Vascularized Composite Allotransplantation Research Articles

Evaluation of an eLearning System to Train Health Professionals to Communicate about Vascularized Composite Allotransplantation with Donor Families

Introduction: Vascularized composite allotransplantation (VCA) donation relies on obtaining surrogate authorization. Yet, many donor professionals have limited experience discussing composite allograft donation. Using virtual and interactive elements, the eLearning program, Communicating Effectively about Donation for Vascularized Composite Allotransplantation (CEaD-VCA), was developed to enhance the quality of donor professionals' communication approach. Research Questions: We tested the effectiveness of the eLearning program in improving donor professionals' knowledge, preparedness, and confidence leading discussions with families. Design: Donor professionals who primarily obtain family authorization for solid organ and tissue donation were recruited from 2 regional Organ Procurement Organizations. The training was evaluated using a nonrandomized pre-post design. Participants completed an online survey with items assessing their knowledge, preparedness, and confidence for donation discussions. Pre- and post-training responses were compared using paired sample t-tests. Results: The sample included 42 donor professionals. The majority (71.4%) had at least 3 years of work experience, and over half (52.4%) had no experience discussing VCA donation with families. Post-training, significant increases in mean knowledge scores (6.4 pre to 7.0 post, P < 0.01) and mean self-reported preparation (6.6 pre to 7.9 post, P < 0.0001) were observed. There were significant increases in mean confidence scores for discussing face (6.2 pre to 7.9 post, P < 0.0001) and hand (6.2 pre to 8.0 post, P < 0.0001) transplants. Conclusion: The CEaD-VCA program was effective in increasing donor professionals' knowledge, preparation, and confidence when discussing donation, and holds potential for improving donor professional communication during donation discussions.

Procurement and Decellularization of Rat Hindlimbs using an Ex Vivo Perfusion-based Bioreactor for Vascularized Composite Allotransplantation.

Patients with severe traumatic injuries and tissue loss require complex surgical reconstruction. Vascularized composite allotransplantation (VCA) is an evolving reconstructive avenue for transferring multiple tissues as a composite subunit. Despite the promising nature of VCA, the long-term immunosuppressive requirements are a significant limitation due to the increased risk of malignancies, end-organ toxicity, and opportunistic infections. Tissue engineering of acellular composite scaffolds is a potential alternative in reducing the need for immunosuppression. Herein, the procurement of a rat hindlimb and its subsequent decellularization using sodium dodecyl sulfate (SDS) is described. The procurement strategy presented is based upon the common femoral artery. A machine perfusion-based bioreactor system was constructed and used for ex vivo decellularization of the hindlimb. Successful perfusion decellularization was performed, resulting in a white translucent-like appearance of the hindlimb. An intact, perfusable, vascular network throughout the hindlimb was observed. Histological analyses showed the removal of nuclear contents and the preservation of tissue architecture across all tissue compartments.

The Chauvet Workgroup: A Resource for the Psychosocial Aspects of Reconstructive Transplantation

From the first successful hand transplant that ushered in the era of reconstructive transplantation or vascularized composite allotransplantation (VCA), it was apparent that the psychosocial background of the patients and the psychological impact of these visible grafts were of extreme importance to their successful outcome. The outcome that is expected from these grafts includes improving patients’ functional abilities, quality of life, and psychological well-being.1 Notably, the visible and functional nature of most VCA grafts, such as hand, face, or penis, makes the experience of transplantation uniquely different from that of solid organ transplantation.

Recellularization of Bioengineered Scaffolds for Vascular Composite Allotransplantation.

