A Large-Scale Bank of Organ Donor Bone Marrow and Matched Mesenchymal Stem Cells for Promoting Immunomodulation and Transplant Tolerance

Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed “hematopoietic progenitor cell (HPC), Marrow,” recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is >1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to “delayed tolerance.” Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT

The impact of donor pancreas extraction time on graft survival and postoperative complications in pancreas transplant recipients

Background: Simultaneous pancreas kidney transplantation (SPK) is the best therapeutic option for patients with diabetes mellitus type 1 and end-stage renal disease. Recently, donor organ extraction time has been shown to affect kidney and liver graft survival. This study aimed to assess the effect of pancreas donor extraction time on graft survival and postoperative complications. Methods: We retrospectively analyzed all pancreas transplants performed in two Eurotransplant centers. The association of pancreas extraction time with pancreas graft survival was analyzed by a Cox proportional hazards regression analysis after 3 months, 1 and 5 year. Besides, the effect of pancreas extraction time on the incidence of severe postoperative complications was analyzed. Results: A total of 317 pancreas transplants were included in this study. Death-censored pancreas graft survival was 85.7% after one year and 76.7% after five years. Median pancreas donor extraction time was 64 min [IQR: 52-79 min]. After adjustment for potential confounders, death censored graft survival after 30 days (HR 1.01, 95% CI 0.9-1.03 (p = 0.23), 1 year (HR 1.01, 95% CI 0.99-1.03 (p = 0.22) and 5 years (HR 1.00, 95% CI 0.99-1.02 (p = 0.57) was not associated with pancreas donor extraction time. However, extraction time was significantly associated with a higher incidence of Clavien-Dindo >3 complications compared to Clavien-Dindo 1 + 2 complications: OR 1.012, 95% CI 1.00-1.02 (p = 0.039). Conclusions: Our findings suggest that although no effect on graft survival was found, limiting pancreas extraction time can have a significant impact on lowering postoperative complications

Recipient age and outcome after pancreas transplantation:a retrospective dual-center analysis

With a later onset of diabetes complications and thus increasing age of transplant candidates, many centers have extended upper age limits for pancreas transplantation. This study investigates the effect of recipient and donor age on outcomes after pancreas transplantation.We retrospectively analyzed 565 pancreas transplants performed at two Eurotransplant centers. The cohort was split at a recipient and donor age of 50 and 40 years, respectively. Median recipient age in old patients (≥50 years; 27.2%) was 54 years and 40 years in young patients (<50 years). Compared to young recipients, old recipients had an inferior patient survival rate (≥50: 5yr, 82.8%; 10yr, 65.6%; <50: 5yr, 93.3%; 10yr, 82.0%; P < 0.0001). Old recipients demonstrated comparable death-censored pancreas (≥50: 1yr, 80.6%; 5yr, 70.2%; <50: 1yr, 87.3%; 5yr, 77.8%; P = 0.35) and kidney graft survival (≥50: 1yr, 97.4%; 5yr, 90.6%; <50: 1yr, 97.8%; 5yr, 90.2%; P = 0.53) compared to young recipients. Besides a lower rate of kidney rejection, similar relative risks for postoperative complications were detected in old and young patients. This study shows that despite an increased mortality in old recipients, excellent graft survival can be achieved similar to that of young patients. Age alone should not exclude patients from receiving a pancreas transplant

European Society for Organ Transplantation (ESOT) Consensus Statement on the Role of Pancreas Machine Perfusion to Increase the Donor Pool for Beta Cell Replacement Therapy

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney’s and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the “Role of pancreas machine perfusion to increase the donor pool for beta cell replacement,” the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.</p

Elective surgery system strengthening: development, measurement, and validation of the surgical preparedness index across 1632 hospitals in 119 countries

