The history of human composite tissue allotransplantation.

Restoration of amputations and disfigurement are represented in ancient mythology, but the modern history of composite tissue allotransplantation begins with World War II injuries that generated seminal immunologic experiments by Medawar and co-workers. These studies led to the first successful human allografts in the 1950s by Peacock with composite tissue and Murray and co-workers with solid organs. Pharmacologic immunosuppression brought rapid growth of solid organ transplantation over the next 50 years, but composite tissue transplantation virtually disappeared. This evolution was judged to be a consequence of the greater antigenicity of skin, which that was insurmountable by the available immunosuppression. In the mid-1990s, progress in immunosupression allowed skin-bearing grafts, led by successful hand transplants, which produced a renaissance in composite tissue allotransplantation. Since then, graft types have expanded to over 10, and graft numbers to over 150, with success rates that equal or exceed solid organs. The field has emerged as one of the most exciting in contemporary medicine, although accompanied by substantial challenges and controversy. This paper reviews the origins and progress of this field, assessing its potential for future evolution.

Alemtuzumab: key for minimization of maintenance immunosuppression in reconstructive transplantation?

Minimization of immunosuppression has become the key effort in solid organ transplantation. Alemtuzumab, the humanized CD-52 monoclonal antibody, is an effective depleting agent increasingly used in transplantation trials. In this article, we summarize the current experience with alemtuzumab use in hand transplantation and discuss its role in current and future approaches toward minimization of maintenance immunosuppression in reconstructive transplantation.

Composite tissue transplantation: a rapidly advancing field.

Composite tissue allotransplantation (CTA) is emerging as a potential treatment for complex tissue defects. It is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed through 30 hand transplantation, 3 facial reconstructions, and vascularized knee, esophageal, and tracheal allografts. A major drawback for CTA is the requirement for lifelong immunosuppression. The toxicity of these agents has limited the widespread application of CTA. Methods to reduce or eliminate the requirement for immunosuppression and promote CTA acceptance would represent a significant step forward in the field. Multiple studies suggest that mixed chimerism established by bone marrow transplantation promotes tolerance resulting in allograft acceptance. This overview focuses on the history and the exponentially expanding applications of the new frontier in CTA transplantation: immunology associated with CTA; preclinical animal models of CTA; clinical experience with CTA; and advances in mixed chimerism-induced tolerance in CTA. Additionally, some important hurdles that must be overcome in using bone marrow chimerism to induce tolerance to CTA are also discussed.

Atypical acute rejection after hand transplantation.

Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse, patchy or focal, and distributed over forearms and dorsum of the hands. This 'classical' pattern of rejection usually spares the skin of the palm and does not affect the nails. Herein, we report the experience on four cases presenting with an 'atypical' pattern of rejection that is novel in involving the palmar skin and the nails. All patients were young and exposed to repetitive and persistent mechanical stress of the palm. Characteristic features of rejection included a desquamative rash associated with dry skin, red papules, scaling and lichenification localized to the palm. Skin lesions were associated with nail dystrophy, degeneration, deformation or loss. Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells (CD3+, CD4+ and CD8+), with small numbers of B cells (CD20+ and CD79a+) and a low number of Forkhead transcription factor 3 (FOXP3)-positive cells in one patient. The lesions persisted over weeks to months, responded poorly to steroid treatment and were managed with antithymocyte globulin (ATG; Thymoglobulin, Genzyme, Cambridge, MA), alemtuzumab and/or intensified maintenance immunosuppression.

Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program.

This paper reviews the formulation and evolution of the ethical component in one of the earliest clinical composite tissue allograft (CTA) programs, the hand transplantation program in Louisville, Kentucky, USA. The purpose was to derive lessons and define principles to give guidance for future programs and introduction of new CTA. We reviewed the initial ethical considerations, including input from respected ethical scholars, guidelines for innovative procedures transparency in public and professional scrutiny, and compliance with human studies regulations (IRB approval). We found the initial focus on ethics, scholarly input, guidelines for innovative procedures, and human studies protection regulations to be valid. Moreover, we noted the effect of autonomy in subjective, quality-of-life benefits on equipoise and effective risk-benefit analysis in effective informed consent. We found that psychiatric screening and support to be exceptionally valuable in protecting autonomy, suitability for participation, assessing personality organization, and determining compliance ability. We conclude that the program ethical principles were validated. For future CTA programs and procedures, we recommend an ethical emphasis with adherence to high standards and transpire to independence to scrutiny and oversight. We recommend protection of autonomy judgments in equipoise judgment and informed consent. We recommend skilled psychiatric screening and support. We endorse scholarship, scientific accuracy, and data sharing.

Hand transplantation.

The surgical techniques necessary to perform hand transplantation have been available for at least 25 years. In this article, the authors provide a review of hand transplantation, including its history, preoperative evaluation, and case reports. Data on transplant preparation, operation data, immunosuppression, rejection, immunologic assessment, and functional assessment are presented in easy-to-use table format.

Different reference frames can lead to different hand transplantation decisions by patients and physicians.

Different frames of reference can affect one's assessment of the value of hand transplantation. This can result in different yet rational decisions by different groups of individuals, especially patients and physicians. In addition, factors other than frames of reference can affect one's evaluation of hand transplantation, which can result in different decisions.

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. Louisville Hand Transplant Team.