Traumatic injuries or cancer resection resulting in large volumetric soft tissue loss requires surgical reconstruction. Vascular composite allotransplantation (VCA) is an emerging reconstructive option that transfers multiple, complex tissues as a whole subunit from donor to recipient. Although promising, VCA is limited due to side effects of immunosuppression. Tissue-engineered scaffolds obtained by decellularization and recellularization hold great promise. Decellularization is a process that removes cellular materials while preserving the extracellular matrix architecture. Subsequent recellularization of these acellular scaffolds with recipient-specific cells can help circumvent adverse immune-mediated host responses and allow transplantation of allografts by reducing and possibly eliminating the need for immunosuppression. Recellularization of acellular tissue scaffolds is a technique that was first investigated and reported in whole organs. More recently, work has been performed to apply this technique to VCA. Additional work is needed to address barriers associated with tissue recellularization such as: cell type selection, cell distribution, and functionalization of the vasculature and musculature. These factors ultimately contribute to achieving tissue integration and viability following allotransplantation. The present work will review the current state-of-the-art in soft tissue scaffolds with specific emphasis on recellularization techniques. We will discuss biological and engineering process considerations, technical and scientific challenges, and the potential clinical impact of this technology to advance the field of VCA and reconstructive surgery.

Bionic Prostheses: The Emerging Alternative to Vascularised Composite Allotransplantation of the Limb.

Twenty years have surpassed since the first vascularised composite allotransplantation (VCA) of the upper limb. This is an opportunity to reflect on the position of VCA as the gold standard in limb reconstruction. The paucity of recipients, tentative clinical outcomes, and insufficient scientific progress question whether VCA will remain a viable treatment option for the growing numbers of amputees. Bionic technology is advancing at a rapid pace. The prospect of widely available, affordable, safely applied prostheses with long-standing functional benefit is appealing. Progress in the field stems from the contributions made by engineering, electronic, computing and material science research groups. This review will address the ongoing reservations surrounding VCA whilst acknowledging the future impact of bionic technology as a realistic alternative for limb reconstruction.

Cytomegalovirus-related Complications and Management in Facial Vascularized Composite Allotransplantation: An International Multicenter Retrospective Cohort Study.

There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation. This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed. We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R-). CMV viremia was noted in 6 patients (all 4 D+/R- patients and 2 D-/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R- patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R- patients suffered allograft loss due to rejection (longest follow-up: 121 mo). D+/R- patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R- patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R- face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.

VCA in the Era of the COVID-19 Pandemic.

VCA in the Era of the COVID-19 Pandemic.

Non-HLA Antibodies in Hand Transplant Recipients Are Connected to Multiple Acute Rejection Episodes and Endothelial Activation.

The role of anti-HLA antibodies in transplant rejection is well-known but the injury associated with non-HLA antibodies is now widely discussed. The aim of our study was to investigate a role of non-HLA antibodies in hand allografts rejection. The study was performed on six patients after hand transplantation. The control group consisted of: 12 kidney transplant recipients and 12 healthy volunteers. The following non-HLA antibodies were tested: antibody against angiotensin II type 1 receptor (AT1R-Ab), antibody against endothelin-1 type-A-receptor (ETAR-Ab), antibody against protease-activated receptor 1 (PAR-1-Ab) and anti-VEGF-A antibody (VEGF-A-Ab). Chosen proinflammatory cytokines (Il-1, IL-6, IFNγ) were used to evaluate the post-transplant humoral response. Laboratory markers of endothelial activation (VEGF, sICAM, vWF) were used to assess potential vasculopathy. The patient with the highest number of acute rejections had both positive non-HLA antibodies: AT1R-Ab and ETAR-Ab. The same patient had the highest VEGF-A-Ab and very high PAR1-Ab. All patients after hand transplantation had high levels of laboratory markers of endothelial activation. The existence of non-HLA antibodies together with multiple acute rejections observed in patient after hand transplantation should stimulate to look for potential role of non-HLA antibodies in humoral injury in vascular composite allotransplantation.

Ethical challenges in vascularized composite allotransplantation of the lower extremity: lessons learned from hand transplantation and implications for the future

Vascularized composite allotransplantation (VCA) is a novel surgical practice that involves the transplantation of multiple tissue types as a functional unit without the primary purpose of extending life. While VCA of the upper extremity is becoming increasingly accepted and performed, VCA of the lower extremity remains largely unexplored despite its acknowledged potential value. There are inherent ethical concerns surrounding VCA that are dominated by a conflict between the principles of beneficence and maleficence. The primary question is whether the quality-of-life benefits to the patient outweigh the risks associated with long-term immunosuppression for a non-lifesaving procedure. In addition, the ethical conversation involves concerns regarding informed consent, donor autonomy, patient privacy and public disclosure, patient selection, and unique considerations in the pediatric patient. Lower extremity VCA has additional ethical issues compared to upper extremity VCA, as current lower limb prostheses provide excellent, near baseline function that upper limb constructs have not yet been able to achieve. In this review, we discuss the ethical challenges of lower extremity VCA using available evidence for the upper extremity. We also compare ethical considerations of VCA of the extremity with other surgical alternatives to limb loss - namely, limb salvage and replantation - and address how the conversation may be altered with further advancements in immunosuppression and prosthetic technology.

