Composite Allotransplantation Research Articles

A Guide to the Implementation and Design of Ex Vivo Perfusion Machines for Vascularized Composite Allotransplantation.

Ex vivo machine perfusion (EVMP) is a versatile platform utilized in vascularized composite allotransplantation (VCA) to prolong preservation, salvage tissue, and evaluate graft viability. However, there is no consensus on best practices for VCA. This article discusses the common components, modifications, and considerations necessary for a successful VCA perfusion. A systematic literature review was performed in several databases (PubMed, Scopus, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov) to identify articles published on VCA EVMP (face, limb, abdominal wall, uterus, penis, and free flaps) before August 2022. Graft type and animal model, general perfusion parameters, core components of the circuit, and optional components for enhanced monitoring were extracted from the articles. A total of 1370 articles were screened, and 46 articles met inclusion criteria. Most articles (84.8%) were published in the last 10 years. Pigs were the main model used, but 10 protocols used human grafts. Free flaps were the most common graft type (41.3%), then upper extremities/forelimbs (28.3%), uteruses (17.4%), and hindlimbs (13.0%). Postperfusion replantation occurred in 15.2% of studies. Normothermic perfusion predominated (54.1%), followed by hypothermic (24.3%), and subnormothermic (21.6%). The majority of studies (87.0%) oxygenated their systems, most commonly with carbogen. EVMP is a rapidly growing area of research. Leveraging EVMP in VCA can optimize VCA procedures and allow for expansion into replantation, flap salvage, and other areas of plastic surgery. Currently, VCA EVMP is achieved through a variety of approaches, but standardization is necessary to advance this technology and attain clinical translation.

Lymph Node Inclusion in a Modified Osteomyocutaneous Allograft for Vascularized Composite Allotransplantation: Establishment and Feasibility Assessment in a Pig Model.

Representative translational animal models play a key role in vascularized composite allotransplantation (VCA) research. A composite porcine hindlimb flap, previously described, is a relevant preclinical model. However, its bulkiness and the absence of critical immunologic tissues make it less suitable for investigating the unique immunologic features of VCA. We aimed to further develop this model by reducing its bulkiness and by including donor-draining lymph nodes. We conducted an anatomic study by harvesting 11 porcine osteomyocutaneous flaps (4 conventional and 7 modified techniques), which were characterized by computed tomography. Furthermore, 8 allotransplantations were performed in Swiss landrace pigs. After the procedure, animals were assigned to a model development and control group (N = 4 per group). No immunosuppression was given, and animals were followed up until grade 3 rejection. With the modified technique, the flap weight was significantly reduced with a mean weight of 831 g, corresponding to 1.8% total body weight versus 1710 g in the conventional technique, representing 4.2% of total body weight (P < 0.0001). The muscle/bone ratio was reduced from 8.24 (conventional) to 2.92 (modified), (P = 0.03). Histologically, graft-draining lymph nodes showed typical changes related to rejection and no signs of ischemia after in vivo transplantation. By modifying the surgical technique, the bulkiness of the flap was markedly reduced, without impairing its vascularization and reliably including vascularized graft-draining lymph nodes. Our modified VCA model in the pig presents distinct advantages for surgery as well as immunologic analysis, warranting a large-scale use for experimental reconstructive transplantation studies.

Future directions in transmasculine genital gender-affirming surgery: tissue substitutes and transplant.