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 and clobetasol. Temperature, pain, and pressure sensation had developed in the hand and fingers by one year. At one year, the patient had regained the ability to perform many functional activities with his left hand that he had not been able to perform with his prosthesis, such as throwing a baseball, turning the pages of a newspaper, writing, and tying his shoelaces. CONCLUSIONS: Early success has been achieved in hand transplantation with the use of currently available immunosuppressive drugs.

Osteomyocutaneous flap as a preclinical composite tissue allograft: swine model.

Composite tissue allotransplantation (CTA) constitutes one of the last frontiers of microsurgery. Prior to its clinical application, the long-term efficacy of modern immunotherapy must be tested in a pre-clinical CTA model. Based on the concept of osteomyocutaneous forearm flap, we developed a CTA flap model in swine. After identifying the vascular territory of the flaps in six pigs (vascular casting), flaps were transplanted from mismatched donor to recipient pigs (n = 6). Rejection was assessed daily by visual inspection and histopathology of biopsy specimens. Recipient pigs were able to ambulate immediately following surgery. There were no flap failures owing to technical or surgical complications. Rejection occurred over a period of 7 days as manifested by edema, cellular infiltration, epidermalysis, and thrombosis. This pre-clinical flap model is excellent for evaluating the effectiveness of modern immunotherapy because it is anatomically and immunologically relevant and because the minimal morbidity caused to the animal permits long-term studies.

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.

Swine composite tissue allotransplant model for preclinical hand transplant studies.

Our laboratory previously developed and used an orthotopic radial forelimb osteomyocutaneous flap in the pig as a preclinical composite tissue allograft (CTA) model. To ensure that it mimicked the clinical situation as closely as possible we developed this model taking many immunologic and reconstructive considerations into account. While our original pig CTA model was ideal for studying the methods of preventing skin, muscle, bone, vessel and nerve rejection, and systemic toxicity, it did not include specialized tissues/structures of a joint and digit. Therefore, we were unable to evaluate rejection of these specialized tissues and their functional properties. Recognizing the importance of assessing joint rejection and function in hand transplantation research we developed a new swine forelimb CTA model that included the animal's medial digit. The present study describes the anatomy and the transplantation technique used in this new preclinical CTA model. We transplanted a radial osteomyocutaneous flap that included the medial digit between two size- (17-21 kg) and age- (6-8-week) matched farm pigs. We removed the digit from the recipient pig's forelimb in continuity with a section of the radial bone and replaced it with the same structure transplanted from a donor pig. After transplantation, a full-length cast was placed on the recipient pig's operated limb and changes in flap color, temperature and the presence of edema were monitored continuously for 6 h, and then regularly at predetermined intervals over 4 days. No weight bearing restrictions were placed on the animal's operated limb. After 4 days, the animal was euthanized. Direct visual monitoring of the allograft during 4 days revealed it was viable with no signs of graft failure due to technical complications associated with the transplant procedure. Upon waking from anesthesia, the animal stood and wandered freely about its cage with no apparent difficulty. Based on the animal's high level of activity at this time, we concluded that the procedure caused it minimal morbidity. At 4 days after the operation, early signs of rejection (skin erythema and edema) were observed. By incorporating a digit into our original CTA pig forelimb model we have made it a better model for performing preclinical hand transplant studies. The added advantage of being able to assess methods of preventing rejection in the specialized joint/digital tissues (articular cartilage, digital flexor and extensor systems, the nail complex) and assess long-term function of these structures is important. The fact that the procedure does not cause major morbidity to the animal makes it possible to conduct long-term graft survival and functional studies.

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.

Scoring of skin rejection in a swine composite tissue allograft model.

BACKGROUND: For the first time, we define and correlate visual and histologic grading systems of composite tissue allograft (CTA) skin rejection in a large-animal model and determine the utility of these grading systems for early diagnosis and monitoring of rejection. MATERIALS AND METHODS: Sixteen pairs of outbred swine underwent transplant of a forelimb osteomyocutaneous free flap. Group I (n = 6) did not receive immunosuppressive therapy. Group II (n = 10) received oral cyclosporin A, mycophenolate mofetil, and prednisone. The flap was visually inspected and protocol skin biopsies were taken at frequent intervals over a 90-day period. Visual Grades 0 (no rejection) to 4 (severe rejection) were assigned based on skin color, bleeding from biopsy site, and blister formation. Histologic Grades 0 to 4 were assigned based on the degree of vasculitis, folliculitis, dermal inflammation, and epidermal degeneration present. RESULTS: All Group I animals progressively rejected their graft by Day 7. Group II grafts survived from 19 and 90 days; 93% of 115 biopsy specimens were read to be within +/-1 histologic score of their assigned flap visual grade. Visual assessment carried an 8% false positive and 39% false negative rate with regard to biopsy-proven rejection. However, 81% of missed rejection specimens were histologic Grade 1. Biopsy, when visually indicated, would detect all rejection episodes when histologically Grade 1 or 2 and still potentially reversible. CONCLUSIONS: Visual scoring of CTA skin serves as a useful tool for initially detecting rejection, but repeated histologic evaluation is necessary for monitoring the subsequent course of the graft.

The role of emergency free flaps for hand trauma.

Primary closure of a wound with free flap requires minimizing the risk of infection in an effort to cover vital exposed structures. Careful patient selection, radical débridement of the wound, and an experienced microsurgical team are important for the routine application of this technique. Primary reconstruction of all injured structures is an extension of this technique that enables efficient management of severe upper extremity problems in a single setting.