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Vascularized Composite Allotransplantation (VCA) Research

The Emerging Field

Background
Organ transplantation is a definitive intervention for the management of solid organ failure, most notably heart, kidney, liver and lung. The success of solid organ transplantation has led several clinical teams to apply this technology to patients with non-salvageable injuries such as severe burns or limb amputation, and is now known as a Vascularized Composite Allograft (VCA). VCA refers to the transplantation of multiple tissues such as muscle, bone, nerve and skin, as a functional unit (e.g. a hand, or face) from a deceased donor to a recipient with a severe injury. These grafts serve as potential replacements for traumatic tissue losses such as limb loss from explosive devices, accidents with farm machinery, burns or other major injuries. VCAs tolerate only limited ischemia time (cannot be processed or stored), require rapid re-establishment of blood flow, and donor-recipient matching, thus sharing identical issues with transplanted organs (governed by UNOS regulations) rather than tissue (for which none of these stipulations apply) and thus have unique characteristics for regulatory purposes.

Currently, most reconstructive procedures for major tissue defects due to trauma, tumor removal, or congenital anomalies are performed with autologous (the patient's own) tissue. However, there are severe defects that cannot be reconstructed this way. In complex injuries or defects not amenable to conventional reconstruction, VCA could potentially achieve near normal tissue restoration and improved functional and esthetic outcomes. During the past decade, over 90 patients have received a VCA worldwide. 46 patients have received 66 hand transplants, and 17 facial transplants have been performed with promising functional outcomes and intermediate to long-term allograft survival. These early successes have established the proof of concept that VCA can be successful and indicate those areas most in need of further investigation.

General Considerations for Investment
The consensus view is that VCA has gained increasing importance in clinical practice and may evolve into an important component of multidisciplinary approaches to reconstruction after severe injuries. Given the risks, expense, and complexity involved, it is unlikely that VCA will be appropriate for solely cosmetic concerns, but rather as therapy for injuries associated with major functional or psychological deficits. Investment in VCA research is now becoming essential, should be targeted to specific critical areas of need, and administered only after appropriate peer review. Studies should include applicable animal models, translational research, and clinical outcome studies. If this important field is to advance, it is critical to support early clinical successes with a solid clinical and basic research structure to better understand VCA and ultimately optimize outcomes.

VCA - The Challenges and Opportunities
1. Composite tissue grafts, like most transplanted organs, are subject to immune rejection by the recipient. However, unlike in other solid organ transplantation, VCAs are composed of multiple tissues with different immunogenic and functional properties, including skin, muscle, bone and nerve. Therefore, there is a need to elucidate the basic aspects of the unique immunological features, and mechanisms of VCA rejection.
2. To date, human VCA has proceeded successfully with drug regimens similar to those used for solid organ transplantation with recipients of VCA grafts requiring longterm immunosuppression with complications associated with immunosuppression in other settings. However, unlike most solid organ recipients, VCA grafts require potential immunosuppression in the treatment of non-life threatening conditions. Studies in relevant animal models, however, suggest that less toxic regimens can be developed for clinical use, but require investment in pre-clinical animal models to generate data necessary to design and validate clinical regimens.
3. Reflecting its novelty, VCA has yet to develop accepted standards to define success. This limits the ability to interpret and compare outcomes from disparate groups, particularly in light of the small number of patients being treated worldwide. Specifically, the criteria for assessing complications, diagnosing immune rejection, and comparing the results of VCA relative to other therapeutic options (e.g. prostheses, extensive reconstructive surgery) are not validated. Thus, investment is required to develop objective histopathological evaluation of VCA grafts, the coding of outcomes, and outcomes research to adequately assess improvement, or lack of same, over current standard of reconstruction. Importantly, surgical, medical and psychological strategies for coping with graft failure (e.g. suboptimal functional outcomes, unacceptable immune complications, requirement for graft excision) need to be developed and codified.
4. Similar to other solid organ transplants, VCA requires a multi-disciplinary team (including reconstructive and transplant surgeons, immunologists, pathologists, infectious disease specialists, psychiatrists, ethicists, therapists, and social workers) along with a comprehensive institutional infrastructure. Furthermore the complexity of VCA requiring advanced surgical and medical expertise, with a major institutional commitment.
5. Unlike organ transplants, functionality of VCAs is dependent on growth of recipient nerves into the grafted donor tissue. Although nerve growth has been demonstrated, the rate of growth is a limiting factor in return of graft function. Furthermore whether the central nervous system accommodates to and organizes new nerve growth remains incompletely understood. Therefore research in nerve repair and growth is required for optimal use of VCA. These issues may be similar to those associated with traumatic nerve and brain injury and may be able to be merged with research portfolios in these areas.

In summary, the recommendations of the AST's VCA Task Force for prioritized funding are as follows:

Clinical Research:
Multi-center clinical outcome studies based on registry data allowing institutional protocols with the goal to define:
a. Optimal immunosuppression in VCA
b. Diagnostic criteria to define both clinical and histopathological aspects of rejection
c. Standards for measuring functional outcomes including nerve regeneration and rehabilitation
d. Quality of life, social and economic outcomes including comparative effectiveness analysis studies to assess the degree of improvement of VCA over current standard of reconstructive surgery

Basic Research:
e. Develop animal models of VCA to study the unique immunological features and mechanisms of VCA rejection and graft acceptance in each of the component tissues
f. Explore VCA-specific aspects of Rejection and Treatment emphasizing immune activation and immunogenicity peculiar to VCA

Approved by the AST Executive Committee on June 1, 2011