Hand Transplantation Research Articles

Tracheal transplantation: lessons learned that may apply to lung transplantation.

The purpose of this review is to explore the lessons learned from experimental and human tracheal transplantation to determine if this information may be applied to lung transplantation. Experimental work in animal models and the recent human tracheal transplantation suggests that a robust tracheal vascular supply prevents anastomotic complications. Further, this work demonstrates that tracheal allografts undergo a progressive chimerism as recipient epithelium repopulates the allograft. In contrast to most vascularized composite allografts such as hand and face transplantation that experience high rates of rejection, the tracheal allograft did not demonstrate rejection. This may suggest that tissue chimerism plays a role in evading immune-mediated allograft rejection. While anastomotic complications and chronic allograft rejection are the most common complications related to lung transplantation, the findings associated with tracheal transplantation may have implications for both reducing complications associated with lung transplantation.

Establishing an upper extremity transplantation program: lessons learnt over 12 years.

As one of the early hand transplant programs in the world, we are often asked to educate other programs on the lessons we have learned and on how to set up a successful hand transplantation program. Two decades of global experience with vascularized composite allotransplantation (VCA) of the upper limb have demonstrated improved functional outcomes and quality of life for carefully screened patients. Despite initial reticence about VCA, over 30 patients in the USA have benefited from hand transplantation, with around 80% long-term successes. We have experience with four bilateral upper extremity patients who have undergone bilateral upper extremity allotransplants. This review article highlights our personal experience and lessons with respect to VCA team assembly, logistics, patient selection, perioperative planning, the operative procedure, and postoperative management. Continual learning and critical evaluation are crucial to maintaining a successful upper extremity VCA program. This will ensure that patients who stand to benefit most from this life-enhancing procedure are identified and are others optimized to achieve the best possible outcomes.

Molecular Signature Associated With Acute Rejection in Vascularized Composite Allotransplantation.

A deeper understanding of acute rejection in vascularized composite allotransplantation is paramount for expanding its utility and longevity. There remains a need to develop more precise and accurate tools for diagnosis and prognosis of these allografts, as well as alternatives to traditional immunosuppressive regimens. Twenty-seven skin biopsies collected from 3 vascularized composite allotransplantation recipients, consisting of face and hand transplants, were evaluated by histology, immunohistochemistry staining, and gene expression profiling. Biopsies with clinical signs and symptoms of rejection, irrespective of histopathological grading, were significantly enriched for genes contributing to the adaptive immune response, innate immune response, and lymphocyte activation. Inflammation episodes exhibited significant fold change correlations between the face and hands, as well as across patients. Immune checkpoint genes were upregulated during periods of inflammation that necessitated treatment. A gene signature consisting of CCL5, CD8A, KLRK1, and IFNγ significantly predicted inflammation specific to vascularized composite allografts that required therapeutic intervention. The mechanism of vascularized composite allograft-specific inflammation and rejection appears to be conserved across different patients and skin on different anatomical sites. A concise gene signature can be utilized to ascertain graft status along with a continuous scale, providing valuable diagnostic and prognostic information to supplement current gold standards of graft evaluation.

Changes in functional and structural brain connectivity following bilateral hand transplantation

As a surgical treatment following amputation or loss of an upper limb, nearly 200 hand transplantations have been completed to date. We report here a magnetic resonance imaging (MRI) investigation of functional and structural brain connectivity for a bilateral hand transplant patient (female, 60 years of age), with a preoperative baseline and three postoperative testing sessions each separated by approximately six months. We used graph theoretical analyses to estimate connectivity within and between modules (networks of anatomical nodes), particularly a sensorimotor network (SMN), from resting-state functional MRI and structural diffusion-weighted imaging (DWI). For comparison, corresponding MRI measures of connectivity were obtained from 10 healthy, age-matched controls, at a single testing session. The patient's within-module functional connectivity (both SMN and non-SMN modules), and structural within-SMN connectivity, were higher preoperatively than that of the controls, indicating a response to amputation. Postoperatively, the patient's within-module functional connectivity decreased towards the control participants' values, across the 1.5 years postoperatively, particularly for hand-related nodes within the SMN module, suggesting a return to a more canonical functional organization. Whereas the patient's structural connectivity values remained relatively constant postoperatively, some evidence suggested that structural connectivity supported the postoperative changes in within-module functional connectivity.

The role of C4d and donor specific antibodies in face and hand transplantation-a systematic review.