The present study reviews contemporary literature focused on transplantation and tissue substitutes for the purposes of masculinizing genital gender affirming surgery. Additional background is provided for both topics to provide a more comprehensive understanding of the modern applications. Genitourinary vascularized composite allotransplantation has become a reality in recent years with several cases reported worldwide in cisgender men with promising reports of urinary and sexual function. A natural extension might be to apply these techniques to gender affirming surgery (GAS). Technical barriers include anatomic differences between vasculature supporting penoscrotal and vulvovaginal anatomy as well as size discrepancies between the corporal bodies which complicate the required anastomoses. Whether the smaller caliber of biologic female pelvic vasculature can support erection of a neophallus is another obstacle. Ethically, resource allocation, elective immunosuppression, society response to organ donation and gender identity, as well as the psychosocial safety of the patient given charged public opinion must all be considered.Tissue substitutes have long been used in urologic reconstruction but more recently applied to masculinizing gender affirmation surgery which has traditionally relied on autografting. The focus has been on restoring form and function to the donor site as well as facilitating treatment of urethral stricture and wound complications after phalloplasty. Furthermore, aesthetic applications have also been described, most recently for glans atrophy. The field of masculinizing gender affirmation surgery represents an exciting frontier for surgeons and patients alike. Given the relative nascency of the specialty and its propensity to draw techniques from various surgical disciplines there exists a unique opportunity for rapid innovation to overcome challenging problems posed by these complex procedures as evidenced by discussions around applying penile transplantation and the use of novel tissue grafting techniques.

Grasping time - longevity of vascularized composite allografts.

Despite significant advancements in the field of vascularized composite allotransplantation, challenges, particularly regarding the long-term viability and functionality of vascularized composite allotransplantation (VCA) grafts, persist. This paper provides a review of the current literature on the longevity of VCA grafts, focusing on factors influencing graft survival, immunological considerations and clinical outcomes. Longevity of VCA grafts is influenced by a variety of peri- and postoperative factors including cold ischemia time, human leukocyte antigen matching, environmental exposure, psychosocial factors, adherence, immunosuppression, and complications. Due to the limited number of VCA transplants performed and heterogenous reporting, direct correlation of single factors with VCA outcomes remains inconclusive. Indirect evidence, however, supports their importance. High immunosuppressive burden, frequent occurrence of acute and accumulating cases of chronic rejection remain a significant challenge of the field. Insights gained from this review aim to inform clinical practice and guide future research endeavors with the goal of ameliorating outcomes after VCA transplantation and facilitate wider use of VCA grafts for restoration of tissue defects.

Pathological Characteristics of Muscle Rejection and Dysfunction in a Swine Vascularized Composite Allotransplantation Model and a Scoring Proposal: A Pilot Study.

Pathological Characteristics of Muscle Rejection and Dysfunction in a Swine Vascularized Composite Allotransplantation Model and a Scoring Proposal: A Pilot Study.

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.

The current state of tolerance induction in vascularized composite allotransplantation.

Significant advancements have been made in the field of vascularized composite allotransplantation (VCA); however, like solid organ transplantation, bypassing the recipient's immune response remains a significant obstacle to long-term allograft survival. Therefore, strategies to overcome acute and chronic rejection and minimize immunosuppressive therapy are crucial for the future of VCA. This review highlights recent attempts to induce tolerance in VCA and discusses key findings through a clinical lens. Promising VCA tolerance protocols are being investigated, with five recent studies illustrating various successes. These preclinical approaches demonstrate a correlation between the presence of donor-derived T cells and VCA tolerance, the importance of using clinically available reagents within preclinical protocols, and the ability to induce sustained tolerance through nonmyeloablative methods. Furthermore, environmental factors, such as NB-UVB light are being investigated for their immunomodulation properties and may influence VCA graft rejection. To widen the scope of VCA, minimization of immunosuppression is needed. Overall, tolerance induction protocols should have a low-toxicity level, minimally invasive induction therapies, and utilize short-term immunosuppressive medications. By examining the milestones of recent studies, researchers can gain new technical approaches to immune modulation and make data-driven amendments to tolerance protocols in preparation for clinical translation.

