Heart valve replacement in children is a serious problem because there are no heart valve implants that grow with the patient. The valves that are currently employed need to be changed as the patient grows with a very high associated mortality rate (~40%). In response to this clinical need, we are pioneering an entirely new approach to deliver growing heart valve implants, which we are calling partial heart transplantation(PHT). PHT differs from heart transplantation because only the part of the heart containing a valve is transplanted. Based on our preliminary data in immuno suppressed piglets, we recently performed the world's first human partial heart transplant on 4/22/2022 with demonstrated valve growth. However, the chance of a donor partial heart transplant being available at just the right time is low. Therefore, we propose development of a network of tissue banks with technology licenses at major pediatric cardiovascular medical centers nationwide in preparation for clinical application. Our central hypothesis is that vitrified and nanowarmed PHT scan fulfill both their hemodynamic and biological functions after orthotopic transplantation in growing children. In this Phase I proposal there are three specific aims: First we propose optimization of short-term preservation protocols. Our working hypothesis for this aim is that PHTs will tolerate longer post-mortem cold is chemictimes than intact hearts. The impact of procurement and refrigeration on piglet-derived PHTs will be evaluated by assessment of viability in vitro. This will establish the anticipated geographic range for PHT procurement after dissection based upon estimated refrigerated travel time. In the second specific aim we will optimize vitrification protocols for PHTs. Our working hypothesis for this aim is that ice-free cryo-preservation employing tissue vitrification, rapid nanowarming and apoptosis inhibition developed for adult porcine pulmonary heart valves can be further optimized for smaller PHTs required for pediatric cases. Different cryoprotectant loading times, exposure conditions, and apoptosis inhibitors will be evaluated by assessment of viability in vitro. This will establish the optimal vitrification protocol for pediatric PHTs. In the final aim we will evaluate post-transplant growth, leaflet viability and hemodynamic function of optimally vitrified and nanowarmedcryo preserved PHTs. Our working hypothesis for this aim is that optimized protocols will allow vitrified PHTs that were banked for one month to function in vivo like fresh PHTs. The optimized protocols developed in the earlier aims will be evaluated in a swine leukocyte antigen matched growing immuno suppressed piglet PHT model by transplantation. This will establish the PHT vitrification, warming, and banking methods for future clinical application.
Public Health Relevance Statement: Narrative: Congenital heart defects cause over 180,000 neonatal and infant deaths per year world-wide. Many of these deaths are caused by heart valve dysfunction and the poor treatment options available. We propose development of living partial heart transplants that can be banked after ice-free vitrification and nanowarmed rapidly from cryogenic storage temperatures to avoid risks of ice-induced tissue damage. Commercialization will be by development of a network of tissue banks with HLA and blood group antigen typed tissues available for matching with patients upon demand.
Project Terms: 21+ years old; Adult Human; adulthood; Adult; aortic valve replacement; Autopsy; necropsy; postmortem; Blood Group Antigens; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Cause of Death; Cell Survival; Cell Viability; Child; 0-11 years old; Child Youth; Children (0-21); kids; youngster; Cryopreservation; Cryofixation; cold preservation; cold storage; Dissection; Donor person; transplant donor; Engineering; Future; Geography; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Heart; Congenital Heart Defects; Congenital Cardiac Defects; congenital cardiac anomalies; Heart Transplantation; Cardiac Transplantation; Heart Grafting; cardiac graft; heart transplant; Heart Valves; Cardiac Valves; hemodynamics; HLA Antigens; HL-A Antigens; Human Leukocyte Antigens; Leukocyte Antigens; Human; Modern Man; Ice; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; In Vitro; Infant; Ischemia; Lung; Lung Respiratory System; pulmonary; Methods; mortality; Names; name; named; naming; Organ Transplantation; Grafting Procedure; Organ Transplants; organ allograft; organ graft; organ xenograft; Parents; parent; Patients; Refrigeration; Repeat Surgery; Reoperation; Risk; Family suidae; Pigs; Suidae; Swine; porcine; suid; Technology; Temperature; Time; Tissue Banks; Tissue Collection; Tissue repository; Tissue Donors; Tissues; Body Tissues; Transplantation; transplant; Autologous Transplantation; Autograft; Autotransplant; autologous graft; autotransplantation; Travel; cardiac valve replacement; heart valve replacement; Clinical; repair; repaired; Phase; Ensure; Evaluation; pediatric; Childhood; Blood flow; Licensing; Ventricular Dysfunction; Biological Function; Biological Process; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Transplant Recipients; transplant patient; Mechanics; mechanic; mechanical; neonatal death; neonatal demise; human tissue; Protocols documentation; Protocol; Source; Allografting; infant death; death in first year of life; infant demise; infantile death; Medical center; Tissue Engineering; bioengineered tissue; engineered tissue; experience; cryogenics; Animal Model; Animal Models and Related Studies; model of animal; Disease model; disorder model; response; Regenerative Medicine; Apoptosis Inhibitor; Apoptosis Inhibitor Gene; valve replacement; Tissue Viability; Data; Inhibition of Apoptosis; in vivo; in vivo Model; Preparation; preparations; Development; developmental; immunosuppressed; neonate; new approaches; novel approaches; novel strategy; novel strategies; Outcome; innovate; innovative; innovation; clinical applicability; clinical application; Implant; commercialization; operations; operation; trauma care; clinically translatable; clinical translation; preservation; transplant model; homograft; post-transplantation; posttransplant; posttransplantation; post-transplant; nanowarming; pig model; piglet model; swine model; porcine model; technology platform; technology system
