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Enhancing the Neuromuscular Regenerative Potential of Replanted Extremities Using Ex Situ Hypothermic Perfusion.

Subject Area Orthopaedics, Traumatology, Reconstructive Surgery
Term from 2022 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 508239629
 
Final Report Year 2024

Final Report Abstract

About 150,000 annual limb losses occur in the United States alone, with estimates of over 1.3 million traumatic limb amputations by 2050. The gold standard in treatment is cold storage followed by replantation, however this is often not feasible due to damage of the amputated part. In this case, prosthetics or vascularized composite allotransplantation (VCA) are additional treatment options to restore function in upper or lower extremities and improve patients’ quality of life. However, both procedures (replantation and allotransplantation) are limited by short muscle ischemia time and hereby resulting ischemia reperfusion injury (IRI). IRI induces anaerobic glycolysis, mitochondrial burst of reactive oxygen species (ROS) and results in mitochondrial dysfunction. Dysfunctional mitochondria activate innate immune cells through damage-associated molecular patterns (DAMPs) that were released by the mitochondria, such as mitochondrial DNA (mtDNA) which can lead to episodes of acute rejection that can result in graft failure. Reducing cellular damage and inflammation caused by IRI is therefore object of research not only in VCA but solid organ transplantation (SOT) as well. Peri-transplant tissue damage as a result of ischemia-reperfusion injury (IRI) is a main concern with both VCA and SOT procedures. Hence, preventing or reducing IRI could result in the extension of transplanted organ lifespan within the recipient, while simultaneously increasing the pool of organs that can be utilized. One approach to reduce IRI is delivering oxygen by ex-vivo machine perfusion (EVMP) of the amputated limb. SOT related research has demonstrated significant benefits of EVMP in clinical use for heart and liver transplantation. Nevertheless, a clinically applicable ex-vivo machine perfusion hasn’t been established for human limb perfusion yet. An additional approach to reduce IRI could be to decrease mitochondrial dysfunction by delivery of antioxidant drugs that are targeting mitochondria and hereby minimizing the development of ROS. So far, the promising antioxidant compound MitoQ has proven to reduce IRI in experimental rodent heart, pig kidney and human kidney models. The results revealed a substantial effect on inflammatory pathways due treatment with MitoQ. MitoQ treatment led to significantly greater urine output and blood flow in pig kidneys and protected against IRI by blocking graft oxidative damage while reducing the early pro-inflammatory response in a murine syngeneic heart transplant model. However, the effect of the antioxidant treatment on the immune system and IRI in skeleton muscle with MitoQ is currently unknown. Based heron, our group has established a rodent ischemia reperfusion model to test MitoQ in VCA for the first time and to evaluate whether the administration of MitoQ reduces IRI and sterile inflammation in a rat hindlimb model. With our findings we aim to contribute to combine the beneficial effects of oxygen supply via EVMP and simultaneously targeting of the mitochondria as major source of ROS. The overall goal is to extend ischemia time to enable replantation and allotransplantation following traumatic limb amputation in humans to a greater extend of patients and hereby increasing patient´s quality of life.

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