Evaluation of Early Markers of Ischemia-reperfusion Injury and Preservation Solutions in a Modified Hindlimb Model of Vascularized Composite Allotransplantation.

Background.Ischemia-reperfusion injury plays an important role in vascularized composite allotransplantation (VCA). Currently, there is no ideal preservation solution for VCA. In this study, we investigated the effects of 4 different preservation solutions on different tissues within an allogeneic hindlimb rat model.Methods.Sprague Dawley rat hindlimbs were flushed and placed at 4°C for 6 h in heparinized saline, histidine-tryptophan-ketoglutarate, University of Wisconsin (UW), and Perfadex and heterotopically transplanted for ease of ambulation. Apoptosis, necrosis, and the extracellular matrix of the tissues within the allograft were analyzed 2 h posttransplantation using immunohistochemistry, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) assay, and enzyme-linked immunoassay.Results.Higher expression of cleaved caspase 3, a significant increase of high-mobility group box 1 and TUNEL-positive apoptotic cells were observed in the muscle and vessels preserved with heparinized saline compared with UW and Perfadex following reperfusion. Higher expression of TUNEL-positive apoptotic cells was observed in the skin at 12 h of ischemia and in the nerve following reperfusion with histidine-tryptophan-ketoglutarate as a preservation solution.Conclusions.Our data suggest that UW and Perfadex are preferred solutions in VCA. The vessels within the allografts appear to be very susceptible, with laminins and CD31 playing a role in ischemia-reperfusion injury.

Engineering Vascularized Composite Allografts Using Natural Scaffolds: A Systematic Review.

Vascularized composite allotransplantation (VCA) refers to the transplantation of multiple tissues as a functional unit from a deceased donor to a recipient with a severe injury. These grafts serve as potential replacements for traumatic tissue losses. The main problems are the consequences of the long immunosuppressive drugs and the lack of compatible donor. To avoid these limitations, decellularization/recellularization constitutes an attractive approach. The aim of decellularization/recellularization technology is to develop immunogenic free biological substitutes that will restore, maintain, or improve tissue and organ's function. A PubMed search was performed for articles on decellularization and recellularization of composite tissue allografts between February and March 2021, with no restrictions in publication year. The selected reports were evaluated in terms of decellularization protocols, assessment of decellularized grafts, and evaluation of their biocompatibility and repopulation with cells both in vitro and in vivo. The search resulted in a total of 88 articles. Each article was reviewed, 77 were excluded, and the remaining 11 articles reported decellularization of 12 different vascular composite allografts in humans (4), large animals (3), and small animals (rodents; 5). The decellularization protocol for VCA varies slightly between studies, but majority of the reports employ 1% sodium dodecyl sulfate as the main reagent for decellularization. The immunological response of the decellularized scaffolds remain poorly evaluated. Few authors have been able to attempt the recellularization and transplantation of these scaffolds. Successful transplantation seems to require prior recellularization. Decellularization/recellularization is a promising, growing, and emerging developing research field in vascular composite allotransplantation. Impact statement Tissue engineering for vascular composite allotransplantation using decellularization and recellularization approach is a fast-growing area of interest in the reconstructive surgery field. This review will be a very useful tool to get a clear overview for researchers interested in this field.

Personality, Success, and Beyond: The Layperson's Perception of Patients With Facial Transplantation.