To date, little is known about the mechanisms of rejection in vascularized composite allotransplantation, particularly for antibody mediated rejection. Additionally, no clear guidelines exist for the diagnosis and management of antibody-mediated rejection in vascularized composite allotransplantation. A systematic review of electronic databases (Embase and PubMed) was conducted to evaluate the relationship of donor specific antibodies and C4d deposition in correlation with cellular rejection following hand and face transplantation reported by centers between 1998 and July 2023. We extracted data on serum donor specific antibodies at the time of biopsy proven rejection according to Banff classification and C4d staining of target tissues. Mann-Whitney U tests were performed to compare rejection grade between groups divided by status of C4d deposition and serum donor specific antibodies, and Fisher's Exact test was used to assess association between the two markers. This review adhered to PRISMA guidelines. A total of 26 patients (5 face, 21 hand) were identified and data on 90 acute rejection episodes with information on Banff grade, donor specific antibody status, and C4d deposition were available. Donor specific antibodies were found to be associated with higher rejection grade (p = 0.005). C4d was not found to be associated with higher rejection grade (p = 0.33). Finally, no significant association was found between concurrent status of the two markers (p = 0.23). These findings suggest that the presence of donor specifc antibodies may be associated with higher grades of acute cellular rejection following hand and face transplantation. More consistent reporting on rejection episodes is needed in order to better understand antibody-mediated rejection in vascularized composite allotransplantation.

346.3: Hand and upper limb transplant – the UK experience.

346.3: Hand and upper limb transplant – the UK experience.

The role of the purposeful shared decision making model in vascularized composite allotransplantation.

For some patients who have lost the lower part of an arm, hand transplant offers the possibility of receiving a new limb with varying degrees of sensation and function. This procedure, Vascularized Composite Allotransplantation (VCA), is demanding for patients and their care community and comes with significant risks. As a high-stakes decision, patients interested in VCA are subject to extensive clinical evaluation and eligibility decision making. Patients and their care community must also decide if hand transplant (versus other approaches including rehabilitative therapies with or without prosthesis) is right for them. This decision making is often confusing and practically and emotionally fraught. It is complicated in four ways: by the numerous beneficial and harmful potential effects of hand transplant or other options, the number of people affected by VCA and the diverse or conflicting positions that they may hold, the practical demands and limitations of the patient's life situation, and the existential significance of limb loss and transplant for the patient's being. Patients need support in working through these treatment determining issues. Evaluation does not provide this support. Shared decision making (SDM) is a method of care that helps patients think, talk, and feel their way through to the right course of action for them. However, traditional models of SDM that focus on weighing possible beneficial and harmful effects of treatments are ill-equipped to tackle the heterogeneous issues of VCA. A recent model, Purposeful SDM extends the range of troubling issues that SDM can help support beyond opposing effects, to include conflicting positions, life situations, and existential being. In this paper we explore the pertinence of these issues in VCA, methods of SDM that each require of clinicians, the benefits of supporting patients with the breadth of issues in their unique problematic situations, implications for outcomes and practice, and extend the theory of the Purposeful SDM model itself based on the issues present in hand transplant decision making.

Computerized Surgical Planning in Face Transplantation.

Face transplantation (FT) has emerged as a critical intervention for patients with complex facial deformities unsuitable for conventional reconstructive methods. It aims to restore essential functions such as facial expression, mastication, and speech, while also improving psychosocial health. The procedure utilizes various surgical principles, addressing unique challenges of craniofacial complexity and diverse injury patterns. The integration of Computerized Surgical Planning (CSP) leverages computer-aided technologies to enhance preoperative strategy, intraoperative navigation, and postoperative assessment. CSP utilizes three-dimensional computed tomography, printing, angiography, and navigation systems, enabling surgeons to anticipate challenges and reduce intraoperative trial and error. Through four clinical cases, including a groundbreaking combined face and bilateral hand transplant, CSP's role in FT is highlighted by its ability to streamline operative processes and minimize surgical revisions. The adoption of CSP has led to fewer cadaveric rehearsals, heightened operative precision, and greater alignment with preoperative plans. Despite CSP's advancements, it remains complementary to, rather than a replacement for, clinical expertise. The demand for technological resources and multidisciplinary teamwork is high, but the improved surgical outcomes and patient quality of life affirm CSP's value in FT. The technology has become a staple in reconstructive surgery, signaling a step forward in the evolution of complex surgical interventions.

Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation?

The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures.

Immunosuppressive strategies in face and hand transplantation: a comprehensive systematic review of current therapy regimens and outcomes.

