Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review

Abstract

Liver transplantation is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. This has necessitated the adoption of innovative technologies and strategies to protect these higher-risk grafts from the deleterious effects of traditional preservation and ischaemia reperfusion injury (IRI). The advent of normothermic machine perfusion (NMP) and rapid growth in the clinical adoption of this technology has accelerated efforts to utilise NMP as a platform for therapeutic intervention to optimise donor livers. In this review we will explore the emerging preclinical data related to ameliorating the effects of IRI, protecting the microcirculation and reducing the immunogenicity of donor organs during NMP. Exploiting the window of opportunity afforded by NMP, whereby the liver can be continuously supported and functionally assessed while therapies are directly delivered during the preservation period, has clear logistical and theoretical advantages over current preservation methods. The clinical translation of many of the therapeutic agents and strategies we will describe is becoming more feasible with widespread adaptation of NMP devices and rapid advances in molecular biology and gene therapy, which have substantially improved the performance of these agents. The delivery of novel therapeutics during NMP represents one of the new frontiers in transplantation research and offers real potential for successfully tackling fundamental challenges in transplantation such as IRI.

Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury—An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies

“…Pharmacological agents targeting IRI and microcirculation regulatory pathways, administered during machine perfusion or as donor/recipient therapy. [4,6,89,[170][171][172][173][174][175][176][177][178][179] Allograft viability assessment Perfusate, bile, tissue biomarkers of viability. New analytical technologies e.g., proteomics and metabolomics.…”

“…In the future, the better and more complex understanding of the mechanisms of IRI could help us not only to better design clinical trials but also in the identification of novel therapeutic targets and techniques [ 4 , 6 , 162 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 ] ( Table 4 ). Gene therapy (e.g., genetic preconditioning) is one of the novel approaches finding its way into IRI therapy [ 151 ].…”

Ex-Vivo Pharmacological Defatting of the Liver: A Review

“…use of these grafts for transplantation, if the defatting succeeds, constitutes a goal in itself for developing such therapies [6].…”

“…However, discarded highly steatotic grafts, which are not suitable for transplantation but can be maintained on normothermic machine perfusion (NMP), may represent the ultimate experimental model to assess various therapeutic defatting strategies. Moreover, the direct impact on the possible use of these grafts for transplantation, if the defatting succeeds, constitutes a goal in itself for developing such therapies [ 6 ].…”

Appropriate timing for hypothermic machine perfusion to preserve livers donated after circulatory death

“…Multiple mechanisms contribute to the process of IRI, of which inflammation and oxidative stress display major roles ( 3 , 4 ). After transplantation, patients who receive marginal organs are more likely to develop early allograft dysfunction, liver rejection and biliary complications, and thus have a higher risk of unfavorable short- and long-term outcomes ( 5 ). Therefore, the effective maintenance and optimization of the quality of organs donated after circulatory death (DCD) are urgent problems in the field of organ transplantation.…”