While the goal of facial vascularized composite allotransplantation (FVCA) is to provide patients with improved physical and social function, no study has evaluated layperson perception of social acceptance and perceived career success of patients with FVCA. The purpose of this study was to determine how FVCA changes social acceptance and perceived career success of patients with facial disfiguration. Eight hundred fifteen laypersons were surveyed through Mechanical Turk to evaluate their perceptions of patients with FVCA. Respondents were shown facial photographs of patients pre-FVCA, post-FVCA, and matched controls and evaluated these photos on 26 items of perceived social acceptance and career success. Responses were analyzed using descriptive statistics and the Wilcoxon signed-rank test. Both male and female post-FVCA photos were perceived as significantly more socially accepted and professionally successful than their pre-FVCA photos in at least 21 out of 26 items (P < 0.001 for all), but the posttransplant patients scored lower than their control in at least 25 out of 26 items (P < 0.001 for all). Additionally, there were discrepancies in findings based on patient gender. This study suggests that while FVCA has a significantly positive impact on social acceptance and perceived professional success, it does not fully reinstate these qualities. Furthermore, varying surgical outcomes and/or cognitive biases (such as gender) may impact perceptions of the individual by the public. Our findings suggest a need to standardize practices to better predict and improve outcomes and encourage surgeons to consider patient factors such as gender when planning these procedures.

Policies and Price Tags: The Public's Perception of Face Transplantation and Its Funding.

Survey study. Facial vascularized composite allotransplantation (FVCA) can cost over 1 million dollars per procedure and is usually not covered by insurance, yet this financial burden and public opinion surrounding this procedure are not well understood. This study is the first to evaluate the layperson's opinions on the allocation of financial responsibility for FVCA and its inclusion in organ donation registries. Eight hundred and fifteen laypersons were surveyed through MTurk to assess their agreement with 11 statements about FVCA perceptions, funding, and inclusion on organ donation registries. Responses were analyzed with the Wilcoxon Signed-Rank test, the Kruskal-Wallis test, and the Dunn's test. The majority of respondents were supportive of FVCA in 10 out of 11 statements (P < 0.0001). They would be willing to undergo FVCA if they suffered from facial disfigurement; believe FVCA is as important as other organ transplants; believe faces should be included on the organ donation registry; support insurance companies providing coverage for FVCA regardless of trauma etiology; support tax dollars funding the procedure; and believe FVCA improves physical appearance and quality of life. Although respondents generally supported their tax dollars funding the procedure, fewer supported this for self-inflicted trauma (P > 0.01). This study highlights a disconnect between public preference for insurance coverage of FVCA and current lack of coverage in practice. Respondents' acceptance of including faces in organ donation registries may help alleviate the issue of locating a donor, and increasing financial coverage may broaden this procedure's accessibility to a wider range of individuals.

Sensitization and Desensitization in Vascularized Composite Allotransplantation.

Vascularized composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from severe tissue loss in a selected group of patients. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in this type of quality-of-life transplant. The initial management of extensive soft tissue injury can lead to the development of anti-HLA antibodies through injury-related factors, transfusion and cadaveric grafting. The role of antibody-mediated rejection, donor-specific antibody (DSA) formation and graft rejection in the context of VCA still remain poorly understood. The most common antigenic target of preexisting alloantibodies are MHC mismatches, though recognition of ABO incompatible antigens, minor histocompatibility complexes and endothelial cells has also been shown to contribute to rejection. Mechanistically, alloantibody-mediated tissue damage occurs primarily through complement fixation as well as through antibody-dependent cellular toxicity. If DSA exist, activation of complement and coagulation cascades can result in vascular thrombosis and infarction and thus rejection and graft loss. Both preexisting DSA but especially de-novo DSA are currently considered as main contributors to late allograft injury and graft failure. Desensitization protocols are currently being developed for VCA, mainly including removal of alloantibodies whereas treatment of established antibody-mediated rejection is achieved through high dose intravenous immunoglobulins. The long-term efficacy of such therapies in sensitized VCA recipients is currently unknown. The current evidence base for sensitizing events and outcomes in reconstructive transplantation is limited. However, current data show that VCA transplantation has been performed in the setting of HLA-sensitization.

