Friday, April 19, 2024
4/19/2024
Project Summary/Abstract This R21 application for the NOSI: Bold New Bioengineering Research for Heart, Lung, Blood and Sleep Disorders and Diseases details the technical development of a unique method to maintain whole human lungs for an extended period in order to revolutionize solid organ transplantation and human translational research. Normothermic ex situ, or ex vivo, organ perfusion (EVOP) is a clinically accepted method of preserving, evaluating, and rehabilitating whole organs for transplantation. EVOP has also been utilized by scientists for translational research and emerged as an important platform to study organs with fully intact cell-cell interactions, endothelial and epithelial interfaces, and with the entire spectrum of cellular compartments seen in vivo. Therefore, EVOP provides a unique platform to preserve organs for transplantation, as well as to study human physiology and pathology through preclinical translational studies. Unfortunately, EVOP is currently severely limited due to the short time frame of organ health stability currently provided by the technology. Therefore, there is an unmet need in EVOP strategies that requires new technology. The investigative team has the needed experience in organ transplantation, pulmonary physiology, biomedical engineering and vascular biology in order to ensure success of the proposed work. Aim 1 will leverage the expertise of the investigators with a porcine model of lung EVOP to extended stable organ preservation to at least 5 days through several key technology advances, including metabolic substrate support, waste product removal, dual perfusion, and the use of cellular enriched perfusate. Porcine lungs were utilized extensively for the initial development of lung EVOP and provide a high-fidelity model for translational work. In Year 2, Aim 2 will leverage and validate lessons learned during Aim 1 using human lungs from consented organ donors. The overall objective of this proposal is to obviate the current limitation of time for lung EVOP by adapting existing ex vivo lung perfusion strategies to allow for perpetual organ preservation and rehabilitation, or POPR. POPR would radically change allocation and availability of organs, allow time for interventions that could rehabilitate otherwise unusable organs, improve organs via immunomodulation or microbiologic clearance, and potentially mitigate other factors that limit the use of potential organ donors. Therefore, the development of POPR would be of tremendous public health importance and our proposal leverages the transdisciplinary expertise of lung transplantation, organ preservation, vascular endothelial health and biomedical engineering specialists. The technology proposed herein, once developed, could be used by transplant programs clinically and by researchers in specialized centers across the country. Importantly, principals developed herein can be applied to other solid organs, including heart, kidney, and small bowel, to extend solid organ transplantation and research.
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