Background: The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs. Methods: First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score. Findings: In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1–84·9), which varied between HIC (88·5 [89·0–88·0]), MIC (81·8 [82·5–81·1]), and LIC (66·8 [64·9–68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0–4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1–5·5]; p<0·0001), MIC (2·8 [2·0–3·7]; p<0·0001), and LIC (3·8 [1·3–6·7%]; p<0·0001) settings. InterpBackground The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs. Methods: First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score. Findings: In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1–84·9), which varied between HIC (88·5 [89·0–88·0]), MIC (81·8 [82·5–81·1]), and LIC (66·8 [64·9–68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0–4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1–5·5]; p<0·0001), MIC (2·8 [2·0–3·7]; p<0·0001), and LIC (3·8 [1·3–6·7%]; p<0·0001) settings. Interpretation: The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs.retation The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Mechanische Irritation und Absto fung in der vaskularisierten Gewebetransplantation

Hintergrund: In den letzten Jahren wurden mehrere Fallberichte zu atypischen Absto fungen nach Handtransplantationen ver\uf6ffentlicht. Diese Absto fungen unterschieden sich nicht nur in der Lokalisation, sondern auch im Muster der Immunzellzusammensetzung sowie im therapeutischen Ansprechen von der klassischen akuten Absto fung. Alle Patienten mit dieser atypischen Form der Absto fung hatten gemein, dass ihre Transplantate unmittelbar vor dem Einsetzten der Ver\ue4nderungen einem gro fen mechanischen oder thermischen Reiz ausgesetzt waren. Ziel dieser Studie war es den Einfluss von standardisierter mechanischer Irritation auf ein vaskularisiertes Gewebetransplantat im Kleintiermodell zu untersucht. Methoden: Es wurden syngene (Lewis\ue0Lewis) und allogene (Brown Norway\ue0Lewis) Hinterlauftransplantationen in Ratten (200 \u2013 250 g) durchgef\ufchrt. Am Tag der Transplantation und am dritten Tag danach wurden allen allogen transplantierten Tieren jeweils 500 \u3bcl Antilymphozytenkonzentrat verabreicht. Zus\ue4tzlich erfolgte die t\ue4glichen intraperitonealen Injektionen von Tacrolimus (0,3 mg/kg; in weiterer Folge reduziert auf 0,1mg/kg). Zwanzig (syngen) oder drei fig (allogen) Tage nach der Transplantation wurde mittels standardisiertem mechanischem Irritationsger\ue4t die Haut der transplantierten Fu fsohle irritiert. Dies erfolgte mit einem Druck von 5 Newton f\ufcr jeweils zehn Minuten viermal t\ue4glich f\ufcr zehn Tage. Die makroskopischen Ver\ue4nderungen wurden t\ue4glich dokumentiert. Gewebeproben wurden nach der letzten Stimulation oder nach f\ufcnf weiteren Tagen entnommen. Neben der histologischen Aufarbeitung der Proben erfolgte zudem die Bestimmung von Zytokinen und Chemokinen mittels Luminex Technologie. Ergebnisse: Die durch die mechanische Irritation hervorgerufenen Hautver\ue4nderungen waren im Vergleich zu den Ver\ue4nderungen bei naiven und syngenen Kontrolltieren in allotransplantierten Tieren deutlich ausgepr\ue4gter (p < 0,0001 und p = 0,0023). In der histologischen Aufarbeitung zeigte sich, dass allogen