Upper extremity composite allotransplantation

Introduction

Millions of people each year suffer from major upper extremity trauma, resection of upper extremity tumors, or are born with major congenital defects that require many complex reconstructive procedures to repair large upper extremity defects. Conventional management of these tissue deficiencies includes prosthetic rehabilitation or autologous reconstruction, but these modalities are often limited by highly variable outcomes. There are many factors that adversely affect outcomes from traditional approaches, including a prolonged timeline and cost of rehabilitation, multiple surgeries, limited autologous tissue for reconstruction, and secondary morbidity from extensive autologous donor-site surgery. For complex injuries not amenable to conventional reconstruction, vascularized composite allotransplantation (VCA) can achieve near perfect primary restoration of tissue defects with improved functional and aesthetic outcomes. VCA is a newly developed focus area in transplantation medicine and combines the time-tested techniques of reconstructive microsurgery with the immunologic principles of transplantation. The goal of VCA is to improve quality of life for patients with significant composite tissue defects by leveraging the plastic surgery principle of replacing “like with like” to optimize both functional outcomes and aesthetic outcomes.

In the US alone, approximately 1,285,000 upper extremity amputations are performed per year. In 2005, there were approximately 1.6 million individuals living in the US with upper or lower extremity limb loss. Of these 1.6 million patients, nearly 540,000 individuals have had upper extremity amputations. Even if only 1% of these patients were deemed candidates for upper extremity allotransplantation, this would mean that more than 5000 patients could potentially benefit from this life-changing treatment. Thus far, only some 70 patients have undergone upper extremity allotransplantation in the past two decades. However, despite the fact that surgical, immunological, and functional results are highly encouraging, the need for long-term and high-dose immunosuppression to enable graft survival and to treat/reverse acute skin rejection episodes remains a rate-limiting obstacle towards widespread application. The risks of immunosuppression are significant and include, but are not limited to: infection, cancer, and metabolic derangements. All these risks greatly affect the recipient’s quality of life, alter risk profile, and jeopardize the potential benefits of upper extremity transplantation. Furthermore, unlike in solid organs, clinical success is dictated not only by graft acceptance and survival but also by nerve regeneration, which determines ultimate functional outcomes. Novel strategies such as cellular and biologic therapies that integrate the concepts of immune regulation with those of nerve regeneration have shown promising results in small and large animal models. Clinical translation of these insights to upper extremity reconstructive transplantation could further minimize the need of immunosuppression and optimize functional outcomes, enabling greater feasibility and wider application of these procedures as an option for upper extremity amputees.

Historical development and milestones

The earliest accounts of organ transplantation date to the Chinese physician Pien Chi’ao, who in 500 bce performed a dual-heart transplant on warriors Gong Hu and Qi Ying. In addition, in the Sushruta Samhita , a surgical report written by the Indian surgeon Sushruta who lived around the fifth to sixth century BCE. He describes in detail the techniques of rhinoplasty and pedicled autografts from the forehead, neck, and cheek to restore mutilating injuries of the nose and ear. About 900 years later, the patron saints Cosmos and Damian are credited with performing the first limb allotransplantation. Legend has it that around the year 348, they successfully transplanted the right leg of a dead Moor onto the Roman deacon Justinian, after amputating his cancerous/gangrenous leg ( Fig. 41.1 ). The first description of skin allografting was done by the sixteenth-century Italian surgeon Gaspare Tagliacozzi from Bologna, who in his book De curtorum chirurigia per insitionem (“On the surgery of mutilation by grafting”) described a novel method of nasal and aural allo-reconstruction, where he used skin from the inner aspect of the arm from a slave to reconstruct the nose of a wealthy patient who injured it during a sword fight. In this book, Tagliacozzi goes on to describe one of the first descriptions of tissue rejection, when he discusses the practical difficulty of binding two different individuals (referring to tissue rejection) to one another for a sufficient length of time.

