Composite Allotransplantation Research Articles

Developing online communication training to request donation for vascularized composite allotransplantation (VCA): improving performance to match new US organ donation targets.

Approaching families of dying or newly deceased patients to donate organs requires specialized knowledge and a mastery of relational communication. As the transplantation field has progressed, Donation Professionals (DPs) are also leading conversations with family decision makers (FDMs) about the donation of uncommon anatomical gifts, such as face, hands, genitalia, referred to as Vascularized Composite Allotransplants (VCA) without much training or experience. To address the need for training, we adapted and beta tested an evidenced-based communication training program for donation discussions to VCA requests. The overarching goal of Communicating Effectively about Donation for Vascularized Composite Allotransplantation (CEaD-VCA) is to increase the number of VCA authorizations and to improve the socioemotional outcomes of FDMs. We developed CEaD-VCA, an online, on-demand training program based on the previously tested, evidenced-based communication skills training program designed to train DPs to have conversations about solid organ donation. The training was modified utilizing data from a national telephone survey with DPs and results of 6 focus groups conducted with members of the general public. The survey and focus groups assessed knowledge, attitudes, and barriers to VCA donation. The training was shaped by a partnership with a leading industry partner, the Gift of Life Institute.™ RESULTS: Using the results as a guide, the existing CEaD training program, consisting of interactive eLearning modules, was adapted to include technical information about VCA, foundational communication skills, and two interactive example VCA donation request scenarios to facilitate active learning. Forty-two DPs from two partner Organ Procurement Organizations (OPOs) participated in the beta test of CEaD-VCA. Pre- and post-test surveys assessed the impact of the training. The training was scored highly by DPs in effectiveness and ease of use. This project created a standardized, accessible, and comprehensive training for DPs to communicate about VCA donation. CEaD-VCA is an example of how to develop a communication skills training for difficult conversations utilizing input from stakeholders, guided by communication theory. It also demonstrates how gaps in communication skills during medical education can be filled utilizing advanced online Learning Management Systems. The training specifically addresses new CMS rules concerning OPO performance metrics.

First-in-Human Whole-Eye Transplantation: Ensuring an Ethical Approach to Surgical Innovation

As innovations in the field of vascular composite allotransplantation (VCA) progress, whole-eye transplantation (WET) is poised to transition from non-human mammalian models to living human recipients. Present treatment options for vision loss are generally considered suboptimal, and attendant concerns ranging from aesthetics and prosthesis maintenance to social stigma may be mitigated by WET. Potential benefits to WET recipients may also include partial vision restoration, psychosocial benefits related to identity and social integration, improvements in physical comfort and function, and reduced surgical risk associated with a biologic eye compared to a prosthesis. Perioperative and postoperative risks of WET are expected to be comparable to those of facial transplantation (FT), and may be similarly mitigated by immunosuppressive protocols, adequate psychosocial support, and a thorough selection process for both the recipient and donor. To minimize the risks associated with immunosuppressive medications, the first attempts in human recipients will likely be performed in conjunction with a FT. If first-in-human attempts at combined FT-WET prove successful and the biologic eye survives, this opens the door for further advancement in the field of vision restoration by means of a viable surgical option. This analysis integrates recent innovations in WET research with the existing discourse on the ethics of surgical innovation and offers preliminary guidance to VCA programs considering undertaking WET in human recipients.

Need for Kidney Transplantation Following Vascularized Composite Allotransplantation: An International, Multi-Center Experience

Need for Kidney Transplantation Following Vascularized Composite Allotransplantation: An International, Multi-Center Experience

Incorporating Trauma-informed Approaches to Care in Vascularized Composite Allotransplantation.