Vascularised Composite Allotransplantation – A guide to optimal dissemination of scientific outputs

PurposeThe impact of academic research is not just important within the clinical domain but within society as a whole. Altmetric Attention Score (AAS) offers a means of assessing how scholarly outputs are interacted with online. Vascularised Composite Allotransplantation (VCA) is a modern but rapidly evolving topic which encompasses a broad range of complex and clinically significant surgical interventions. Primarily VCA is utilised in the reconstruction of complex, composite tissue defects, including limb and face transplantation. There is also a growing interest in the role of VCA as an early means of real-time immuno-monitoring, in sentinel skin flap transplant (SSF). Materials & methodsIn July 2024, a search was conducted using the Altmetric Explorer (AE) database using the search term ‘vascular-composite’ AND ‘allograft’ OR ‘allotransplant’. A simultaneous literature search was carried out using Web of Science (WoS) database utilising the same search terms with extraction of traditional citation-based metrics as well as relevant ‘meso’ and ‘micro’ subject headings. Corresponding citation-based metrics were extracted utilising SCImago. Data was compiled and analysed using a linear regression model with level of significance set at p < 0.05. ResultsThe Top 100 (T100) performing articles relating to VCA displayed a mean Altmetric Attention Score (AAS) of 3.31. All T100 papers were published in the English language. Sixty percent (n = 60) of T100 papers were published in Q1 Journals. News outlet mentions (r = 6.95), blog mentions (r = 6.20), and Twitter/X mentions (r = 0.52) demonstrated the greatest positive impact on AAS upon application of a linear regression model (p < 0.05). ConclusionAltmetric Scores offer a means of appraising the impact of research outputs in both academic and societal domains. Such modern metrics are useful in evolving topics such as VCA as AAS is not dependent on citation counts. Publishing of outputs in high quartile, open access journals with timely utilisation of news and social media outlets should be utilised by researchers aiming to maximise dissemination of research outputs in the field of VCA.

Combined Whole Eye and Face Transplant: Microsurgical Strategy and 1-Year Clinical Course.

Catastrophic facial injury with globe loss remains a formidable clinical problem with no previous reports of reconstruction by whole eye or combined whole eye and facial transplant. To develop a microsurgical strategy for combined whole eye and facial transplant and describe the clinical findings during the first year following transplant. A 46-year-old man who sustained a high-voltage electrical injury with catastrophic tissue loss to his face and left globe underwent combined whole eye and face transplant using personalized surgical devices and a novel microsurgical strategy at a specialized center for vascularized composite allotransplantation. Reperfusion and viability of the whole eye and facial allografts, retinal function, and incidence of acute rejection. The patient underwent a combined whole eye and face transplant from an immunologically compatible donor with primary optic nerve coaptation and conventional postoperative immunosuppression. Globe and retinal perfusion were maintained throughout the immediate postoperative period, evidenced by fluorescein angiography. Optical coherence tomography demonstrated atrophy of inner retinal layers and attenuation and disruption of the ellipsoid zone. Serial electroretinography confirmed retinal responses to light in the transplanted eye. Using structural and functional magnetic resonance imaging, the integrity of the transplanted visual pathways and potential occipital cortical response to light stimulation of the transplanted eye was demonstrated. At 1 year post transplant (postoperative day 366), there was no perception of light in the transplanted eye. This is the first report of whole eye transplant combined with facial transplant, demonstrating allograft survival including rejection-free graft survival and electroretinographic measurements indicating retinal response to light stimuli. These data highlight the potential for clinical allotransplantation for globe loss.

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.

P.545: Deciphering the interplay of lymph node profiles with outcomes in vascularized composite allotransplantation.

P.545: Deciphering the interplay of lymph node profiles with outcomes in vascularized composite allotransplantation.

P.546: A porcine vascularized composite allotransplantation model for assessing early prognostic biomarkers of rejection.

P.546: A porcine vascularized composite allotransplantation model for assessing early prognostic biomarkers of rejection.

