Earl Owen

Human hand allograft: report on first 6 months

BACKGROUND Long-term survival of animal limb allografts with new immunosuppressant combinations and encouraging results of autologous limb replantations led us to believe that clinical application of hand transplantation in human beings was viable. METHODS On Sept 23, 1998, we transplanted the right distal forearm and hand of a brain-dead man aged 41 years on to a man aged 48 years who had had traumatic amputation of the distal third of his right forearm. The donors arm was irrigated with UW organ preservation solution at 4 degrees C, amputated 5 cm above the elbow, and transported in a cool container. We dissected the donor limb and the recipients arm simultaneously to identify anatomical structures. Appropriate lengths of viable structures were matched. Transplantation involved bone fixation, arterial and venous anastomoses (ischaemic time 12.5 h), nerve sutures, joining of muscles and tendons, and skin closure. Immunosuppression included antithymocyte globulins, tacrolimus, mycophenolic acid, and prednisone. Maintenance therapy included tacrolimus, mycophenolic acid, and prednisone. Follow-up included routine post-transplant laboratory tests, skin biopsies, intensive physiotherapy, and psychological support. FINDINGS The initial postoperative course was uneventful. No surgical complications were seen. Immunosuppression was well tolerated. Mild clinical and histological signs of cutaneous rejection were seen at weeks 8-9 after surgery. These signs disappeared after prednisone dose was increased (from 20 mg/day to 40 mg/day) and topical application of immunosuppressive creams (tacrolimus, clobetasol). Intensive physiotherapy led to satisfactory progress of motor function. Sensory progress (Tinels sign) was excellent and reached the wrist crease (20 cm) on day 100 for the median and ulnar nerves, and at least 24 cm to the palm by 6 months when deep pressure, but not light touch sensation, could be felt at the mid palm. INTERPRETATION Hand allotransplantation is technically feasible. Currently available immunosuppression seems to prevent acute rejection. If no further episode of rejection occurs, the functional prognosis of this graft should be similar to if not better than that reported in large series of autoreconstruction.

Clinicopathologic features of graft rejection of the first human hand allograft

Background. The first human hand allograft, performed in Lyon, France, on September 23, 1998, was removed during month 29 posttransplantation as the result of rejection because the patient did not comply with the immunosuppressive treatment. Methods. The patient was regularly examined from the day of transplantation to amputation. Biopsies were taken from the skin of the allograft and examined immunohistologically. After amputation, various tissue specimens obtained from the allograft (including skin, tendons, bone, muscles, and joints) were studied. Results. From month 15 onward, the allografted skin presented lichenoid papules that progressively spread and coalesced into diffuse erythematous-scaly lesions over the allografted hand. Histologically, these showed an aspect of chronic lichenoid cutaneous graft-versus-host disease. At the time of amputation, erosive and necrotic areas over the skin were present. Pathologic examination of the allograft showed that the most severe changes were found in the skin. Mild inflammation was found in muscles and tendons. Bones (including bone marrow) and joints were spared. Conclusions. The skin is the main target of rejection in human hand allografts. Close clinicopathologic monitoring of the skin is the most reliable way to detect rejection in human composite tissue allografts.

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.

Functional results of the first human double-hand transplantation

Objective Objective of this study was to analyze fifteen months after surgery the sensorimotor recovery of the first human double hand transplantation. Summary Background Data As for any organ transplantation the success of composite tissue allografts such as a double hand allograft depends on prevention of rejection and its functional recovery. Methods The recipient was a 33-year-old man with bilateral amputation. Surgery included procurement of the upper extremities from a multiorgan cadaveric donor, preparation of the graft and recipients stumps; then, bone fixation, arterial and venous anastomoses, nerve sutures, joining of tendons and muscles and skin closure. Rehabilitation program included physiotherapy, electrostimulation and occupational therapy. Immunosuppressive protocol included tacrolimus, prednisone and mycophenolate mofetil and, for induction, antithymocyte globulins and then CD25 monoclonal antibody were added. Sensorimotor recovery tests and functional magnetic resonance imaging (fMRI) were performed to assess functional return and cortical reorganization. All the results were classified according to Ipsens classification. Results No surgical complications occurred. Two episodes of skin acute rejection characterized by maculopapular lesions were completely reversed increasing steroid dose within 10 days. By fifteen months the sensorimotor recovery was encouraging and the life quality improved. fMRI showed that cortical hand representation progressively shifted from lateral to medial region in the motor cortex. Conclusion Even though at present this double hand allograft, treated using a conventional immunosuppression, allowed to obtain results at least as good as those achieved in replanted upper extremities, longer follow-up will be necessary to demonstrate the final functional restoration.

