58. In vivo preconditioning: An advanced donation algorithm for cryopreservation of organs for transplantation

Abstract

Improved cryopreservation techniques could potentially achieve long-term organ storage and therefore solve the problem of worldwide organ shortage for transplantation. Current experimental approaches mostly rely on complex ex vivo machine perfusion protocols for organ preconditioning after explantation. These machines deliver cocktails of cryoprotectants, nanoparticles and other agents through the vasculature of organs and into the cells in order to overcome major hurdles regarding the cooling and thawing processes. However, many of the commonly used agents are toxic and the procedures are technically challenging, and introduce prolonged times that can decrease organ quality. While research efforts are focusing on even more complex attempts to address the aforementioned problems ex vivo, beating heart donor organ transplantation offers an extensive time frame for manipulation in vivo. In current practice, the donor is “only” maintained and monitored during this period. In the future, the period of time when the brain-dead donor has a beating heart could be used to apply several approaches where the donor becomes a production and delivery platform in order to improve organ quality for the purpose of cryopreservation. In nature, animals provide multiple examples of how in vivo preconditioning induces freeze tolerance to prepare for hibernation. Utilizing the normothermic circulation in a physiological environment provided by the donor, the production of beneficial proteins could be induced. This strategy would not only involve drug application such as microRNA transfection for protein synthesis regulation, but also the application of physical triggers, using the donor’s physiological responses. For example, the production of heat shock proteins that have recently been demonstrated to have a potential protective effect against chilling injury can be induced systemically within the donor by local external heat application. If these strategies are applied shortly after consent for donation, there is time to induce protein production and for the proteins to take effect. Going forward, suitable animal models should be developed to assess the effectiveness of externally induced in vivo preconditioning. An ethical debate is needed to address whether the extra physical and chemical stress that the beating heart donors will have to undergo is justifiable. In conclusion, under the current algorithm for organ donation, valuable time and treatment opportunities for organ preconditioning are unutilized during the period of time while beating heart donors are awaiting organ procurement. The physiological environment in heart beating donors enables treatment options that cannot be provided by extracorporeal perfusion systems after explantation. Therefore, utilizing the donor body for preconditioning of the organs may enable new protocols that are less toxic and reduce the duration of ex vivo preconditioning to ultimately facilitate success in cryopreservation.