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

ABSTRACT: 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.

SUBMITTER: Rostami S

PROVIDER: S-EPMC8670593 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Advances in machine perfusion, organ preservation, and cryobiology: potential impact on vascularized composite allotransplantation.

Project description:PURPOSE OF REVIEW:In this review, we discuss novel strategies that allow for extended preservation of vascularized composite allografts and their potential future clinical implications for the field of vascularized composite allotransplantation (VCA). RECENT FINDINGS:The current gold standard in tissue preservation - static cold preservation on ice - is insufficient to preserve VCA grafts for more than a few hours. Advancements in the field of VCA regarding matching and allocation, desensitization, and potential tolerance induction are all within reasonable reach to achieve; these are, however, constrained by limited preservation time of VCA grafts. Although machine perfusion holds many advantages over static cold preservation, it currently does not elongate the preservation time. More extreme preservation techniques, such as cryopreservation approaches, are, however, specifically difficult to apply to composite tissues as the susceptibility to ischemia and cryoprotectant agents varies greatly by tissue type. SUMMARY:In the current scope of extended preservation protocols, high subzero approaches of VCA grafts will be particularly critical enabling technologies for the implementation of tolerance protocols clinically. Ultimately, advances in both preservation techniques and tolerance induction have the potential to transform the field of VCA and eventually lead to broad applications in reconstructive transplantation.

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Costimulation Blockade in Vascularized Composite Allotransplantation.

Project description:Vascular 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 infections or traumatic amputation in a selected group of patients. VCA is performed in centers with appropriate expertise, experience and adequate resources to effectively manage the complexity and complications of this treatment. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in VCA. VCA is considered a quality of life transplant and the risk-benefit ratio is dissimilar to life saving transplants. Belatacept seems a promising drug that prolongs patient and graft survival in kidney transplantation and it could also be an alternative approach to VCA immunosuppression. In this review, we are summarizing current literature about the role of costimulation blockade, with a focus on belatacept in VCA.

| S-EPMC7527523 | biostudies-literature

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Ensuring Racial and Ethnic Inclusivity in Facial Vascularized Composite Allotransplantation.

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tsRNAs Are Potential Biomarkers of Acute Rejection in Vascularized Composite Allotransplantation

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2022-07-20 | GSE190008 | GEO

Emerging Implications for Extracellular Matrix-Based Technologies in Vascularized Composite Allotransplantation.

Project description:Despite recent progress in vascularized composite allotransplantation (VCA), limitations including complex, high dose immunosuppression regimens, lifelong risk of toxicity from immunosuppressants, acute and most critically chronic graft rejection, and suboptimal nerve regeneration remain particularly challenging obstacles restricting clinical progress. When properly configured, customized, and implemented, biomaterials derived from the extracellular matrix (ECM) retain bioactive molecules and immunomodulatory properties that can promote stem cell migration, proliferation and differentiation, and constructive functional tissue remodeling. The present paper reviews the emerging implications of ECM-based technologies in VCA, including local immunomodulation, tissue repair, nerve regeneration, minimally invasive graft targeted drug delivery, stem cell transplantation, and other donor graft manipulation.

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A chronic rejection model and potential biomarkers for vascularized composite allotransplantation.

Project description:BackgroundChronic rejection remains the Achilles heel in vascularized composite allotransplantation. Animal models to specifically study chronic rejection in vascularized composite allotransplantation do not exist so far. However, there are established rat models to study chronic rejection in solid organ transplantation such as allogeneic transplantation between the rat strains Lewis and Fischer344. Thus, we initiated this study to investigate the applicability of hindlimb transplantation between these strains to imitate chronic rejection in vascularized composite allotransplantation and identify potential markers.MethodsAllogeneic hindlimb transplantation were performed between Lewis (recipient) and Fischer344 (donor) rats with either constant immunosuppression or a high dose immunosuppressive bolus only in case of acute skin rejections. Histology, immunohistochemistry, microarray and qPCR analysis were used to detect changes in skin and muscle at postoperative day 100.ResultsWe were able to demonstrate significant intimal proliferation, infiltration of CD68 and CD4 positive cells, up-regulation of inflammatory cytokines and initiation of muscular fibrosis in the chronic rejection group. Microarray analysis and subsequent qPCR identified CXC ligands 9-11 as potential markers of chronic rejection.ConclusionsThe Fischer344 to Lewis hindlimb transplantation model may represent a new option to study chronic rejection in vascularized composite allotransplantation in an experimental setting. CXC ligands 9-11 deserve further research to investigate their role as chronic rejection markers.

| S-EPMC7319338 | biostudies-literature

TRFs and tiRNAs sequence in acute rejection for vascularized composite allotransplantation.

Project description:Illumina tRFs & tiRNAs-seq analysis was used to characterize the whole transcriptomes of acute rejection caused by vascularized composite allotransplantation (VCA). tRFs & tiRNAs-seq information for muscle samples with VCA was obtained and compared with similar information for same age- and sex-matched healthy control subjects. The expression of 16 tRFs and tiRNAs, including 5 up-regulated target genes and 11 down-regulated target genes, were significantly different. According to bioinformatics analysis and reverse transcription quantitative polymerase chain reaction, we speculate that tiRNA-1-34-Glu-CTC-1 plays an important role in VCA-induced acute rejection by regulating the CACNA1D gene in the MAPK signaling pathway The findings provide the whole-transcriptome signatures of acute rejection for VCA, allowing further exploration of gene expression patterns/signatures associated with the various clinical symptoms of acute rejection for VCA.

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IGF-1 and Chondroitinase ABC Augment Nerve Regeneration after Vascularized Composite Limb Allotransplantation.

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