It took another 300 years before these “practical difficulties” in transplantation began to be elucidated. During this time, advancements in antisepsis, anesthesia, hemostasis, organ preservation and, most importantly, microvascular surgery led to the rapid progress of reconstructive microsurgery. Alexis Carrel in 1902 described the surgical technique of vascular anastomosis, thus laying the foundation for conventional vascular and microsurgery. Carrel successfully obtained the revascularization of experimental organ allografts, but failed to achieve permanent graft acceptance. Carrel attributed this “organ failure” to vascular complications because he had no knowledge of the process of rejection. In 1932 and 1937, the first attempts at skin grafting were performed between identical twins. Again, no mention was made of rejection. In 1944, Hall published the first detailed theoretical account of cadaveric donor upper extremity transplantation (at the mid-humeral level). In his protocol, Hall described that an experienced surgical team within a well-equipped hospital was needed to perform the procedure. Additionally, his protocol included important and innovative descriptions of organ preservation, osteosynthesis, and vascular anastomoses. Lastly, potential complications related to thrombosis and infections were discussed, but, again, no reference was made to the occurrence of rejection. Strikingly, Hall was not aware that Sir Peter Brian Medawar, a young zoologist in Britain, and Thomas Gibson, a plastic surgeon, had made the historic discovery of the immunologic phenomenon of skin allograft rejection that very same year (1944). The challenge of skin transplantation led to the exploration of new frontiers in organ transplantation. In 1954, a plastic surgeon, Joseph E. Murray, with his team members, John P. Merrill and J. Hartwell Harrison in Boston, performed the first successful human kidney transplantation between identical twins. This was followed in 1957, by the first clinical attempt at allotransplantation of an en bloc composite digital flexor tendon mechanism by a plastic surgeon, Erle E. Peacock, Jr. Indeed, it was Peacock who coined the term “composite tissue allograft” to differentiate these transplants that were composed of multiple tissues unlike solid organs.

Our understanding of the immunologic behavior of allografts lagged behind technical developments in surgery. It was only the knowledge gained from landmark discoveries in the past century that facilitated the manipulation or suppression of the immune response, allowing successful prolongation of graft survival. After Medawar’s demonstration that rejection was an immunologic event, the next logical question was: Why not prevent this phenomenon by suppressing the immune system? In the 1950s, corticosteroids and irradiation were used for immunosuppression. In the 1960s, the antimetabolites 6-mercaptopurine and its derivative azathioprine were introduced, along with agents such as antilymphocyte globulin. These drugs were used either alone or in combination with corticosteroids. Graft survival improved but surgical outcomes were dismal because these drugs acted indiscriminately and were associated with severe organ-specific and systemic adverse effects.

In 1964, the first hand transplantation was performed using pharmacologic immunosuppression. Dr Gilbert in Guayaquil, Ecuador, transplanted the right forearm of a 28-year-old sailor who had lost his limb at the wrist level owing to a hand-grenade explosion the previous day. The donor was a laborer who had died of hematemesis (with gastric bleeding) a few hours earlier. The recipient was given heparin, dextran, and a broad-spectrum antibiotic after the surgery and was maintained on a combination regimen of prednisone and 6-mercaptopurine (6-mercaptopurine was replaced 24 hours later by azathioprine). These drugs are considered primitive according to present day standards, and unfortunately, signs of acute allograft rejection occurred after two and half weeks. The patient was then moved to Peter Bent Brigham Hospital in Boston, where at 3 weeks, aggressive rejection set in, and the forearm had to be re-amputated at 4 cm above the wrist level. Unfortunately, the advanced state of necrosis prevented any histopathologic evaluation of the graft. This bold and pioneering attempt at hand transplantation laid the foundation to the successful attempts yet to come.

In 1976, another major breakthrough in transplantation came with the discovery of the immunosuppressive properties of the calcineurin inhibitor cyclosporine A. In 1978, cyclosporine was first used clinically in organ as well as bone marrow transplantation with remarkable results. The FDA approved cyclosporine A in 1983. Cyclosporine A, along with agents like anti-CD3 antibody (OKT3, introduced in 1981), effectively reduced the reliance on high-dose steroids for the prevention of rejection. The calcineurin inhibitor tacrolimus (FK 506) was discovered in 1987, clinical trials were conducted in 1989, and FDA approval came in 1994. Tacrolimus led to dramatic improvements in solid organ transplantation, allowing highly immunogenic grafts such as the small bowel to be transplanted. The success of the calcineurin inhibitors cyclosporine A and tacrolimus made them the cornerstone drugs of the modern era of transplantation. The 1990s saw the introduction of novel drugs such as the antimetabolite mycophenolate mofetil (MMF, approved by FDA in 1995) and rapamycin (sirolimus, discovered in 1976 but approved by FDA only in 1999). Combining these drugs with a calcineurin inhibitor was found to significantly reduce rejection and improve solid organ graft survival with a reduction in adverse effects.

Clinical experience with upper extremity allotransplantation