transplantierte und stimulierte Tiere einen Trend zu h\uf6heren histologischen Absto fungsgraden aufwiesen. Nach Beendigung der mechanischen Irritationen bildeten sich die makroskopischen Ver\ue4nderungen der Haut in syngen transplantierten Tieren rasch zur\ufcck. In allogenen Tieren hingegen kam es zu einer weiteren Verschlechterung. In allogen transplantierten und stimulierten Tieren zeigte sich, analog zu akut absto fenden Tieren, ein h\uf6herer Anteil von CD8+ T Zellen. IL-1b, IL-2 und IFNy waren in akut absto fenden Tieren signifikant erh\uf6ht. Eine \ue4hnliche jedoch weitaus geringere Erh\uf6hung zeigte sich auch in allogen transplantierten und stimulierten Tieren. Schlussfolgerung: Mechanische Irritation der Haut kann in der vaskularisierten Gewebetransplantation lokalisierte Hautver\ue4nderungen induzieren, welche akuter Absto fung \ue4hneln.Background: In a subset of recipients of vascularized composite allografts a new form of rejection has been described. All of the patients had one thing in common: a history of intense mechanical or thermal irritation of the graft. The aim of the present study was to investigate the impact of environmental irritants on rejection in VCA. Methods: For orthotopic hind limb transplantations male Lewis (donor/recipient) and Brown Norway (donor) rats weighting 200-250 g were used. All animals received anti-lymphocyte serum (500 \u3bcg) on POD 0 and 3, and daily intra-peritoneal injections of tacrolimus (0.3 mg/kg; tapered to 0.1 mg/kg). Starting from day 20 (syngeneic) or 30 (allogeneic) post-transplant, mechanical irritations were performed using a standardized irritation device with a pressure of 5 Newton for 10 minutes four times daily for ten consecutive days. Macroscopic changes were documented throughout the study. At the end of the irritation or after additional five days of observation, tissue biopsies were collected for further histological and protein expression analysis. Results: Animals that received an allotransplantation had significantly more pronounced macroscopic skin alterations compared to na\uefve and syngeneic control animals (p<0.0001 and p = 0.0023). Histopathologic analysis of allogeneic animals tended to display higher grades (median II, range I-IV) of inflammation and leukocytic infiltrate than naive controls (median I-II, range 0-II; p = 0.28). After cessation of irritation, all macroscopic changes recovered quickly in syngeneic animals (median grade I, range 0-I to II) within the five days of observation; in allogeneic ones, however, even worsened (median grade III, range I-IV). In allogeneic stimulated skin, a significant increase in CD8+ T cells was observed compared to na\uefve and na\uefve stimulated skin (p = 0.013 and p = 0.029). IL-1b, IL-2 and INF-y levels were significantly upregulated in rejecting skin. Though not statistically significant, a similar trend in protein expression was seen in allogeneic rejecting skin. Conclusion: This study could prove, that an intense mechanical irritation can trigger localized skin alterations/inflammation that share many features seen in acute rejection.eingereicht von Dr. med. univ. Franka MessnerAbweichender Titel laut cbersetzung der Verfasserin/des VerfassersKumulative Dissertation aus einem ArtikelDissertation Medizinische Universit\ue4t Innsbruck 202