Since 1998, vascularized composite allotransplantation (VCA) has been a growing area of research in the field of reconstructive surgery. Although conditions treated with VCA often result from a traumatic injury, there has been limited emphasis on incorporating trauma-informed care (TIC) models in VCA. Considering the importance of psychosocial well-being in VCA candidates and recipients, applying best practices in TIC to the face, upper extremity, and penile transplantation may be critical in minimizing retraumatization throughout the perioperative process. There are six main principles of TIC: safety; trustworthiness and transparency; peer support; collaboration and mutuality; empowerment and choice; and cultural, historical, and gender issues, which may be further incorporated in care for VCA patients. Evaluating for PTSD and incorporating TIC may have substantial benefit to postoperative outcomes.

Synchronous Abdominal Wall and Small Bowel Transplantation: Critical Insights at 4-Year Follow-up

AbstractThis 4-year follow-up of synchronous abdominal wall vascular composite allotransplantation (AW-VCA) and small bowel transplantation reveals novel insights and innovations in abdominal wall VCA. The case, involving a 37-year-old male Army veteran, showcases the benefits of AW-VCA in addressing loss of abdominal domain in intestinal transplantation (ITx). The events leading to ultimate rejection of both the AW-VCA and small bowel graft at 4 years highlights the complex interplay between graft survival, patient compliance, and immunosuppressive management. Notably, a significant discordance between AW-VCA and ITx rejection patterns was identified, questioning the reliability of skin components in AW-VCA as early indicators of ITx rejection. Furthermore, the behavior of the vascularized abdominal fascia, observed postexcision of the small bowel graft, offers new understanding of the immunologic response to fascia-only grafts. This follow-up emphasizes the complexities of graft survival, patient compliance, and immunosuppressive management, underscoring the need for ongoing research and innovation in the field.

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.

Towards Optimizing Sub-Normothermic Machine Perfusion in Fasciocutaneous Flaps: A Large Animal Study.

Machine perfusion has developed rapidly since its first use in solid organ transplantation. Likewise, reconstructive surgery has kept pace, and ex vivo perfusion appears as a new trend in vascularized composite allotransplants preservation. In autologous reconstruction, fasciocutaneous flaps are now the gold standard due to their low morbidity (muscle sparing) and favorable functional and cosmetic results. However, failures still occasionally arise due to difficulties encountered with the vessels during free flap transfer. The development of machine perfusion procedures would make it possible to temporarily substitute or even avoid microsurgical anastomoses in certain complex cases. We performed oxygenated acellular sub-normothermic perfusions of fasciocutaneous flaps for 24 and 48 h in a porcine model and compared continuous and intermittent perfusion regimens. The monitored metrics included vascular resistance, edema, arteriovenous oxygen gas differentials, and metabolic parameters. A final histological assessment was performed. Porcine flaps which underwent successful oxygenated perfusion showed minimal or no signs of cell necrosis at the end of the perfusion. Intermittent perfusion allowed overall better results to be obtained at 24 h and extended perfusion duration. This work provides a strong foundation for further research and could lead to new and reliable reconstructive techniques.

Surgical Feasibility Study on Cadaver for Vascularized Wrist Joint Transplantation

Despite modern advancements in the treatment of late stages of wrist joint degeneration, few reliable options exist for patients requiring motion-preserving reconstruction of their radiocarpal and midcarpal joints. Vascularized composite allotransplantation (VCA) could be considered an option for wrist reconstruction in the future. The goal of this study was to describe the relevant anatomy and design a potential surgical technique for wrist VCA. Anatomic studies were performed on 17 human upper extremities. The arterial system of each cadaver was injected with latex dye or radiographic contrast. After injecting a contrast medium visible on a computerized tomography (CT) scan, the initial three specimens were examined using microCT. This confirmed joint vascular patency and allowed for the dissection of the other specimens that were injected with latex for the study of joint vascularization and the design of the wrist VCA. We then outlined a donor and recipient surgical technique for transplant based on recipient CT scans. Customized cutting guides were designed for the transplant procedure. After the procedure, we performed angiography of the VCA to determine the vascularity of the transplant. Using a combined volar and dorsal approach, we were able to perform a complete wrist VCA procedure. After the completed transplant procedure, angiographic imaging of the specimens demonstrated that the flap dissection and transplantation preserved the nutrient endosteal supply to the distal end of the radius and ulna, as well as to the carpal bones and the metacarpal bases. The dissection of the donor, recipient, and the entire vascularized joint transplant procedure served to illustrate the anatomical feasibility of the cadaveric surgical technique. This establishes an anatomic basis for the possibility of future human clinical applications. This study helps investigate the anatomical feasibility of a wrist VCA.