Optimal parameters for laser tissue soldering. Part I: Tensile strength and scanning electron microscopy analysis

The use of liquid and solid albumin protein solders to enhance laser tissue repairs has been shown to significantly improve postoperative results. The published results of laser‐solder tissue repair studies have, however, indicated inconsistent success rates. This can be attributed to variations in laser irradiance, exposure time, solder composition, chromophore type, and concentration. An in vitro study was performed using indocyanine green‐doped albumin protein solders in conjunction with an 808 nm diode laser to determine optimal laser and solder parameters for tissue repair in terms of tensile strength and stability during hydration.

First human double hand transplantation: efficacy of a conventional immunosuppressive protocol

Abstract: Based on the results achieved in single human hand transplantations, we decided to perform the first double hand transplantation with a conventional immunosuppressive protocol in a patient with a high potential for functional recovery. Two years after transplantation the efficacy and the safety of this immunosuppressive protocol are evaluated. The recipient was a 33‐yr‐old man suffering from a traumatic amputation of both hands in 1996. Five HLA‐A, ‐B, and ‐DR mismatches were present with the donor; T and B cell cross‐match was negative. Immunosuppressive protocol included tacrolimus, prednisone, mycophenolate mofetil and, for induction, antithymocyte globulins and then anti CD25 monoclonal antibody. Reconstitution of lymphocyte populations proceeded normally. Neither anti‐HLA antibodies nor chimerism in peripheral blood were detected. Two episodes of acute rejection characterized by maculopapular lesions occurred on days 53 and 82 after transplantation. Skin biopsies revealed a dermal lymphocytic infiltrate. Both episodes were completely and rapidly reversed by topical clobetasol and increased systemic corticosteroid therapy. The only side‐effects related to treatment were reversible serum sickness and hyperglycemia. No infectious complications and malignancies occurred. No signs of graft‐versus‐host disease have been detected. This case of double hand transplantation shows that conventional immunosuppression is effective and safe to ensure survival and functional recovery of the grafted limb.

Photothermal effects of laser tissue soldering

Low-strength anastomoses and thermal damage of tissue are major concerns in laser tissue welding techniques where laser energy is used to induce thermal changes in the molecular structure of the tissues being joined, hence allowing them to bond together. Laser tissue soldering, on the other hand, is a bonding technique in which a protein solder is applied to the tissue surfaces to be joined, and laser energy is used to bond the solder to the tissue surfaces. The addition of protein solders to augment tissue repair procedures significantly reduces the problems of low strength and thermal damage associated with laser tissue welding techniques. Investigations were conducted to determine optimal solder and laser parameters for tissue repair in terms of tensile strength, temperature rise and damage and the microscopic nature of the bonds formed. An in vitro study was performed using an 808 nm diode laser in conjunction with indocyanine green (ICG)-doped albumin protein solders to repair bovine aorta specimens. Liquid and solid protein solders prepared from 25% and 60% bovine serum albumin (BSA), respectively, were compared. The efficacy of temperature feedback control in enhancing the soldering process was also investigated. Increasing the BSA concentration from 25% to 60% greatly increased the tensile strength of the repairs. A reduction in dye concentration from 2.5 mg ml(-1) to 0.25 mg ml(-1) was also found to result in an increase in tensile strength. Increasing the laser irradiance and thus surface temperature resulted in an increased severity of histological injury. Thermal denaturation of tissue collagen and necrosis of the intimal layer smooth muscle cells increased laterally and in depth with higher temperatures. The strongest repairs were produced with an irradiance of 6.4 W cm(-2) using a solid protein solder composed of 60% BSA and 0.25 mg ml(-1) ICG. Using this combination of laser and solder parameters, surface temperatures were observed to reach 85+/-5 degrees C with a maximum temperature difference through the 150 microm thick solder strips of about 15 degrees C. Histological examination of the repairs formed using these parameters showed negligible evidence of collateral thermal damage to the underlying tissue. Scanning electron microscopy suggested albumin intertwining within the tissue collagen matrix and subsequent fusion with the collagen as the mechanism for laser tissue soldering. The laser tissue soldering technique is shown to be an effective method for producing repairs with improved tensile strength and minimal collateral thermal damage over conventional laser tissue welding techniques.

