1 in 5 liver waitlist patients do not receive a new liver in time, while many more patients are never listed but could benefit from liver replacement. While "bridge-to-transplant" technologies (ventricular assist devices and dialysis) have transformed the outlook for heart failure and kidney failure, no such treatment exists for patients with liver failure. Current liver sharing limits (approx. 500 miles) are based on limited preservation durations (6-10 hours). By extending preservation to just a few days we can enable nationwide (theoretically global) donor-recipient matching, allowing many livers that go untransplanted today (e.g. subsets of extended criteria donor livers that have been shown to offer substantial survival benefits) to be offered to the patients who most need them. Transplant surgeons have expressed excitement about this possibility, and it is thought that this achievement would have a profound impact on liver waitlist mortality. Among other benefits, this can also increase graft lifespan and reduce immunological rejection, eliminate the need for costly jet and helicopter transport, transform the practice of liver transplantation from emergency surgery to a flexibly scheduled procedure, and mitigate the severe disparities in liver transplantation. It will also allow immune tolerance induction protocols that have now achieved success in living donation to be adapted to the deceased donor context. To meet these needs, we will develop a comprehensive system for banking human livers for transplantation for periods of 5-7 days with a stretch goal of 10+ days or longer. We have created an integrated two-pronged approach to develop new stasis cocktails optimized for the critical phases of liver preservation: preconditioning and protection (prior to storage), preservation (during storage) and revival- resuscitation-repair (after storage). In parallel, we are creating devices for advanced perfusion, storage, and organ assessment before transplant decision. Our approach adapts the best strategies of freeze-tolerant and hibernating species, augmenting them with recent scientific and bioengineering advances. Importantly, we do not seek to solve all the problems of classical cryopreservation, but rather to be the first to develop preservation in thermodynamic equilibrium at high subzero (HSZ) temperatures (-10°C to -30°C), combined with programmed metabolic depression and enhanced stress tolerance. Feasibility of this approach has already been demonstrated; we have banked rat livers for 5 days at HSZ temperatures, and successfully preserved the first whole human liver lobe at -15°C. For this fast-track proposal, the Phase 1 goal will be to further refine our protocols and validate our initial unprecedented storage duration by banking rat livers for 5-7 days and using comprehensive post-preservation normothermic machine perfusion with functional assessment. We will also scale to whole human liver lobes, with subsequent hepatocyte isolation. Phase 2 will focus on optimizing key parameters that affect preservation outcomes in rat and human livers. Our goal is 6-10+ days of storage via (i) optimal modulation of ice growth, (ii) nature-inspired de-toxify/reenergize perfusion phase and (iii) precise control of thermodynamics using a prototype Bio-Thermodulator device.
Public Health Relevance Statement: NARRATIVE Liver transplantation is the only treatment for the tens of thousands of patients suffering from liver failure in the U.S., yet thousands of potentially transplantable livers are discarded each year. The ability to preserve donor livers, and organs in general, could eventually be life-saving for hundreds of thousands, if not millions, of people around the world. To help overcome these barriers, we have developed a nature inspired, holistic solution to dramatically extend organ preservation times which has the potential to immediately make accessible lifepreserving liver transplants for emergency cases, while facilitating widespread banking of all types of organs and tissues in the future.
Project Terms: Achievement; Achievement Attainment; Affect; Animals; Arizona; Back; Dorsum; Biological Assay; Biologic Assays; Bioassay; Assay; Biomedical Engineering; bioengineering; bio-engineers; bio-engineered; Biomedical Research; Cell Body; Cells; cold storage; cold preservation; Cryofixation; Cryopreservation; dialysis therapy; Dialysis; Dialysis procedure; Economics; Emergencies; Emergency Situation; balance function; balance; Equilibrium; Freezing; Future; Goals; Transplantation Rejection; Transplant Rejection; Graft Rejection; ontogeny; Tissue Growth; Generalized Growth; Growth; cardiac failure; Heart failure; Helicopter; Modern Man; Human; Ice; immunological paralysis; immune unresponsiveness; immune system tolerance; Immunologic Tolerance; Immune Tolerance; In Vitro; Inventory; Equipment and supply inventories; renal; Kidney Urinary System; Kidney; kidney tx; Renal Transplants; Renal Transplantation; Kidney Transplants; Kidney Grafting; Kidney Transplantation; Learning; hepatic organ system; hepatic body system; Liver; Liver Transplant; Liver Grafting; Hepatic Transplantation; liver transplantation; lifespan; life span; Length of Life; Longevity; mortality; Organ Preservation; Organ Procurements; organ xenograft; organ graft; organ allograft; Organ Transplants; Grafting Procedure; Organ Transplantation; Patients; Perfusion; QOL; Quality of life; Rats Mammals; Rat; Common Rat Strains; Rattus; Renal Insufficiency; Renal Failure; Kidney Insufficiency; Kidney Failure; Resort; Resuscitation; Savings; Technology; Temperature; Thermodynamic; Thermodynamics; Time; Body Tissues; Tissues; Translating; transplant; Transplantation; Universities; waitlist; Waiting Lists; Work; Hepatic Failure; Liver Failure; Businesses; Schedule; Custom; Acute Liver Failure; fulminant hepatic failure; Fulminating Liver Failure; Fulminating Hepatic Failure; Fulminant Liver Failure; Acute Hepatic Failure; Injury; base; Organ; improved; Procedures; Area; Clinical; repaired; repair; Phase; Evaluation; Hepatocyte; Liver Cells; Hepatic Parenchymal Cell; Hepatic Cells; Recovery; Organ Donations; Letters; Nature; Whole Blood; Life; animation; Hour; Protocols documentation; Protocol; System; stress tolerance; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; Transplant Surgeon; Tissue Engineering; engineered tissue; biomaterial compatibility; biocompatibility; experience; liver preservation; success; Stretching; Devices; Lobe; lobes; Modeling; preconditioning; high throughput screening; High Throughput Assay; Length; ventricular assist device; Ventricle-Assist Device; Artificial Ventricles; Artificial Heart Ventricle; Data; Slice; Validation; Immunologics; Immunologically; Immunological; Immunologic; Immunochemical Immunologic; cost; design; designing; novel strategies; novel strategy; novel approaches; new approaches; Outcome; combinatorial; prototype; flexibility; flexible; trauma care; metabolic depression; laboratory equipment; laboratory technology; lab equipment; preservation; human model; transplant model