QS9: Decellularization Of Vascularized Composite Allografts In The Rat

Purpose:The decellularization of Vascularized Composite Allotransplantation (VCA) represents a first step in circumventing the need for immunosuppression by depleting donor cells from VCAs. Here we present a model of decellularization of VCAs in rats.Methods:Rat hind limbs based upon the common femoral artery were harvested and perfused through the vascular pedicle at 1ml/min through with 1% sodium dodecyl sulfate (SDS) (group 1) or 0.2% SDS (group 2) or were immersed in SDS 1% (group 3), followed by perfusion (group 1 and 2) or immersion (group 3) in 1% Triton X-100. The degree of decellularization was assessed quantitatively by determining DNA content and qualitatively by histology in all groups at the same locations. The group yielding best decellularization outcome was selected for further assessment for the preservation of ECM content and vasculature and was transplanted orthotopically to assess the ability to reperfuse these decellularized limbs in vivo. RESULTS - Gross examination and DNA quantification of less than 50 ng/mg tissue demonstrated successful decellularization only in group 2 while preserving tissue matrix architecture, including vessels. The arterial network was found to be perfusable and intact during in vivo orthotopic transplantation of the decellularized limb. No outflow was observed, however, after 115 minutes of arterial reperfusion.Conclusions:We describe a successful decellularization protocol for rat hindlimb VCAs by perfusion ex-vivo of 1% SDS. During its in vivo transplantation, decellularization alone allows for a perfusable arterial network and with further optimization, we aim to achieve venous perfusion as well.

QS1: Pre-implanted Nerve Grafts (PING) to Improve Functional Outcomes in VCA

Purpose:Improved graft reinnervation and functional recovery would greatly enhance the utility of vascularized composite allotransplantation (VCA). Pre-implantation of nerve grafts in a limb transplant recipient prior to transplantation to increase the length of the severed nerves in the amputation stump offers a novel, readily translatable approach to this problem. At the time of transplantation a pre-implanted nerve graft (PING) would be elevated from its wound bed in the amputated stump and unfurled distally into the transplanted limb, allowing for a more distal nerve coaptation.Methods:We used a reversed sciatic-tibial nerve isograft coapted end-to-end to a median nerve in a rat to: (1) determine viability of distal axons after elevating PINGs; and (2) assess for ischemic injury to axons in the distal PING following elevation from the wound bed. For axonal viability, grafts of varying lengths (2cm,3cm,4cm, n≥5/group) were left to regenerate for 8 weeks. The distal ends were then biopsied prior to elevation, and again one week after elevation. For ischemia assessment, blood flow along 4cm long PINGs was measured with laser doppler at multiple timepoints: baseline (at time of grafting), 8 weeks after grafting (before elevation), immediately after elevation, and 3 and 7 days post-elevation (n=8/timepoint). Means were compared with t-tests and ANOVA. A pig forelimb model was used to assess the functional impact of PINGs. A 6cm long reversed ulnar-PING was coapted to the proximally transected ulnar nerve. After 12 weeks of regeneration, the distal PING was transferred end-to-end to the median nerve just proximal to the elbow. A control group underwent ulnar-to-median nerve transfer 6cm proximal to the elbow (n=4 limbs/group). Hoof flexion force was measured every three weeks.Results Axonal viability:after 8 weeks, axons had regenerated into the distal grafts in all lengths: mean myelinated axon counts (±SD): 7043 (±790), 6066 (±1838), 6491 (±983) in 2cm,3cm,4cm grafts, with no differences between graft lengths (p=0.48). One week after elevation and unfurling, the number of myelinated axons was significantly decreased in all groups (p<0.006): 3821 (±567), 2953 (±1107), 2894 (±1761) in 2cm,3cm,4cm grafts, with no differences between lengths (p=0.91). Ischemic injury: immediately after elevating a PING, blood flow within the distal half of the graft fell to baseline levels (i.e. no blood flow). 3 days after elevation, blood flow throughout the graft was significantly above baseline (p≤0.04) and matched/exceeded flow measured immediately prior to elevation. Functional impact: preliminary results suggest PINGs can deliver rapid functional recovery.Conclusions:Axons remain present in clinically relevant numbers at the distal ends of PINGs after elevation and unfurling. A decrease in axon counts after elevation may relate to ischemia in the distal PING immediately after elevation. Preliminary functional results show PINGs are capable of delivering early functional recovery.

