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 recipientThe maximum tolerable cold ischemic times for hearts and lungs are generally considered less than or up tohoursand preferred by cardiac transplant surgeons to be less thanhours in clinical practiceIn this SBIR projectthe goal is to develop a system to preserve donor hearts for a leasthours and beyondallowing unprecedented storage durations of donated heartsFully realizedthe system will give patients greater access to compatible donor hearts and may substantially reduce the costs associated with urgent and extreme logisticsi eallow more time to coordinate the patientsurgeonand donor heartAt Sylvatica Biotechthe foundation for our approach comes from mechanisms observed in freeze tolerant species combined with principles from bioengineeringThe three pillars of innovation in this proposal are isochoricconstant volumechamber storagecold storage solution formulations with cryoprotective agentsCPAsinspired by natureand advanced multi thermic machine perfusionThese technologies will be integrated to achieve ice freesubzero storage of whole heartsMore broadlythe 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 `humanizedandaposxeno organsIn preliminary work we have demonstrated that a combination of nature inspired cryoprotective agentsCPAsand isochoric storage resulted in functional hearts after reaching temperatures as low asCTo our knowledgethis is the first demonstration of ventricular function recovery in a whole heart following storage as low asCIn this Phase I projectthe Sylvatica Biotech teamled by DrMichael Taylor and supported by collaborators at UC Berkeleythe Medical University of South Carolinaand thought leaders in organ preservationwill build on these resultsThe overall objective is to demonstrate feasibility for the target heart preservation system by storing whole rat hearts at temperatures as low asC for at leasthoursrepresenting at least ax increase over the current standard methodsThis will be accomplished in three specific aimsIdentify heart optimized CPA formulations and isochoric temperature control protocols in an in vitro cellular heart modelDevelop protocols for preparing whole hearts for isochoric storage using machine perfusionandCombine the CPA formulations and machine perfusion methods with isochoric storage to prepare whole hearts for subzero storagestore them for at leasthoursand recover for functional assessmentAchieving the milestones associated with these aims will show feasibility for the preservation system and justify translating the approach toward human useIn Phase II we will apply these successes to adapt the system to porcine heart and other models of human heart transplantand work with our established commercialization partners to begin prototyping a clinically relevant device to prepare and store human donor hearts NARRATIVE Heart transplants cost around $millionand aboutof donated hearts are not transplanted with thousand remaining on the waiting listThe high costs and low transplant rate are largely due to technical limitations in donor heart preservation technologiesThe technology developed in this proposal aims to fill the unmet need for advanced donor heart banking and preservationdecreasing the costs of heart transplant and increasing availability of donor hearts to patients in needThe proposed preservation system can be expanded to additional donor organsmaking it a commercially viable solution with access to many indications and organ transplant markets