Donor organ shortage is the main limitation to liver transplantation as a
treatment for end-stage liver disease (ESLD) and acute liver failure (ALF).
Liver regenerative medicine may in the future offer an alternative form of
therapy for these diseases, be it through cell transplantation, bioartificial
liver (BAL) devices, or bioengineered whole organ liver transplantation. All
three strategies have shown promising results in the past decade. However,
before they are incorporated into widespread clinical practice, the ideal cell
type for each treatment modality must be found, and an adequate amount of
metabolically active, functional cells must be able to be produced. Research is
ongoing in hepatocyte expansion techniques, use of xenogeneic cells, and
differentiation of stem cell-derived hepatocyte-like cells (HLCs). HLCs are a
few steps away from clinical application, but may be very useful in
individualized drug development and toxicity testing, as well as disease
modeling. Finally, safety concerns including tumorigenicity and xenozoonosis
must also be addressed before cell transplantation, BAL devices, and
bioengineered livers occupy their clinical niche. This review aims to highlight
the most recent advances and provide an updated view of the current state of
affairs in the field of liver regenerative medicine.
The limited preservation duration of organs has contributed to the shortage of organs for transplantation. Recently, a tripling of the storage duration was achieved with supercooling, which relies on temperatures between −4 and −6 °C. However, to achieve deeper metabolic stasis, lower temperatures are required. Inspired by freeze-tolerant animals, we entered high-subzero temperatures (−10 to −15 °C) using ice nucleators to control ice and cryoprotective agents (CPAs) to maintain an unfrozen liquid fraction. We present this approach, termed partial freezing, by testing gradual (un)loading and different CPAs, holding temperatures, and storage durations. Results indicate that propylene glycol outperforms glycerol and injury is largely influenced by storage temperatures. Subsequently, we demonstrate that machine perfusion enhancements improve the recovery of livers after freezing. Ultimately, livers that were partially frozen for 5-fold longer showed favorable outcomes as compared to viable controls, although frozen livers had lower cumulative bile and higher liver enzymes.
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