2: Ex-vivo Normothermic Preservation Of Amputated Limbs With A Hemoglobin-based Oxygen Carrier (HBOC-201) Perfusate

Background:Ex-vivo normothermic perfusion (EVNP) has been used as an alternative to static cold storage (SCS) to improve allograft quality in solid organ and vascularized composite allotransplantation (VCA). Perfusates containing red blood cells (RBCs) have shown to improve outcomes during ex vivo normothermic organ perfusion when compared to acellular perfusates. However, the use of blood products is challenging due to limited availability, the need for cross-matching, and potential blood-borne infection transmission. To avoid limitations associated with the use of blood-based products, we evaluated the feasibility of EVNLP utilizing a polymerized Hemoglobin-Based Oxygen Carrier-201 (HBOC-201).Methods:Twenty-four porcine forelimbs were procured from Yorkshire pigs following euthanasia. Six forelimbs underwent EVNLP with an HBOC-201 based perfusate, six with an RBC-based perfusate, and twelve served as static cold storage (SCS) controls. EVNLP termination criteria included systolic arterial pressure ≥115 mmHg, fullness of compartments, or tissue oxygen saturation drop by 20%. Limb contractility, weight change, compartment pressure, tissue oxygen saturation, oxygen uptake rates (OUR) were assessed. Perfusate fluid-dynamics, gases, electrolytes, metabolites, methemoglobin (MetHb), creatine kinase (CK), and myoglobin concentration were measured. Limb viability was assessed with indocyanine green (ICG) angiography, infrared thermography (IRT), and muscle histology.Results:Warm ischemia time before EVNLP was 35.50±8.62 min in HBOC-201 perfused limbs and 30.17±8.03 min in RBC-perfused limbs (p=0.07). EVNLP duration in HBOC-201 and RBC-perfused limbs was 22.5±1.7 and 28.2±7.3 hours, respectively (p=0.04). Vascular flow (325±25 vs. 444.7±50.6 ml/min; p=0.39), OUR (2.0±1.45 vs. 1.3±0.92 mlO2/min*g of tissue; p=0.80), lactate (14.66±4.26 vs. 13.11±6.68 mmol/L; p=0.32), and perfusate pH (7.53±0.25 HBOC-201; 7.50±0.23 RBC; p=0.82) were not significantly different between treatment groups. Additionally, flexor (28.3±22.0 vs. 27.5±10.6; p=0.99) and extensor (31.5±22.9 vs. 28.8±14.5; p=0.82) compartment pressures, contractility (3±2 vs. 4±1 p=0.57), and percent weight change (23.1±3.0% vs. 13.2±22.7%; p=0.07) were not significantly different between HBOC-201 and RBC groups. In HBOC-201 perfused limbs, MetHb levels increased, reaching 47.8±12.1% at endpoint. Methemoglobin saturation did not affect OUR (ρ = -0.15, r2 = 0.022; p=0.45). Distal tissue preservation was confirmed by IRT and ICG angiography in both EVNLP groups. Hypoxic cell clusters were identified in the SCS control group at endpoint and were absent in both treatment arms.Conclusion:HBOC-201- and RBC-based perfusates similarly support isolated limb physiology, metabolism, and function. Optimization of modifiable factors, including HBOC-201 oxidation, may extend EVNLP durations employing HBOC-201 and overcome logistical constraints of the utilization of traditional blood products.

Presence of Donor Lymph Nodes Within Vascularized Composite Allotransplantation Ameliorates VEGF-C-mediated Lymphangiogenesis and Delays the Onset of Acute Rejection.

