The long term goal of this project is to increase the number of Donation after Cardiac Death (DCD) livers available for transplantation by developing a new hypothermic machine perfusion (HMP) solution for recovery and preservation. Currently DCD livers are transplantable and have the potential to increase the donor pool 20-40%. However, they are largely under utilized due to poor preservation by the current method of simple cold storage (SCS). Studies show that HMP can improve graft survival in animal models. However, as warm ischemic time is increased, preliminary studies show that the current HMP solution is not sufficient to address the increase stresses of extended warm ischemia. A new solution has been developed to address depletion of energy substrates, increased membrane instability, increased oxidation damage, and microcirculation disruption. Preliminary studies suggest that this new HMP solution has potential to recover and preserve extended warm ischemic livers. The goal of this Phase I SBIR is to test the feasibility of a new HMP to recover and preserve extended warm ischemic livers in the rat model by accomplishing the following Specific Aims: 1) Determine the efficacy of the new HMP solution to improve recovery and preservation of 60 min warm ischemic livers in an isolated liver perfusion model, 2) transplantation study of extended warm ischemic livers preserved by the new HMP solution. Functional recovery evaluated in an isolated perfusion system allows greater control and assessment with a broad spectrum of endpoints. Hepatocellular and endothelial cell functions and damage will be assessed by bile production, hyaluronic acid uptake, tissue energy state, oxygen consumption, histology, and release of enzymes. This system can assess whether grafts experience primary non-function, a major cause of failure in DCD organs. In the transplant studies, survival, enzyme release, bilirubin, and histology will be evaluated. The success of this project will be directly related to the establishment of a critical partnership between the team of transplant surgeon, the scientist and biomedical engineer who will collaboratively test, and modify as needed the new HMP solution. This project will form the basis for further testing in a Phase II SBIR application for recovery and preservation of extended warm ischemic livers in a pre-clinical animal transplant model. In addition, the solution will be optimized and a time limit for recovery will be determined. Although liver transplantation is considered the only definitive therapy for endstage liver disease, many patients who require transplants cannot receive them because of the shortage of viable donor livers. The ultimate goal of this proposal is to develop a complete system that will allow recovery of a pool of currently unused potential donor livers resulting in a significant expansion in the number of viable donors available for transplant.
Thesaurus Terms: isolation perfusion, liver preservation, liver transplantation, nonhuman therapy evaluation, solution, technology /technique development, tissue donor animal mortality, bile, bilirubin, bioenergetics, cellular pathology, cold temperature, enzyme biosynthesis, hyaluronate, liver cell, liver function, liver ischemia /hypoxia, respiratory oxygenation histology, laboratory rat, male