Sub-zero non-freezing of vascularized composite allografts in a rodent partial hindlimb model

Ischemia is a major limiting factor in Vascularized Composite Allotransplantation (VCA) as irreversible muscular injury can occur after as early as 4–6 h of static cold storage (SCS). Organ preservation technologies have led to the development of storage protocols extending rat liver ex vivo preservation up to 4 days. Development of such a protocol for VCAs has the added challenge of inherent ice nucleating factors of the graft, therefore, this study focused on developing a robust protocol for VCA supercooling. Rodent partial hindlimbs underwent subnormothermic machine perfusion (SNMP) with several loading solutions, followed by a storage solution with cryoprotective agents (CPA) developed for VCAs. Storage occurred in suspended animation for 24h and VCAs were recovered using SNMP with modified Steen. This study shows a robust VCA supercooling preservation protocol in a rodent model. Further optimization is expected to allow for its application in a transplantation model, which would be a breakthrough in the field of VCA preservation.

Whole-Eye Transplantation: How Far Are We From a Breakthrough?

Traumatic facial injuries and resultant eye enucleation remain a devastating life-changing event for many. However, whole-eye transplantation (WET) has remained a distant goal until recently. This narrative review explores the existing literature on WET, assesses current hurdles to its success, and considers the ethical challenges to the expansion of WET programs globally. The authors identified pertinent keywords by conducting an initial literature exploration which were subsequently used to search scientific databases. In line with the narrative methodology employed in this article, specific inclusion and exclusion criteria were not explicitly defined. Nevertheless, the review focused exclusively on articles relating to ocular restoration and reconstructive surgery. Though vision restoration remains elusive, burgeoning surgical techniques such as vascularized composite allotransplantation have opened the scope for surgeons to consider WET when planning facial transplants. Dr. Rodriguez and the New York University Langone team's success supports the recent advancements made in surgical innovation and the potential of CD34-positive stem cells as neuroprotective agents when injected at the optic nerve connection of the recipient. For WET to succeed, vascular and neural structures and the transplanted eye must be considered. Such requirements have been strengthened by the development of microsurgical techniques. In addition to addressing the technical feasibility of WET, it is crucial to deliberate on ethical considerations such as the lifelong implications associated with immunosuppression and, challenges related to the fair division of ocular tissue for WET versus keratoplasty. WET amid significant facial trauma has great potential to restore the quality of life in patients, however, more research is required to demonstrate its long-term viability.

Advancing Precision in Vascularized Composite Allografts through Multiplex Sensing of Predictive Biomarkers