The lymphatic system plays an active role in modulating inflammation in autoimmune diseases and organ rejection. In this work, we hypothesized that the transfer of donor lymph node (LN) might be used to promote lymphangiogenesis and influence rejection in vascularized composite allotransplantation (VCA). Hindlimb transplantations were performed in which (1) recipient rats received VCA containing donor LN (D:LN+), (2) recipient rats received VCA depleted of all donor LN (D:LN-), and (3) D:LN+ transplantations were followed by lymphangiogenesis inhibition using a vascular endothelial growth factor receptor-3 (VEGFR3) blocker. Our data show that graft rejection started significantly later in D:LN+ transplanted rats as compared to the D:LN- group. Moreover, we observed a higher level of VEGF-C and a quicker and more efficient lymphangiogenesis in the D:LN+ group as compared to the D:LN- group. The presence of donor LN within the graft was associated with reduced immunoactivation in the draining LN and increased frequency of circulating and skin-resident donor T regulatory cells. Blocking of the VEGF-C pathway using a VEGFR3 blocker disrupts the lymphangiogenesis process, accelerates rejection onset, and interferes with donor T-cell migration. This study demonstrates that VCA LNs play a pivotal role in the regulation of graft rejection and underlines the potential of specifically targeting the LN component of a VCA to control graft rejection.

Long-term Outcomes After Facial Allotransplantation: Systematic Review of the Literature.

Facial vascularized composite allotransplantation (fVCA) represents a reconstructive approach that enables superior improvements in functional and esthetic restoration compared with conventional craniomaxillofacial reconstruction. Outcome reports of fVCA are usually limited to short-term follow-up or single-center experiences. We merge scientific literature on reported long-term outcome data to better define the risks and benefits of fVCA. We conducted a systematic review of PubMed/MEDLINE databases in accordance with PRISMA guidelines. English full-text articles providing data on at least 1 unique fVCA patient, with ≥3 years follow-up, were included. The search yielded 1812 articles, of which 28 were ultimately included. We retrieved data on 23 fVCA patients with mean follow-up of 5.3 years. More than half of the patients showed improved quality of life, eating, speech, and motor and sensory function following fVCA. On average, the patients had 1 acute cell-mediated rejection and infectious episode per year. The incidence rates of acute rejection and infectious complications were high within first-year posttransplant but declined thereafter. Sixty-five percent of the patients developed at least 1 neoplastic or metabolic complication after transplantation. Chronic vascular rejection was confirmed in 2 patients, leading to allograft loss after 8 and 9 years. Two patient deaths occurred 3.5 and 10.5 years after transplant due to suicide and lung cancer, respectively. Allograft functionality and improvements in quality of life suggest a positive risk-benefit ratio for fVCA. Recurrent acute rejection episodes, chronic rejection, immunosuppression-related complications, and heterogeneity in outcome reporting present ongoing challenges in this field.

Donor and Recipient Matching in Facial Vascularized Composite Allotransplantation: A Closer Look at the Donor Pool.

Identifying a donor for facial vascularized composite allotransplant recipients can be a lengthy, emotionally challenging process. Little is known about the relative distribution of key donor characteristics among potential donors. Data on actual wait times of patients are limited, making it difficult to estimate wait times for future recipients. The authors retrospectively reviewed charts of nine facial vascularized composite allotransplant patients and provide data on transplant wait times and patient characteristics. In addition, they analyzed the United Network for Organ Sharing database of dead organ donors. After excluding donors with high-risk characteristics (e.g., active cancer or risk factors for blood-borne disease transmission), the authors calculated the distribution of relevant donor-recipient matching criteria (i.e., ethnicity, body mass index, age, ABO blood group, cytomegalovirus, Epstein-Barr virus, hepatitis C virus) among 65,201 potential donors. The median wait time for a transplant was 4 months (range, 1 day to 17 months). The large majority of United Network for Organ Sharing-recorded deaths from disease were white (63 percent) and male (58 percent). Female donors of black, Hispanic, or Asian descent are underrepresented, with 7, 5, and 1 percent of all recorded deaths from disease, respectively. Potential donors show cytomegalovirus and Epstein-Barr virus seropositivity of 65 and 95 percent, respectively. The number of annual hepatitis C-positive donors increased over time. Actual facial vascularized composite allotransplant wait times vary considerably. Although most patients experience acceptable wait times, some with underrepresented characteristics exceed acceptable levels. Cytomegalovirus-seropositive donors present a large portion of the donor pool, and exclusion for seronegative patients may increase wait time. Hepatitis C-seropositive donors may constitute a donor pool for underrepresented patient groups in the future.