Emerging outcomes from several VCA programs confirm that patient-centered aspects including understanding of risks and benefits, decision-making, motivation, and matched expectations regarding the transplant, dissatisfaction with functional outcomes, poor commitment/compliance with study regimens (e.g., nonadherence [NA] to immunosuppressive or lack of engagement with rehabilitation regimens), maladaptation with the transplants and coping with graft failure are all key challenges to VCA recipients. Regardless of the efficacy of the immunosuppressive or immunomodulatory protocol, without patient adherence to medication [17], commitment to physical therapy, and provider recommendations, no VCA will be successful in the long term.

We need to improve methods, tools, and guidelines for psychosocial screening to understand how eligible VCA subjects transition into the role of RT recipients and assimilate information about the lifelong burdens of transplant including risks of immunosuppression and of surgery (e.g., death in the event of catastrophic graft failure or systemic life threatening complications), commitments to the physician recommendations, and financial and caregiver stresses. Chemical dependency or dissatisfaction with transplant outcomes can all mar such a transition. Currently, no teams actively measure NA in VCA. Arguably, prevalence of NA in VCA may thus be under-detected/reported. Postoperative assessment of patient behavior combined with selected clinical metrics can help better estimate NA, ensuring timely and specific intervention with graft-sparing measures that improve overall outcomes. Development of consensus guidelines for NA in VCA will allow larger RT trials for superior validation of surrogate metrics.

With patient-centered models of medical care growing in popularity and clinical attention increasingly focused on the spiritual, emotional, and sociocultural factors affecting patient decision-making it is timely to implement qualitative, data-driven research methods in the clinical understanding of RT/VCA protocols and outcomes. This is especially important given the small numbers/cohorts of patients undergoing these procedures. It is key for future studies to look at RT/VCA outcomes and adherence challenges from the viewpoint of the people they affect most: patients and their families.

It is important to highlight that “barriers” in existing VCA patients could help enhance outcomes in future VCA recipients, most notably the high number of wounded service members, by improving patient selection and institution of proactive/preventative psychosocial, caregiver, and other supportive measures in select patients.

The VCA surgeon (provider) must not consider a defect/deformity as “treatable” just because VCA is “technically feasible” but rather thoroughly balance this against failed or nonavailable conventional reconstructions, nontransplant alternatives (e.g., prostheses), psychosocial benefits versus known/unknown complications of life long immunosuppression/chronic rejection, or salvage/exit strategies (death in a face transplant patient versus amputation in a hand transplant patient). However, a review of the literature of RT procedures reveals a scenario where providers have performed VCA in recipients with co-existing morbidities such as HIV, HCV, associated active infection or malignancy under the premise of advancing the field with seminal procedures [18, 19].

These decisions become extremely difficult given the varying complexity of face and hand VCA, especially highly risky combination VCA (face and hands or hands and feet). As more complex VCA become technically facile, VCA surgeons are boldly embarking on “bigger” “more extensive” “riskier” procedures (especially craniofacial transplants). VCA teams may feel pressure to enroll patients to be the “first” to perform a procedure, compromising on thoroughness and due diligence in screening/indications. All of these issues threaten the field. Just as every graft success of a life changing VCA is a step ahead in for fostering peer scientific, payer reimbursement support or positive public reinforcement for VCA, every graft failure is a step back.

The lay/mass media could sensationalize such cases leading to the risk of the public believing VCA surgeons are not driven by ethical principles of beneficence, justice and most importantly primum-non-nocere (do no harm) [20]. Providers thus bear the burden of pushing the boundaries of the field of RT while cautiously balancing public perception of these advances. Lay media and peer literature reports cover new VCA procedures being performed; however there are no media reports or peer literature reports on VCA failures. Providers also bear the burden of public and peer transparency and accountability with both successes as well as failures—or else there is a threat of losing public trust/support for these procedures.

Overall, intermediate and long-term graft and patient outcomes have been encouraging for extremity and facial VCA with improved quality of life. The prospect of allograft dependency on chronic, lifelong drug immunosuppression, with the risk of infectious, metabolic, or neoplastic complications remains a significant hurdle for clinical advancement of VCA [21]. Thus, development of safe and effective protocols consistent with immunosuppression-free graft survival is an immediate priority in non-life-saving transplants such as VCA. The seminal work of Owen, Medawar, Burnet, and Billingham in the 1940s, laid the foundations for the concepts of immunological tolerance, which is the state of immunologic unresponsiveness of a recipient towards a fully mismatched donor in the absence of immunosuppression [22].

Seventy years since, these findings have galvanized efforts to achieve tolerance in the clinic both in solid organs as well as VCA, although this has proved to be a formidable task. These strategies operate by inducing peripheral or central tolerance to the allograft, but little is known as to their efficacy when confronted with the human immune system: preexisting memory T cells and “heterologous immunity ” in antigen-sensitized recipients (a state not seen with immunologically naïve rodents or other lab animals), or infections and early activation of innate immune response and the related inflammation-induced cytokine milieu that pose significant barriers to tolerance induction [23–25]. The goal of achieving clinical tolerance “up front” is thus enormously challenging, given the genetic heterogeneity of donor-recipient combinations and prior priming of the immune system to environmental antigens, which cross-react with those of the donor organ. Furthermore, continuing improvements with immunosuppressive drugs that produce good medium-term outcomes make it difficult to introduce new “tolerance” protocols that may bear unknown long-term risks including loss of the transplanted organ [25].

The emerging compromise has been to aim at harnessing immunomodulatory (not tolerance per se) mechanisms in RT recipients as a means of minimizing the dose and number of drugs administered [26, 27].

Over the past five decades, more than 50 different methods of tolerance induction have succeeded in small or large animal models including to some extent in nonhuman primates [28]. Some proof of principle has been established for experimental cellular therapies (mesenchymal, dendritic, or regulatory cells) in both SOT and VCA [26, 29, 30]. While there are clinical reports of whole bone marrow infusion after hand and face transplants, there are no reported clinical attempts incorporating other isolated or enriched cell types in VCA [27, 31]. Multiple studies in the preclinical VCA literature reinforce the promise and potential for cell therapies in prolonging allograft survival and other aspects (promoting nerve regeneration, protecting from ischemia reperfusion injury) that could improve overall graft outcomes after VCA. Many questions do persist, such as the mechanisms underlying tolerance or graft acceptance, optimizing the conditioning regimen in the context of induction immunosuppression, the dosing, timing, route and frequency of cell administration and the use of combinations of cells to improve synergistic, complementary, or additive efficacy after VCA [32–35].

Despite the promise of cell-based strategies , tolerance protocols have not widely (routinely) replaced immunosuppression in SOT or RT. The reason for this is straightforward. Many of the tolerance protocols are too risky for clinical application. In other protocols, the risks remain unknown. Therapies designed to reprogram the immune system toward better self-regulation will require biomarkers for monitoring rejection, tolerance, and undesired toxicity, but there are no reliable biomarkers in VCA or solid organs for that matter. Research must be invested in surrogate measures of graft functional and immunologic health, such as in research into 3D functional microtissues, organoids, or in silico computational modeling of cytokine or gene expression profiling to complement clinical trials in RT, especially given the small patient numbers undergoing these procedures [36].