Vascularized Composite Allotransplantation (VCA) is a promising option for extensive tissue reconstruction. Successful graft outcomes in VCA surgeries require close monitoring of immunological reactions and the progression of ischemic conditions. Excessive immunosuppression may lead to chronic infections and dangerous side effects, while inadequate immunosuppression can result in acute or chronic rejection episodes, jeopardizing graft function. Monitoring the immunological status of an allograft becomes critical when exploring innovative tolerance induction protocols or transitioning patients from conventional therapies. Currently, confirming clinical rejection involves invasive biopsies, which are suboptimal for routine monitoring due to associated risks. Thus, developing non-invasive technologies capable of detecting changes in the immunological status of the graft before apparent clinical signs of inflammation and tissue damage become imperative. To address these limitations, this study proposes a low-cost, portable, flexible, miniaturized, and site-of-care (SOC) platform for multiplex sensing of predictive biomarkers (e.g., interleukin 6 (IL6), lactate) and pH to detect instances of VCA rejection before apparent clinical signs of immunogenic reactions such as inflammation and tissue damage.The sensor fabrication was performed on in-house fabricated porous laser-engraved graphene (PLEG)-electrode, utilizing the laser-induced carbonization (LIC) technique on a thin (12.5 µm) polyimide (PI) surface at optimized laser parameters (laser power-22%, speed-5.2%, and gas flow-50%). The PI sheet was laminated on a polyethylene terephthalate (PET) sheet with silicone adhesive in the middle, helping to dissipate the heat generated during the carbonization process. Compared to conventional screen-printed platforms, the PLEG electrode provides higher surface area, receptor loading, electrical conductivity, ease of surface modification, and improved sensitivity with an average resistance of 40 ± 3 Ω/cm. Subsequently, the connection pad and reference electrodes (RE) were coated with silver/silver chloride (Ag/AgCl) conductive paste for improved connection. The RE was stabilized by coating it with polyvinyl butyrate (PVB) and sodium chloride polymeric cocktail. Three working electrodes (WE) were designated as WE-1 (for IL6), WE-2 (for lactate), and WE-3 (for pH). The sensor construction was initiated with surface activation WEs in 0.50 M H2SO4 containing 0.10 M KCl as a supporting electrolyte by sweeping potential between 1.0 and -1.2 V vs. Ag/AgCl reference electrode. For IL-6 sensing, the WEs were incubated with freshly prepared 1-pyrenebutyric acid N-hydroxysuccinimide (PBASE) as a non-covalent crosslinker (10.0 mM) in dimethylformamide (DMF) for 3 hrs., followed by buffer wash (3 times) to remove any unbound crosslinker. Later, a monoclonal antibody to IL6 was immobilized using peptide bond formation between PBASE and the recognition element, passivated by incubating in Bovine serum albumin (BSA) to block non-specific binding. Upon binding, the antigen-antibody complex's formation results in a decrease in voltammetric signal of the redox signal, generating an IL6-dependent change in current. For lactate detection, an amperometric method utilizes a two-electrode electrochemical setup. The WE comprise a composite Glutaraldehyde/BSA/Lactate-Oxidase/Prussian Blue/PLEG-electrode (GA/BSA/LOx/PB/ PLEG). An Ag/AgCl-coated electrode serves as the RE, and counter electrodes (CE). For the pH sensor (PANI/PLEG), polyaniline (PANI) was electrodeposited at 0.80 V for 600 sec on an activated PLEG electrode washed with distilled water and coated with Nafion (0.25% v/v). For pH measurements, the open-circuit potential (OCP) was measured between the PANI/PLEG electrode and the RE.Post characterization, the sensor’s electrochemical measurements to detect IL6, lactate, and pH were performed in buffer, artificial interstitial fluid, porcine blood, and serum samples with portable potentiostat. Under optimal experimental conditions, the devised platform showed a sensitivity of 2.59 µA/(log10IL6), 0.021 µA/mM, and ~49.39 ± 2 mV in spiked serum for IL6, lactate, and pH, respectively. Subsequently, serum samples of porcine VCA recipients were collected on postoperative days (POD) 0, 2, and 6 and tested using the IL-6, lactate, and pH sensors, respectively. The sensors can successfully track the change in the levels of IL6 (increasing) and lactate (increasing) and the change in pH post-surgery and align with clinical observations of inflammation and ischemia post-allograft on POD6. The sensor results were also validated using commercial IL6 ELISA and lactate kits using the same samples and showed a correlation (r) of r = 0.9885 (n=3, for IL6) and r = 0.9896 (n=3, for lactate). Our results demonstrate that the developed miniaturized platform offers a portable, low-cost, robust, and multiplex sensing platform capable of quantifying predictive biomarkers post-VCA surgeries. This platform presents a promising, miniaturized, and cost-effective solution for the real-time monitoring of biomarkers in VCA models. KEYWORDS: Vascularized Composite Allotransplantation (VCA), Ischemia, Interleukin-6, Lactate, Electrochemical sensor, Porous laser engraved graphene, Multiplex sensing

Development of a Porcine VCA Model Using an External Iliac Vessel-Based Vertical Rectus Abdominus Myocutaneous Flap.

