Non-toxic, nature-inspired perfusion and high subzero ice-free isochoric technologies for extending heart preservation - ABSTRACT
Current methods of heart and lung preservation offer extremely limited time between organ donation and
transplantation into the recipient. The maximum tolerable cold ischemic times for hearts and lungs are generally
considered less than or up to 6 hours, and preferred by cardiac transplant surgeons to be less than 3 hours in
clinical practice. In this SBIR project, the goal is to develop a system to preserve donor hearts for a least 24 hours
and beyond, allowing unprecedented storage durations of donated hearts. Fully realized, the system will give
patients greater access to compatible donor hearts and may substantially reduce the costs associated with urgent
and extreme logistics (i.e. allow more time to coordinate the patient, surgeon, and donor heart). At Sylvatica
Biotech, the foundation for our approach comes from mechanisms observed in freeze tolerant species combined
with principles from bioengineering. The three pillars of innovation in this proposal are isochoric (constant
volume) chamber storage, cold storage solution formulations with cryoprotective agents (CPAs) inspired by
nature, and advanced multi-thermic machine perfusion. These technologies will be integrated to achieve ice-free,
subzero storage of whole hearts. More broadly, the approach can be applied to other organs to prevent ischemic
injury and help alleviate key bottlenecks in the development and use of tissue engineered constructs and
`humanized' xeno organs. In preliminary work we have demonstrated that a combination of nature-inspired
cryoprotective agents (CPAs) and isochoric storage resulted in functional hearts after reaching temperatures as
low as -10°C. To our knowledge, this is the first demonstration of ventricular function recovery in a whole heart
following storage as low as -10°C. In this Phase I project, the Sylvatica Biotech team, led by Dr. Michael Taylor
and supported by collaborators at UC-Berkeley, the Medical University of South Carolina, and thought leaders
in organ preservation, will build on these results. The overall objective is to demonstrate feasibility for the target
heart preservation system by storing whole rat hearts at temperatures as low as -20°C for at least 24 hours,
representing at least a 4x increase over the current standard methods. This will be accomplished in three specific
aims: 1) Identify heart-optimized CPA formulations and isochoric temperature control protocols in an in vitro
cellular heart model, 2) Develop protocols for preparing whole hearts for isochoric storage using machine
perfusion, and 3) Combine the CPA formulations and machine perfusion methods with isochoric storage to
prepare whole hearts for subzero storage, store them for at least 24 hours, and recover for functional assessment.
Achieving the milestones associated with these aims will show feasibility for the preservation system and justify
translating the approach toward human use. In Phase II we will apply these successes to adapt the system to
porcine heart and other models of human heart transplant, and work with our established commercialization
partners to begin prototyping a clinically-relevant device to prepare and store human donor hearts.