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.

Application possibilities of artificial intelligence in facial vascularized composite allotransplantation-a narrative review.

Facial vascularized composite allotransplantation (FVCA) is an emerging field of reconstructive surgery that represents a dogmatic shift in the surgical treatment of patients with severe facial disfigurements. While conventional reconstructive strategies were previously considered the goldstandard for patients with devastating facial trauma, FVCA has demonstrated promising short- and long-term outcomes. Yet, there remain several obstacles that complicate the integration of FVCA procedures into the standard workflow for facial trauma patients. Artificial intelligence (AI) has been shown to provide targeted and resource-effective solutions for persisting clinical challenges in various specialties. However, there is a paucity of studies elucidating the combination of FVCA and AI to overcome such hurdles. Here, we delineate the application possibilities of AI in the field of FVCA and discuss the use of AI technology for FVCA outcome simulation, diagnosis and prediction of rejection episodes, and malignancy screening. This line of research may serve as a fundament for future studies linking these two revolutionary biotechnologies.

Supercooling: A Promising Technique for Prolonged Organ Preservation in Solid Organ Transplantation, and Early Perspectives in Vascularized Composite Allografts.

Ex-vivo preservation of transplanted organs is undergoing spectacular advances. Machine perfusion is now used in common practice for abdominal and thoracic organ transportation and preservation, and early results are in favor of substantially improved outcomes. It is based on decreasing ischemia-reperfusion phenomena by providing physiological or sub-physiological conditions until transplantation. Alternatively, supercooling techniques involving static preservation at negative temperatures while avoiding ice formation have shown encouraging results in solid organs. Here, the rationale is to decrease the organ's metabolism and need for oxygen and nutrients, allowing for extended preservation durations. The aim of this work is to review all advances of supercooling in transplantation, browsing the literature for each organ. A specific objective was also to study the initial evidence, the prospects, and potential applications of supercooling preservation in Vascularized Composite Allotransplantation (VCA). This complex entity needs a substantial effort to improve long-term outcomes, marked by chronic rejection. Improving preservation techniques is critical to ensure the favorable evolution of VCAs, and supercooling techniques could greatly participate in these advances.

Vascularized Composite Allograft Versus Prosthetic for Reconstruction After Facial and Hand Trauma: Comparing Cost, Complications, and Long-term Outcome.

In the past decade, vascularized composite allotransplantation (VCA) has become clinical reality for reconstruction after face and hand trauma. It offers patients the unique opportunity to regain form and function in a way that had only been achieved with traditional reconstruction or with the use of prostheses. On the other hand, prostheses for facial and hand reconstruction have continued to evolve over the years and, in many cases, represent the primary option for patients after hand and face trauma. We compared the cost, associated complications, and long-term outcomes of VCA with prostheses for reconstruction of the face and hand/upper extremity. Ultimately, VCA and prostheses represent 2 different reconstructive options with distinct benefit profiles and associated limitations and should ideally not be perceived as competing choices. Our work adds a valuable component to the general framework guiding the decision to offer VCA or prostheses for reconstruction after face and upper extremity trauma.