Vascularized composite allotransplantation (VCA) involves transplanting a functional and anatomically complete tissue graft, such as a hand or face, from a deceased donor to a recipient. Although clinical VCA has resulted in successful outcomes, high rates of acute rejection and increased requirements for immunosuppression have led to significant long-term complications. Of note, immunosuppressed graft recipients are predisposed to infections, organ dysfunction, and malignancies. The long-term success of VCA grafts requires the discovery and implementation of unique approaches that avoid these complications altogether. Here, we describe our surgical technique and initial experience with a reproducible heterotopic porcine VCA model for the preclinical assessment of approaches to improve graft outcomes. Six heterotopic porcine allogeneic vertical rectus abdominis myocutaneous flap transplants were performed using Sinclair donors and Yucatan recipients. Immunosuppressive therapy was not used. Each flap was based on the left external iliac vessel system. Animals were followed postoperatively for surgery-related complications. The six pigs underwent successful VCA and were euthanized at the end of the study. Each flap demonstrated complete survival following vessel anastomosis. For the allogeneic recipients, on average, minimal erythema and healthy flap color were observed from postoperative days 1 to 4. There were no surgery-related animal deaths or complications. We have developed a reproducible, technically feasible heterotopic porcine VCA model based on the left external iliac vessel system. Our results demonstrate this model's potential to improve VCA graft outcomes by exploring tolerance induction and rejection biomarker discovery in preclinical studies.

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.

C-reactive protein orchestrates acute allograft rejection in vascularized composite allotransplantation via selective activation of monocyte subsets

IntroductionDespite advancements in transplant immunology and vascularized composite allotransplantation (VCA), the longevity of allografts remains hindered by the challenge of allograft rejection. The acute-phase response, an immune-inflammatory reaction to ischemia/reperfusion that occurs directly after allogeneic transplantation, serves as a catalyst for graft rejection. This immune response is orchestrated by acute-phase reactants through intricate crosstalk with the mononuclear phagocyte system. ObjectiveC-reactive protein (CRP), a well-known marker of inflammation, possesses pro-inflammatory properties and exacerbates ischemia/reperfusion injury. Thus, we investigated how CRP impacts acute allograft rejection. MethodsPrompted by clinical observations in facial VCAs, we employed a complex hindlimb transplantation model in rats to investigate the direct impact of CRP on transplant rejection. ResultsOur findings demonstrate that CRP expedites allograft rejection and diminishes allograft survival by selectively activating non-classical monocytes. Therapeutic stabilization of CRP abrogates this activating effect on monocytes, thereby attenuating acute allograft rejection. Intravital imagining of graft-infiltrating, recipient-derived monocytes during the early phase of acute rejection corroborated their differential regulation by CRP and their pivotal role in driving the initial stages of graft rejection. ConclusionThe differential activation of recipient-derived monocytes by CRP exacerbates the innate immune response and accelerates clinical allograft rejection. Thus, therapeutic targeting of CRP represents a novel and promising strategy for preventing acute allograft rejection and potentially mitigating chronic allograft rejection.

A World Update of Progress in Lower Extremity Transplantation: What's Hot and What's Not.

The field of vascularized composite allotransplantation (VCA) is the new frontier of solid organ transplantation (SOT). VCA spans life-enhancing/life-changing procedures such as upper extremity, craniofacial (including eye), laryngeal, tracheal, abdominal wall, penis, and lower extremity transplants. VCAs such as uterus transplants are life giving unlike any other SOT. Of all VCAs that have shown successful intermediate- to long-term graft survival with functional and immunologic outcomes, lower extremity VCAs have remained largely underexplored. Lower extremity transplantation (LET) can offer patients with improved function compared to the use of conventional prostheses, reducing concerns of phantom limb pain and stump complications, and offer an option for eligible amputees that either fail prosthetic rehabilitation or do not adapt to prosthetics. Nevertheless, these benefits must be carefully weighed against the risks of VCA, which are not trivial, including the adverse effects of lifelong immunosuppression, extremely challenging perioperative care, and delayed nerve regeneration. There have been 5 lower extremity transplants to date, ranging from unilateral or bilateral to quadrimembral, progressively increasing in risk that resulted in fatalities in 3 of the 5 cases, emphasizing the inherent risks. The advantages of LET over prosthetics must be carefully weighed, demanding rigorous candidate selection for optimal outcomes.