Ex Vivo Storage, Preservation And Rehabilitation Of Living Heart Valves For Allogenic Valve Transplantation - There is an urgent need for cardiac valve replacements capable of growth and self-repair for children with congenital valve disease, for whom the current standard of care is multiple open-heart surgeries to repair or replace structurally-degraded valve prostheses. Living allogenic valve transplantation (LAVT) has recently emerged as a means of delivering valve replacements capable of achieving these goals. However, there are key limitations: (i) restricted availability, (ii) limited ex vivo viability, (iii) the cost, time and resource constraints related to minimizing tissue ischemic time, and (iv) immunogenicity. There is an urgent clinical need to develop methods for storing and preserving living valvular allografts ex vivo, that remain viable and available off-the-shelf for implantation. Our central hypothesis is that integrating a preservation solution which supports interstitial cell metabolic activity with biomimetic mechanical stimulation will maintain valvular viability and growth-capacity for at least 6 weeks ex vivo, while reducing immunogenicity. The rationale is that extending the ex vivo viability of valvular tissue would significantly improve the availability, cost-effectiveness, logistics and widespread clinical adoption of LAVT. First, a biomimetic strategy for the extended storage, preservation and rehabilitation of living valvular allografts will be validated (Aim 1). Tissue preservation over 8 weeks of storage will be evaluated via a multi-scale approach, from the macrostructure to resident cell phenotype. Anticipated outcomes include (i) a preservation solution for valvular tissue, and (ii) a custom bioreactor for long-term storage, which continuously exposes valves to physiologic open/close cycles and transvalvular pressure gradients in a sterile, low-cost fashion. Second, we will evaluate the impact of the storage and rehabilitation strategy on the allograft's capacity for growth and self-repair in a growing piglet model (Aim 2). We anticipate that stored valves will demonstrate growth and self-repair capacity non-inferior to that of freshly transplanted valves and superior to cryopreserved ones. Third, we will characterize the effect of IL-10 and storage time on the allogeneic immune response to valvular allografts in vitro and in vivo (Aim 3). Outcomes evaluate the host immune response to valvular transplants in a large animal model with or without immunosuppression, while simultaneously evaluating whether the risk of an adverse immune response can be mitigated through immunomodulation. The project's success would enable off-the-shelf availability of living allogenic valves, significantly enhancing the spatiotemporal availability and logistic-ease of LAVT. Understanding the allogeneic immune response to valvular allografts will inform clinical immunosuppression protocols, as well as techniques for immunomodulation of valve tissue. Altogether, this innovative approach to living valve storage is paradigm-changing, offering patients the first-ever off-the-shelf available living valve replacement option capable of somatic growth and self-repair, which can act as a life-lasting valve. This work will be carried out by an multidisciplinary team which is uniquely poised for success with an established history of collaboration synergizing translational research with clinical experience.