Laser-activated solid protein bands for peripheral nerve repair: An in vivo study

Severed tibial nerves in rats were repaired using a novel technique, utilizing a semiconductor diode‐laser‐activated protein solder applied longitudinally across the join. Welding was produced by selective laser denaturation of solid solder bands containing the dye indocyanine green.

First human hand transplantation

Hand transplantation is a model of composite tissue allografting ( a A ) . The immunological issues in CTA are extremely complex, as different tissues are involved, each of which has to be considered both individually and as a part of a unit while each has a different time and intensity of rejection. Cartilage, ligaments and fat present low antigenicity, and consequently they lead to a weak rejection; bone, muscles, nerves and vessels show a moderate rejection profile in spite of various degrees of immunogenicity; skin, a complex immunological structure, is the component that develops the most severe rejection, because of the abundance of dentritic cells within epidermis and dermis. Finally, bone marrow, a source of immunocompetent cells, is a major target for rejection, but also a source of contaminating donor T cells that could induce a graft-versus-host disease in a strongly immunosuppressed recipient, and a source of stem cells that might contribute to the development of a microchimerism. Limb transplantation, the most common experimental model of CTA, has met with varying degrees of success; however, results have improved with the introduction of new immunosuppressants, especially tacrolimus and mycophenolic acid [l-71. In humans few cases of isolated muscle [8], bone, joint [9, lo], nerve [ l l ] or vascular allografts [12] have been reported. The first vascularized human hand transplantation was performed on 23 September 1998 in Lyon, and it is described in the present report [13].

Sequential histological and immunohistochemical study of the skin of the first human hand allograft

BACKGROUND On September 1998, the first human hand allograft was successfully performed in Lyon. METHODS A 48-year-old white man who had suffered accidental amputation of the arm in 1984, received a forearm and hand allograft from a 42-year-old white male cadaveric heart-beating donor. Immunosuppressive therapy included prednisone, mycophenolate mofetil, FK506, and antithymocyte globulins. Sequential skin biopsies were taken from the grafted limb and examined (immuno)histologically to detect a possible graft rejection and to evaluate the structural integrity of the skin of the allograft. RESULTS The skin showed histologically a normal appearance, except on days 57 and 63, when a mononuclear perivascular cell infiltrate was observed in the dermis; this appeared concomitantly with erythematous lesions of the skin that developed after a slight decrease of the immunosuppressive treatment. These changes were considered as signs of graft rejection, and were reversed by an increase of the immunosuppressive treatment. No skin necrosis was seen at any time. Immunohistochemically, the main cell types of the skin were present throughout the study. From day 77 onward the epidermis of the grafted hand harbored some epidermal Langerhans cells of recipients origin. CONCLUSION This study shows that the skin of the hand allograft maintains overall a normal histological structure and contains most essential cell types, including cells of recipient origin, such as Langerhans cells. Furthermore, it shows that in this system of composite tissue transplantation, skin biopsies may reveal a starting graft rejection, before the appearance of clinically obvious lesions.