been performed. Several important observations have emerged from translation to the clinic. Although it was predicted that rejection would pose a major limitation, this has not proven true. In fact, steroid-sparing protocols for immunosuppression that have been successfully used in renal transplantation are sufficient to prevent rejection of limbs. Although skin is highly antigenic when transplanted alone in animal models, when part of a CTA, it has not proven to be. Chronic rejection has not been conclusively demonstrated in hand transplant recipients and is difficult to induce in rodent models of CTA. This review focuses on the science of CTA, provides a snapshot of where we are in the clinic, and discusses prospects for the future to make the procedures even more widely available.