Recipients of Vascularized Composite Allotransplants require effective immunosuppressive therapy to prevent graft rejection. This systematic review summarizes the current body of literature on immunosuppressive regimens used in face and hand transplants while summarizing their outcome in terms of rejection, renal failure, and infections. A systematic search of electronic databases was conducted to identify relevant studies from 1998 until July 1st, 2023. We included all studies that discussed immunosuppressive strategies in face and hand transplant recipients according to PRISMA. The standard triple maintenance therapy was mostly adjusted due to nephrotoxicity or high incidence of rejection. The most common alternative treatments utilized were sirolimus (25/91; 27.5%) or everolimus (9/91; 9.9%) following hand- and photophoresis (7/45; 15.6%), sirolimus (5/45; 11.1%) or belatacept (1/45; 2.2%) following face transplantation. Episodes of rejection were reported in 60 (65.9%) of hand- and 33 (73%) of face transplant patients respectively. Graft loss of 12 (13.2%) hand and 4 (8.9%) face transplants was reported. Clinical CMV infection was observed in 6 (6.6%) hand and 7 (15.5%) face transplant recipients. Based on the herein presented data, facial grafts exhibited a heightened incidence of rejection episodes and CMV infections. Facial mucosa adds complexity to the immunological graft composition highlighting the need of individualized immunosuppressive regimens and further research.

Towards Starting a Hand Transplant Unit and Achieving Success in a Hand Transplant: The Standard Operating Procedure.

Vascularized Composite Tissue Allotransplantation (VCA) allows replacement of lost body parts from brain-dead donors. These surgeries are laborious, time-intensive, and require vast planning. With the advent of better immunosuppressants, VCA will increasingly play an important role in the reconstructive field. In this paper, the authors share their standard operating protocol created after much deliberation.

INNOVATIVE THERAPIES IN REGENERATIVE MEDICINE AND TRANSPLANTATION

Introduction: In the past decade we have observed fast development of a new medical fields including regenerative medicine and reconstructive transplantation of the vascularized composite allografts (VCA). The VCA procedures include the new generation of face transplants, hand transplants and many other organs which opened a new reconstructive option for severely damaged patients. The lecture summarizes the risks and benefits of the VCA transplants specifically in the context of the need for life-long immunosuppression to extend VCA survival. Aim: Novel therapeutic strategies of different cell- based therapies are discussed with special emphasizes on the new generation of the donor-recipient chimeric cells used as a supportive tolerogenic therapy for VCA transplants. Material and Methods: Development of the preclinical studies carried in the experimental animal models for creation of the chimeric cells is outlined. This is followed by the creation of the human hematopoietic chimeric cells of the bone marrow and the Umbilical Cord Blood cells origin, confirming tolerogenic and immunomodulatory properties of these new cell-based therapies for application in theVCA and solod organ transplantation. Further development of chimeric cells in the field of regenerative medicine include creation of the Dystrophin Expressing Chimeric (DEC) cells as a novel therapeutic approach for patients with Duchenne muscular dystrophy (DMD). Results: In preparation to clinical applications DEC cells safety and efficacy was tested in the mdx mouse models of DMD. The safety of DEC biodistribution to the DMD- affected target organs of heart, diaphragm and gastrocnemius muscle was confirmed and correlated with improvement in functional tests assessed by echocardiography, plethysmography and standard tests of muscle strengths. These encouraging results observed in preclinical studies lead to the development of the clinical protocol for DMD patients. Currently the DT-DEC01 therapy was applied to seven DMD patients. Both, safety and efficacy of DT-DEC01 cells was confirmed up to 24 months after systemic intraosseous administration to the DMD patients. Conclusions: This pilot clinical study introduces DEC cells as a novel universal therapeutic approach for treatment of DMD and other muscular dystrophies regardless of gene mutation and ambulatory status of the patients.

Reaching New Heights: A Comprehensive Study of Hand Transplantations in Korea after Institutionalization of Hand Transplantation Law.

With the revision of the Organ and Transplantation Act in 2018, the hand has become legal as an area of transplantable organs in Korea. In January 2021, the first hand allotransplantation since legalization was successfully performed, and we have performed a total of three successful hand transplantation since then. By comparing and incorporating our experiences, this study aimed to provide a comprehensive reconstructive solution for hand amputation in Korea. Recipients were selected through a structured preoperative evaluation, and hand transplantations were performed at the distal forearm level. Postoperatively, patients were treated with three-drug immunosuppressive regimen, and functional outcomes were monitored. The hand transplantations were performed without intraoperative complications. All patients had partial skin necrosis and underwent additional surgical procedures in 2 months after transplantation. After additional operations, no further severe complications were observed. Also, patients developed acute rejection within 3 months of surgery, but all resolved within 2 weeks after steroid pulse therapy. Motor and sensory function improved dramatically, and patients were very satisfied with the appearance and function of their transplanted hands. Hand transplantation is a viable reconstructive option, and patients have shown positive functional and psychological outcomes. Although this study has limitations, such as the small number of patients and short follow-up period, we should focus on continued recovery of hand function, and be careful not to develop side effects from immunosuppressive drugs. Through the present study, we will continue to strive for a bright future regarding hand transplantation in Korea.

