Nanowarming and banking of kidneys and kidney slices following metabolic preconditioning and multi-temperature machine perfusion

ABSTRACT The kidney transplant waitlist comprisesof the overall U Sorgan transplant waitlistyet every yearthousands of potentially transplantable kidneys are discardedMore specificallyfor everywaitlist patients who die or become too sick for transplantationkidneys are discardedIn additionthe quality of kidney preservation is linked to graft lifespankidneys having only andltgraft survival afteryearsExperts estimate that extending kidney preservation time todays or more would allow for current state of the art immune tolerance induction protocolswhich are showing good promise in live kidney donation at three clinical centersMGH HarvardStanfordand Northwesternto be used in the context of deceased organ donation to reduce or eliminate the need for lifelong immunosuppressionimprove the lives of kidney transplant recipients and save the healthcare system over $million dollars each yearUsing carefully optimized protocols and effective cryoprotective agentsCPAsdeveloped over a decadeour team and others have successfully cryopreserved multiple tissues in an icefree vitreousglassyoramorphousstateallowing for indefinite storageHoweverthese advances in ice free preservation have not been matched by similar advances to prevent damage from ice growth and or fracturing and cracking during rewarmingRecentlyhoweverour collaborator DrBischof demonstrated a scalable and biocompatible nanowarming technology using radiofrequencyRFexcited iron oxide nanoparticlesIONPsfor ice and fracture avoidanceIn this proposed study we will develop a comprehensive solution for vitrifying and nanowarming kidneys by combining DrBischofandapos s expertise withour deep expertise in organ perfusionour experience with successful commercializationDrTaylorMrBrassil and DrBaicu are lead scientists behind the world market leading organ perfusion system LifePort that enabled the IPO of Organ Recovery Systemsour recent experience adapting a perfusion device for sub zero perfusion of CPAs loaded with IONPsandour successful experiments loading rat livers with IONPsSpecificallywe will begin with precision cut rat kidney slicesPCKSwhich will lend itself to high throughput assessment of CPA toxicityCPA permeationand critical cooling and warming ratesSpecific AimsandThese will provide the basis for studies of whole rat kidneys usingCT and MRI for CPA preconditioning and IONP permeation assessment andin our final stepvitrification and RF nanowarming with functional testing of whole rat kidneysSpecific AimsandThis proposal will provide the basis for large animal studies in Phaseand subsequent extension to the cryopreservation and nanowarming of human kidneysAltogetherour proposed research constitutes an important standalone project whose substrategies will likely enable further breakthroughs in biopreservationtissue engineeringbioemedical researchand clinical practice NARRATIVE The need for organ transplantation is continuing to grow steadily and the official U Sorgan transplant statistics show that there wereX people on the waitlist than recipients of a transplant last yearUNOSand thatof all annual U Sdeaths could be prevented by organ transplantationWith regard to kidneysapproximatelyorgans are discarded for everywaitlist patients due to limitations in preservation quality and durationshort preservation times and risk of ischemia constraining optimal donor recipient matching and preventing strategies of immune tolerance inductionTo overcome these barrierswe have developed a novel approach combining multi temperature multi steps machine perfusion with vitrification and nanowarming for long term kidney cryopreservationwhich has the potential to make readily accessible life saving kidney transplants while facilitating the widespread banking of all types of organ and tissues