Mechanische Irritation und Abstoßung in der vaskularisierten Gewebetransplantation

Hintergrund: In den letzten Jahren wurden mehrere Fallberichte zu atypischen Abstoßungen nach Handtransplantationen veröffentlicht. Diese Abstoßungen unterschieden sich nicht nur in der Lokalisation, sondern auch im Muster der Immunzellzusammensetzung sowie im therapeutischen Ansprechen von der klassischen akuten Abstoßung. Alle Patienten mit dieser atypischen Form der Abstoßung hatten gemein, dass ihre Transplantate unmittelbar vor dem Einsetzten der Veränderungen einem großen mechanischen oder thermischen Reiz ausgesetzt waren. Ziel dieser Studie war es den Einfluss von standardisierter mechanischer Irritation auf ein vaskularisiertes Gewebetransplantat im Kleintiermodell zu untersucht. Methoden: Es wurden syngene (LewisàLewis) und allogene (Brown NorwayàLewis) Hinterlauftransplantationen in Ratten (200 – 250 g) durchgeführt. Am Tag der Transplantation und am dritten Tag danach wurden allen allogen transplantierten Tieren jeweils 500 μl Antilymphozytenkonzentrat verabreicht. Zusätzlich erfolgte die täglichen intraperitonealen Injektionen von Tacrolimus (0,3 mg/kg; in weiterer Folge reduziert auf 0,1mg/kg). Zwanzig (syngen) oder dreißig (allogen) Tage nach der Transplantation wurde mittels standardisiertem mechanischem Irritationsgerät die Haut der transplantierten Fußsohle irritiert. Dies erfolgte mit einem Druck von 5 Newton für jeweils zehn Minuten viermal täglich für zehn Tage. Die makroskopischen Veränderungen wurden täglich dokumentiert. Gewebeproben wurden nach der letzten Stimulation oder nach fünf weiteren Tagen entnommen. Neben der histologischen Aufarbeitung der Proben erfolgte zudem die Bestimmung von Zytokinen und Chemokinen mittels Luminex Technologie. Ergebnisse: Die durch die mechanische Irritation hervorgerufenen Hautveränderungen waren im Vergleich zu den Veränderungen bei naiven und syngenen Kontrolltieren in allotransplantierten Tieren deutlich ausgeprägter (p < 0,0001 und p = 0,0023). In der histologischen Aufarbeitung zeigte sich, dass allogen transplantierte und stimulierte Tiere einen Trend zu höheren histologischen Abstoßungsgraden aufwiesen. Nach Beendigung der mechanischen Irritationen bildeten sich die makroskopischen Veränderungen der Haut in syngen transplantierten Tieren rasch zurück. In allogenen Tieren hingegen kam es zu einer weiteren Verschlechterung. In allogen transplantierten und stimulierten Tieren zeigte sich, analog zu akut abstoßenden Tieren, ein höherer Anteil von CD8+ T Zellen. IL-1b, IL-2 und IFNy waren in akut abstoßenden Tieren signifikant erhöht. Eine ähnliche jedoch weitaus geringere Erhöhung zeigte sich auch in allogen transplantierten und stimulierten Tieren. Schlussfolgerung: Mechanische Irritation der Haut kann in der vaskularisierten Gewebetransplantation lokalisierte Hautveränderungen induzieren, welche akuter Abstoßung ähneln.Background: In a subset of recipients of vascularized composite allografts a new form of rejection has been described. All of the patients had one thing in common: a history of intense mechanical or thermal irritation of the graft. The aim of the present study was to investigate the impact of environmental irritants on rejection in VCA. Methods: For orthotopic hind limb transplantations male Lewis (donor/recipient) and Brown Norway (donor) rats weighting 200-250 g were used. All animals received anti-lymphocyte serum (500 μg) on POD 0 and 3, and daily intra-peritoneal injections of tacrolimus (0.3 mg/kg; tapered to 0.1 mg/kg). Starting from day 20 (syngeneic) or 30 (allogeneic) post-transplant, mechanical irritations were performed using a standardized irritation device with a pressure of 5 Newton for 10 minutes four times daily for ten consecutive days. Macroscopic changes were documented throughout the study. At the end of the irritation or after additional five days of observation, tissue biopsies were collected for further histological and protein expression analysis. Results: Animals that received an allotransplantation had significantly more pronounced macroscopic skin alterations compared to naïve and syngeneic control animals (p<0.0001 and p = 0.0023). Histopathologic analysis of allogeneic animals tended to display higher grades (median II, range I-IV) of inflammation and leukocytic infiltrate than naive controls (median I-II, range 0-II; p = 0.28). After cessation of irritation, all macroscopic changes recovered quickly in syngeneic animals (median grade I, range 0-I to II) within the five days of observation; in allogeneic ones, however, even worsened (median grade III, range I-IV). In allogeneic stimulated skin, a significant increase in CD8+ T cells was observed compared to naïve and naïve stimulated skin (p = 0.013 and p = 0.029). IL-1b, IL-2 and INF-y levels were significantly upregulated in rejecting skin. Though not statistically significant, a similar trend in protein expression was seen in allogeneic rejecting skin. Conclusion: This study could prove, that an intense mechanical irritation can trigger localized skin alterations/inflammation that share many features seen in acute rejection.eingereicht von Dr. med. univ. Franka MessnerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersKumulative Dissertation aus einem ArtikelDissertation Medizinische Universität Innsbruck 202

Grasping time - longevity of vascularized composite allografts

Purpose of review: 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. Recent findings: 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. Summary: 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