Review of machine perfusion studies in vascularized composite allotransplant preservation.

The applications of Vascularized composite allotransplantation (VCA) are increasing since the first successful hand transplantation in 1998. However, the abundance of muscle tissue makes VCA's vulnerable to ischemia-reperfusion injury (IRI), which has detrimental effects on the outcome of the procedure, restricting allowable donor-to-recipient time and limiting its widespread use. The current clinical method is Static cold storage (SCS) and this allows only 6 h before irreversible damage occurs upon reperfusion. In order to overcome this obstacle, the focus of research has been shifted towards the prospect of ex-vivo perfusion preservation which already has an established clinical role in solid organ transplants especially in the last decade. In this comprehensive qualitative review, we compile the literature on all VCA machine perfusion models and we aim to highlight the essentials of an ex vivo perfusion set-up, the different strategies, and their associated outcomes.

Mimicking Clinical Rejection Patterns in a Rat Osteomyocutaneous Flap Model of Vascularized Composite Allotransplantation

IntroductionGraft loss in vascularized composite allotransplantation (VCA) is more often associated with vasculopathy and chronic rejection (CR) than acute cellular rejection (ACR). We present a rat osteomyocutaneous flap model using titrated tacrolimus administration that mimics the graft rejection patterns in our clinical hand transplant program. Comparison of outcomes in these models support a role for ischemia reperfusion injury (IRI) and microvascular changes in CR of skin and large-vessel vasculopathy. The potential of the surgical models for investigating mechanisms of rejection and vasculopathy in VCA and treatment interventions is presented. Materials and MethodsFour rodent groups were evaluated: syngeneic controls (Group 1), allogeneic transient immunosuppression (Group 2), allogeneic suboptimal immunosuppression (Group 3), and allogeneic standard immunosuppression (Group 4). Animals were monitored for ACR, vasculopathy, and CR of the skin. ResultsTransient immunosuppression resulted in severe ACR within 2 wk of tacrolimus discontinuation. Standard immunosuppression resulted in minimal rejection but subclinical microvascular changes, including capillary thrombosis and luminal narrowing in arterioles in the donor skin. Further reduction in tacrolimus dose led to femoral vasculopathy and CR of the skin. Surprisingly, femoral vasculopathy was also observed in the syngeneic control group. ConclusionsTitration of tacrolimus in the allogeneic VCA model resulted in presentations of rejection and vasculopathy similar to those in patients and suggests vasculopathy starts at the microvascular level. This adjustable experimental model will allow the study of variables and interventions, such as external trauma or complement blockade, that may initiate or mitigate vasculopathy and CR in VCA.

Replantation versus transplantation: Where do we stand?

Despite advances in extremity trauma care and reconstructive microsurgery, management of the traumatic amputations remains a challenge. The majority of patients will forever experience some level of disability even with replantation or advanced prosthetics. The goal of this article is to familiarize hand and reconstructive surgeons with the current state of upper extremity transplantation, so they better can educate their amputee patients regarding this as an option following limb loss. Current literature, in addition to the international registry on hand and composite tissue transplantation, was reviewed to assemble a summary of outcomes in upper extremity replantation and transplantation. Sensory and functional outcomes of replantation and transplantation are comparable. Reported complications of immunosuppression are similar to those of other solid organ transplants. The financial cost of hand transplantation is high, but comparable to the lifetime cost of prosthesis use. While the risk of immunosuppression is a serious consideration for patients pursuing hand transplantation, in the well-selected and informed patient, hand transplantation can dramatically improve patient reported to outcomes and quality of life.

Vascularized Composite Allotransplantation of the Hand: A Systematic Review of Eligibility Criteria.

Hand transplantation (HT) has emerged as an intervention of last resort for those who endured amputation or irreparable loss of upper extremity function. However, because of the considerable effort required for allograft management and the risks of lifelong immunosuppression, patient eligibility is critical to treatment success. Thus, the objective of this article is to investigate the reported eligibility criteria of HT centers globally. A systematic review of the HT literature was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines, using PubMed, Cochrane, Ovid/Medline, and Scopus. Program Web sites and clinicaltrials.gov entries were included where available. A total of 354 articles were reviewed, 101 of which met inclusion criteria. Furthermore, 10 patient-facing Web sites and 11 clinical trials were included. The most reported criteria related to the capacity to manage the allograft posttransplantation, including access to follow-up, insurance coverage, psychological stability, and history of medical compliance. Other factors related to the impact of immunosuppression, such as active pregnancy and patient immune status, were less emphasized. Because of the novelty of the field, eligibility criteria continue to evolve. While there is consensus on certain eligibility factors, other criteria diverge between programs, and very few factors were considered absolute contraindications. As the popularity of the field continues to grow, we encourage the development of consensus evidence-based eligibility criteria.

