Therapeutics administered during ex vivo liver machine perfusion: An overview

Table 2 Other major therapeutic additives in models of ex vivo liver machine perfusion

Ref.	Ex vivoperfusion type	Therapeutic	Problem	Animal	Model	Samplesize	Ex vivo perfusiontime (h)	Outcomes
Goldaracena et al[9], 2016	SNMP	Anti-inflammatory agents	IRI	Pig	Transplantation	5	4	During EVLP: lower AST, TNF-α, IL-6
								Lower HA levels, β-galactosidase and higher IL-10 (nonsignificant)
								After transplantation: Lower bilirubin, lower IL-6, lower cleaved caspase 3 staining, intact sinusoidal endothelial cell lining
		(Alprostadil, n-acetylcysteine, carbon monoxide, sevoflurane)
								Lower AST, TNF-α, HA,
								ALP and higher IL-10 (nonsignificant)
Rigo et al[65], 2018	NMP	HLSC-EV	IRI	Rat	EVLP	9	4	HLSC-EV uptake in treated livers
								Reduced necrosis and apoptosis on histology, lower Suzuki tissue injury score, lower apoptosis, lower AST and LDH, lower HIF-1α & TGF-β1 (hypoxia induced markers)
								NMP had low hematocrit to induce hypoxia
Beal et al[66], 2019	NMP	Enkephalin	IRI	Rat	EVLP	6	4	10 μmol/L determined to be optimal concentration in an in vitro model: Lower ALT and MDA; better preservation of structural architecture; decreased caspase-3 expression;
		(δ-opioid agonist)
								decreased TUNEL staining; decreased phosphorylation of p38 and JNK; increased expression of p-Akt, PI3K, p-Bad and Bcl-2
Yu et al[67], 2019	HMP	NLRP3 Inflammasome	IRI	Pig	Transplantation	6	2	All reduced in HMP-postop group with added mcc950 in perfusate and IV administration of mcc950
								After transplantation: TNF-α, IL-1β, β-galactosidase, post-reperfusion serum ALT and AST, MDA, apoptosis staining, caspase-1 levels
		Inhibitor mcc950

SNMP: Subnormothermic machine perfusion; NMP: Normothermic machine perfusion; HMP: Hypothermic machine perfusion; IRI: Ischemia-reperfusion injury; EVLP: Ex vivo liver perfusion; AST: Aspartate aminotransferase; HA: Hyaluronic acid; ALP: Alkaline phosphatase; HLSC-EV: Human liver stem cells-derived extracellular vesicles; LDH: Lactate dehydrogenase; ALT: Alanine aminotransferase; MDA: Malondialdehyde; IV: Intravenous.