A Single Cell and Spatial Transcriptomics Approach to Elucidating CD8 T Cells in Vascularized Composite Allotransplantation Rejection

A Single Cell and Spatial Transcriptomics Approach to Elucidating CD8 T Cells in Vascularized Composite Allotransplantation Rejection

RNA Sequencing Reveals a Conserved Mechanism of T Cell-Mediated Rejection in Vascularized Composite Allotransplantation Across Anatomical Sites

RNA Sequencing Reveals a Conserved Mechanism of T Cell-Mediated Rejection in Vascularized Composite Allotransplantation Across Anatomical Sites

The Synergistic Effect of Full-Spectrum Light Therapy and Transient Immunosuppressants Prolonged Allotransplant Survival.

The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model. Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis. The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) ( P < 0.01). Group 4 also showed a significant increase in regulatory T cells ( P = 0.04) and transforming growth factor-β1 levels ( P = 0.02), and a trend toward a decrease in interleukin-1β levels ( P = 0.03) at 16 weeks after transplantation as compared with control (group 1). FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival. Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.

CD4+CD25+FOXP3+ regulatory T cells: a potential "armor" to shield "transplanted allografts" in the war against ischemia reperfusion injury.

Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the "gold standard" treatment for patients with end-stage organ failure. Recently, vascularized composite allotransplantation (VCA) has reemerged as a feasible treatment option for patients with complex composite tissue defects. In both SOT and VCA, ischemia reperfusion injury (IRI) is inevitable and is a predominant factor that can adversely affect transplant outcome by potentiating early graft dysfunction and/or graft rejection. Restoration of oxygenated blood supply to an organ which was previously hypoxic or ischemic for a period of time triggers cellular oxidative stress, production of both, pro-inflammatory cytokines and chemokines, infiltration of innate immune cells and amplifies adaptive alloimmune responses in the affected allograft. Currently, Food and Drug Administration (FDA) approved drugs for the treatment of IRI are unavailable, therefore an efficacious therapeutic modality to prevent, reduce and/or alleviate allograft damages caused by IRI induced inflammation is warranted to achieve the best-possible transplant outcome among recipients. The tolerogenic capacity of CD4+CD25+FOXP3+ regulatory T cells (Tregs), have been extensively studied in the context of transplant rejection, autoimmunity, and cancer. It was not until recently that Tregs have been recognized as a potential cell therapeutic candidate to be exploited for the prevention and/or treatment of IRI, owing to their immunomodulatory potential. Tregs can mitigate cellular oxidative stress, produce anti-inflammatory cytokines, promote wound healing, and tissue repair and prevent the infiltration of pro-inflammatory immune cells in injured tissues. By using strategic approaches to increase the number of Tregs and to promote targeted delivery, the outcome of SOT and VCA can be improved. This review focuses on two sections: (a) the therapeutic potential of Tregs in preventing and mitigating IRI in the context of SOT and VCA and (b) novel strategies on how Tregs could be utilized for the prevention and/or treatment of IRI.

Novel cell-based strategies for immunomodulation in vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) has become a clinical reality in the past two decades. However, its routine clinical applications are limited by the risk of acute rejection, and the side effects of the lifelong immunosuppression. Therefore, there is a need for new protocols to induce tolerance and extend VCA survival. Cell- based therapies have emerged as an attractive strategy for tolerance induction in VCA. This manuscript reviews the current strategies and applications of cell-based therapies for tolerance induction in VCA. Cellular therapies, including the application of bone marrow cells (BMC), mesenchymal stem cells (MSC), adipose stem cells, regulatory T cells (Treg) cells, dendritic cells and donor recipient chimeric cells (DRCC) show promising potential as a strategy to induce tolerance in VCA. Ongoing basic science research aims to provide insights into the mechanisms of action, homing, functional specialization and standardization of these cellular therapies. Additionally, translational preclinical and clinical studies are underway, showing encouraging outcomes. Cellular therapies hold great potential and are supported by preclinical studies and clinical trials demonstrating safety and efficacy. However, further research is needed to develop novel cell-based immunosuppressive protocol for VCA.

What is needed to ensure long-term sustainability for the field of vascularized composite allotransplantation?