A Single-Center Retrospective Evaluation of Decision-Making and Factors Motivating Hand Transplant Candidates.

Advancements in vascularized composite allotransplantation have made hand transplants possible for persons living with upper limb loss. Hand transplantation is not a life-saving procedure, but rather a quality-of-life enhancing procedure; hence the risk of morbidity and mortality must be weighed against improvements in function and appearance. This study explored the decision-making process of patients evaluated for hand transplantation. A qualitative case series study using retrospective chart data of evaluations was conducted between January 1, 2011 and February 28, 2020. Notes were extracted and read by three reviewers. Each case was summarized noting similarities and differences. Nine patients underwent evaluation. Eight were no longer under evaluation and did not receive transplant; one was still undergoing evaluation. Patient motivations for evaluation were dissatisfaction with prostheses or self-image, chronic pain, performing activities of daily living, occupation, burden placed on caregivers, and concerns about overuse of non-affected limbs. Patients chose not to pursue transplantation due to rehabilitation time, immunosuppression, alternative treatments, and social and financial challenges. The clinical team discontinued evaluations due to unmet evaluation requirements, medical contraindications, or treatment alternatives. Different modes of shared decision-making were present depending on the party most heavily featured in the charts as driving decisions. This was an examination of shared decision-making with hand transplant candidates who did not proceed to transplant. Reasons for choosing alternative strategies for management were multifactorial. Lessons learned regarding patient motivations and shared decision-making can inform future interventions to better support patients.

Psychosocial Risk Stratification in Upper Extremity Transplantation Candidates.

Candidate selection for upper extremity transplantation remains an inherently subjective process. This work evaluated the effect that psychosocial factors have on outcomes, both to standardize evaluation of potential candidates and in optimizing these factors prior to transplantation. Our goal was to measure and quantify the risk that various psychosocial factors have on transplant outcomes. Given that we do not have sufficient post-transplant patients to examine specific factors, we chose to have experts in the field evaluate hypothetical patients based on their experience. We used a Generalized Estimating Equation to estimate and compare surgical candidacy scores using patient scenario vignettes based on the presence or absence of permutations of the following: (1) depression; (2) participation in occupational therapy (OT); (3) expectation of post-transplant function; (4) punctuality; and (5) family support were given to experts in the field. This work suggests there is a decrease in predicted success with increasing numbers of negative factors with participation in OT and realistic expectations of outcomes being most important. An increase in the summarizing risk score from 0 to 1.7 was associated with a decrease in the outcome surgical candidacy score from 8.6 to 5.3, meaning candidates with 2 risk factors would often observe a large drop in surgical candidacy score. Focusing on optimizing psychosocial variables in transplant candidates may help improve hand transplant success.

One Year Experience of the Hand Allotransplantation First Performed after Korea Organ Transplantation Act (KOTA) Amendment.

The revision of the Korea Organ Transplantation Act (KOTA) in 2018 included hand/arm among the organs that can be transplanted. The first hand transplantation since the revision of KOTA took place in January 2021. A 62-year-old male patient experienced hand amputation on July 13, 2018, by a catapult injury. The patient first visited our institute 3 months after the injury. After serial interviews and an overall evaluation, the patient was registered on the hand transplantation waiting list in January 2020. On January 9, 2021, the patient underwent hand transplantation at the right distal forearm level. The total operation time was 17 hours 15 minutes, and the cold ischemic time was 4 hours 9 minutes. Postoperative immunosuppression was administered based on the protocol used for kidney transplantation. Two acute rejection episodes occurred, on postoperative days 33 and 41. Both rejection episodes were reversible with rescue therapy of a higher tacrolimus trough level, steroid pulse therapy, and topical immunosuppressants. Controlled passive range of motion exercise was started on postoperative day 10. Dynamic splint was applied on postoperative day 18. At 1 year, graft maintenance and functional improvement were satisfactory, and the patient showed a Disabilities of Arm, Shoulder and Hand score of 25.8. We successfully performed the first hand transplantation surgery under the KOTA amendment. It came from the organic and effective cooperation of plastic, orthopaedic, and transplantation departments and we believe it will guarantee the future ongoing success.