Project Details
Description
ABSTRACT
Nearly one-third of deceased donor livers are unused for transplant or other purposes. Many of these organs
would be valuable for therapeutic and research applications if preservation times could be extended.
Cryopreservation at ultralow temperatures (< -140°C) can enable indefinite organ storage. Previous attempts at
organ cryopreservation have failed due to cellular and structural disruption caused by ice crystal formation. One
promising approach that overcomes the limitations of conventional strategies is vitrification – that is, cooling
organs so quickly that the water within the organ cannot undergo the phase transition from liquid to solid ice.
With the help of cryoprotective agents (CPAs), the organ enters a stable glass-like state wherein the viable
storage time is theoretically unlimited. The critical challenge, however, is rewarming without ice formation or
cracking. If rewarming is too slow, ice crystals form; if rewarming is not uniform, thermal stress causes cracking.
Hence, speed and uniformity of warming are essential. We have developed a novel rewarming approach
termed “nanowarming” that achieves both objectives. Iron oxide nanoparticles are perfused throughout the
vasculature of the organ along with CPA solutions. The organ can then be vitrified by cooling (an existing
technology) and rewarmed as needed by placing it in a radiofrequency coil that induces heating in the
nanoparticles and, therefore, from within the organ. In preliminary studies, for the first time we have shown that
we can vitrify and nanowarm human sized (i.e. porcine) and rat livers, thereby avoiding ice formation or cracking
and preserving viability and organ-level function. Following on this physical success, we propose here the first
study to assess both transplantation and biological viability/function success of these nanowarmed organs. Our
central hypothesis is that cryopreservation by vitrification and nanowarming will enable functional long-term
whole human liver banking for transplant, therapeutic and biomedical research purposes. While our long-term
goal is to develop a method for cryopreserving human livers for transplant, our goals for this project are to refine
whole-liver preservation technology to 1) improve in vitro and in vivo functionality of preserved rat livers during
normothermic perfusion and in transplant models, 2) determine the mechanisms of cellular stress, injury, and
death resulting from liver cryopreservation and strategies for injury mitigation, and 3) provide further investigation
of large animal (porcine) and human liver cryopreservation and rewarming. If successful, this approach could
revolutionize how these precious resources are allocated and utilized for patient and societal benefit.
Status | Active |
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Effective start/end date | 2/15/23 → 1/31/25 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $685,071.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $606,854.00
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