With more than five times the number of patients on the wait list than will receive a donor organ in the United States, the field of transplantation is facing a serious donor shortage crisis. Overcoming the organ shortage will require integrated strategies, including a particular focus on overcoming ineffective bio-preservation and stabilization protocols. Longer storage durations will provide the infrastructure required to enable global matching programs, eliminate the need to scramble and conduct unplanned surgeries, and reduce unnecessary waste of quality organs. We believe the method for preserving mammalian organs should employ hibernating and freeze-tolerant strategies in nature that are then further augmented using bioengineering principles. Consequently, we seek to develop a protocol for human organ preservation which will achieve high subzero storage temperatures (ranging from -10 to -20 C) in the presence of extracellular ice, and storage durations of weeks to months, using inspiration from in nature. Our approach is unique in organ/tissue preservation literature since we aim to actively initiate ice propagation in the vasculature and extracellular spaces, rather than extreme means of inhibiting ice crystallization as is the current standard. The presence of non-injurious ice will be essential in achieving longer storage durations, while also playing an important role in the scale-up to human livers. While this program targets the banking of human liver, our discoveries and solutions will be translatable to other tissues and organ systems.
In Specific Aim 1, we will adapt endothelial cell-coated microvascular networks already developed by our group3 in order to model and develop strategies to overcome challenges associated with ice propagation. Since endothelial cells in the vasculature will be the most vulnerable to ice propagation, SA#1 will be an essential proof of concept of our novel strategy and we already have promising data.
In Specific Aim 2, we will engineer an ice nucleating agent which will promote non-injurious propagation of ice in extracellular spaces. Ice nucleating agents are essential for restricting ice formation to extracellular spaces and have been identified as critical strategies for freezing survival.
In Specific Aim 3, we will reprogram cells to descend into a state of `suspended animation' with enhanced stress tolerance, as inspired by nature. We will achieve this using both passive temperature effects as well as using pharmacological agents. We will perform in-depth characterization of the molecular impact of our cellular reprogramming efforts. In each specific aim, we scale up rapidly to rat whole liver while also validating in human livers in order to maximize impact.

Public Health Relevance

There are currently over 123,000 patients on the organ transplant waiting list in the US, a number that far exceeds the supply of available organs, and that continues to grow ~5% each year. A major reason is the limitations of our current organ preservation technology, which disallows the transplantation of marginally injured organs and limits preservation duration. This project aims to improve public health by developing a protocol to bank human organs for several weeks up to a few months, enabling global organ matching and potentially utilization of organs unusable with current technology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK114506-01
Application #
9366242
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Sherker, Averell H
Project Start
2017-07-17
Project End
2021-03-31
Budget Start
2017-07-17
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Jaramillo, Maria; Yeh, Heidi; Yarmush, Martin L et al. (2018) Decellularized human liver extracellular matrix (hDLM)-mediated hepatic differentiation of human induced pluripotent stem cells (hIPSCs). J Tissue Eng Regen Med 12:e1962-e1973