The field of vascularized composite allotransplantation (VCA) has demonstrated remarkable advances since its inception with some excellent long-term results in a variety of graft types. However, unlike solid organ transplantation, it has yet to become mainstream. We therefore discuss strategies on ensuring long-term sustainability by addressing continued clinical developments of VCA to improve the risk-to-benefit balance, importance of public support, improved policy and financial support, and need for a bridge to the future of transplant surgery. There has been headway on all fronts and collaboration among the VCA centers for centralization of data and incorporation of patient voices will be essential for continued progress.

Moderate LMWH Anticoagulation Improves Success Rate of Hind Limb Allotransplantation in Mice.

The mouse hind limb model represents a powerful research tool in vascularized composite tissue allotransplantation, but its applicability is limited due to poor graft survival (62%-83%). Vascular thrombosis and massive hemorrhage are the major causes for these drop-outs. We hypothesize that because of better anticoagulation effect and lower risk of thrombocytopenia, application of low molecular weight heparin (LMWH) will minimize vascular complications and enhance graft and animal survival. Fifty allogeneic hind limb transplantations were performed (C57BL/6 to DBA/2 mice) using five different anticoagulation protocols. Bleeding and thromboembolic events were recorded macroscopically by postoperative hemorrhage and livid discoloration of the graft, respectively. Graft perfusion and survival were monitored daily by capillary-refill-time of graft toes within 2-3 seconds. Vascular congestion and tissue necrosis were examined by histological evaluation of hematoxylin-eosin-stained tissue sections. All transplantations were technically successful. Increase in thromboembolic events and a concomitant decrease in bleeding events were observed with the decreasing concentration of heparin in the perfusion solution. Although treatment of donor and recipient with low dose of LMWH could not reduce thromboembolic events, moderate dose effectively reduced these events. Compared with the poor outcome of graft perfusion with heparin alone, additional treatment of donor and recipient with low dose of LMWH improved graft and animal survival by 18%. Interestingly, animals treated with moderate dose of LMWH demonstrated 100% graft and animal survival. Treatment of donor and recipient mice with a moderate dose of LMWH prevents vascular complications and improves the outcome of murine hind limb transplants.

Human Multi-Chimeric Cell (HMCC) Therapy as a Novel Approach for Tolerance Induction in Transplantation

Cellular therapies are regarded as the most promising approach for inducing transplant tolerance without life-long immunosuppression in solid organ and vascularized composite allotransplantation (VCA). Currently, no therapies are achieving this goal. This study introduces a novel Human Multi-Chimeric Cell (HMCC) line created by fusion of umbilical cord blood (UCB) cells, from three unrelated donors as an alternative therapeutic approach to bone marrow transplantation and tolerance induction in solid organ and VCA transplants. We performed eighteen ex vivo polyethylene glycol mediated fusions of human UCB cells from three unrelated donors to create HMCC. Mononuclear cells labeled with PKH26, PKH67, and eFluor™ 670 fluorescent dyes were fused and sorted creating a new population of triple-labeled (PKH26/PKH67/eFluor™ 670) HMCC. The creation of HMCC from three unrelated human UCB donors was confirmed by flow cytometry and confocal microscopy. Genotyping analyses determined the tri-chimeric state of HMCC by presence of parent alleles and selected loci specific for each of three UCB donors. Phenotype characterization confirmed hematopoietic markers distribution, comparable to UCB donors. HMCC maintained viability and displayed a low apoptosis level. The COMET assay revealed absence of genotoxicity, confirming fusion safety. Colony forming units assay showed clonogenic properties of HMCC. This study confirmed the feasibility of HMCC creation from three unrelated human UCB donors and characterized tri-chimeric state, hematopoietic phenotype, viability, safety, and clonogenic properties of HMCC. The created HMCC line, representing genotype characteristics of three unrelated human UCB donors, introduces a novel therapeutic approach for bone marrow, solid organ, and VCA transplants.Graphical