Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature

Table 3 Characteristics of preclinical experiments on large animals in past 10 years

ID	Year	Animal					BAL system					Outcomes		Test for PERV
		Species	No	Sex	Weight(kg)	Inducer	Type	Cell	Mass	Bioreactor	Treatment time	Survival	Other
19	2011	Pig	30	M	10-15	D-galactosamine	FBBAL	Alginate-chitosan encapsulated primary porcine hepatocytes	5 × 109	Choanoid fluidized bed bioreactor	6 h	Survival time: BAL 72.9 ± 4.72 h Sham BAL 54.6 ± 4.09 h Control 54.8 ± 3.98 h	Decreased: lactate; glucose	NR
20	2012	Canine	32	NR	10-15	D-galactosamine	HBAL	Co-cultured porcine hepatocytes and bone marrow mesenchymal stem cells	1x 1010	Multi-layer flat-plate bioreactor + anionic resin adsorption column	3 h	7 day survival: HBAL 7/8 BAL 5/8 NBAL 4/8 Control 3/8	Decreased: transaminases; LDH; ammonia; bilirubin; PT Increased: ALB	Negative (7 d)
21	2013	Pig	13	F	25-30	Hepaticartery ligation	NA	Alginate-encapsulated HepG2cell-spheroids	5 × 1010	Fluidised-bed bioreactor	7 h	Survival time: BAL 10.5 ± 20.7 h SBAL 8.6 ± 21.4 h	Decreased: ICP; ammonia; Increased: bilirubin; acidosis	NR
22	2014	Cynomolgus monkey	15	M	6.5-7.0	D-galactosamine	HBALSS	Human hepatic CL-1 cells grown in microgravity culture	4 × 109	Perfusion bioreactor	6 h	Survival time: 128 h BAL 5/10 Control 0/5	Decreased: bilirubin; TBA; BUN; Cr; ammonia; Fischer indices Increased: ALB	NR
23	2015	Canine	8	NR	10-13	D-galactosamine	HBAL	Co-cultured porcine hepatocytes and bone marrow mesenchymal cells	1 × 1010	Multi-layer flat-plate bioreactor + anionic resin adsorption column	6 h	1 year survival: 7/8	Decreased: transaminases; PT; bilirubin; LDH; ammonia; Increased: ALB	Negative (1 year)
24	2015	Pig	18	F	45	D-galactosamine	SRBAL	Porcine hepatocytes spheroids	200 g	Spheroid reservoir	24 h	Survival 90 h (%) ST 0/6, 0% ST + Non-cell 1/6,17% ST + SRBAL 5/6, 83%	Decreased: ammonia; ICP; brain water content	NR
25	2016	Pig	21	M	10-15	D-galactosamine	FBBAL	Alginate-chitosan encapsulated porcine hepatocytes	5 × 109	Choanoid fluidized bed bioreactor	6h	Survival time: FBBAL 70.4 ± 11.5 h Sham FBBAL 51.6 ± 7.9 h Control 49.3 ± 6.6 h	Decreased: PCs; LPCs; FAs; SM; Increased: CBAs	NR
26	2016	Pig	20	NR	15-25	D-galactosamine	HiHep-BAL	HiHeps	3 × 109	Multi-layer radial-flow bioreactor	3h	Survival 7 d: hiHep-BAL 7/8 Empty-BAL 1/6 No-BAL 0/6	Decreased: transaminase ammonia; bilirubin; PT	NR
27	2017	Pig	25	F	30-35	Surgical ligation of all blood flow to the liver	UCLBAL	3-dimensional (3D) HepG2-cell spheroids	7.3 × 1010	Fuidised bed bioreactor	6h	Survival time: Control-BAL 7.04 ± 1.9h, n = 15 Cell-BAL 8.21 ± 2.3 h, n = 13	Decreased: PT; INR; ICP; ammonia	NR
28	2017	Pig	15	M	45-55	Complete hepatic inflow devascularization	NA	Ca-alginate-immobilized hepatocyte spheroids	2 × 1010	Packed-bed bioreactor	12h	Median survival time: Control 21 h n = 5 BAL 28.5 h n = 5 Cell-free BAL 21 h n = 5	Decreased: ammonia; creatinine ICP; BP Increased: urine	NR
29	2018	Rhesus monkey	30	M	10-20	α-amanitin and lipopolysaccharide	SRBAL	Pig hepatocyte-HUVEC organoids	2.6 × 1010	Spheroid reservoir	6 h	Median survival time: SRBAL 12 h 336 h n = 6 SRBAL 24 h 248 h n = 6 SRBAL 36 h 132 h n = 6 Sham no-cell SRBAL 12 h 90 h n = 6 Control 60.5 h n = 6	Decreased: ammonia; bilirubin Increased: albumin	Negative (6 h)
30	2019	Pig	18	F	20-30	85% hepatectomy	SRBAL	Porcine hepatocyte spheroids	200g	Spheroid reservoir	24 h	Survival rate at 90 h: SMT 0/6 SMT plus no-cell SRBAL 0/6 SMT plus SRBAL (200 g) 5/6	Decreased: ammonia; ICP; INR Increased: volume regeneration	NR

NA: Not applicable; NR: Not reported; BAL: Bioartificial liver; Sex: Male (M) and Female (F); ELAD: Extracorporeal liver assist device; AMC-BAL: Academic medical center bioartificial liver; MELS: Modular extracorporeal liver support; BLSS: Novel bioartificial liver support system; RFB-BAL: Radial-flow bioreactor bioartificial liver; HBAL: Hybrid bioartificial liver; FBBAL: Fluidized bed BAL; HBALSS: Hybrid bioartificial liver support system; SRBAL: Spheroid reservoir bioartificial liver; hiHep: Human-induced hepatocytes; CBAs: Conjugated bile acids; PCs: Phosphatidylcholines; LPCs: Lysophosphatidylcholines; FAs: Fatty acids; SM: Sphingomyelin; ICP: Intracranial pressure; ALB: Albumin; PT: Prothrombin time; INR: International normalized ratio; PERV: Porcine endogenous retrovirus.