Developing normothermic machine liver perfusion for improvement of marginal donor graft quality

Boteon, Yuri Longatto ORCID: 0000-0002-1709-9284 (2019). Developing normothermic machine liver perfusion for improvement of marginal donor graft quality. University of Birmingham. Ph.D.

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Abstract

The studies incorporated in this thesis examined ways to develop ex situ normothermic machine perfusion (NMP) of the liver as a tool to enhance the reconditioning of high-risk extended criteria donor (ECD) organs. Two possible alternatives were investigated: (1) The use of hypothermic oxygenated machine perfusion as a therapeutic intervention preceding NMP; and (2) the delivery of a pharmacological combination of drugs targeting hepatic lipid metabolism during NMP. Using human donor livers discarded for transplantation, the feasibility of a combined protocol of hypothermic oxygenated perfusion (HOPE) and NMP was shown. HOPE optimised hepatic mitochondrial bioenergetic and oxidative status as well as mitigated ischaemia-reperfusion injury, while NMP maintained the organs’ metabolism thus allowing the assessment of its metabolic functions. This combined protocol was facilitated with the use of a single acellular haemoglobin-based oxygen carrier (HBOC)-based perfusate throughout the entire perfusion, using a cold-to-warm machine perfusion protocol. These combined protocols enabled superior recovery of metabolic functions of ECD livers compared to NMP alone. The delivery of a combination of drugs targeting the hepatic lipid metabolism during NMP was also investigated. This approach reduced the intracellular lipid content of discarded human donor livers via enhancement of fatty-acids β-oxidation and solubilisation of lipids in the perfusate. The boosted lipid metabolism improved the metabolic status of the organs optimising their functional recovery and halted oxidative stress-related hepatobiliary injury. These findings are promising and guarantee future clinical investigation, opening a window of opportunity to improve the reconditioning of ECD livers.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):