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

doi:10.3748/wjg.v25.i27.3634

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World Journal of Gastroenterology

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Systematic Reviews

World J Gastroenterol. Jul 21, 2019; 25(27): 3634-3648
Published online Jul 21, 2019. doi: 10.3748/wjg.v25.i27.3634

Table 1 Characteristics of bioartificial liver support system and subjects of clinical trials

ID	Publication year	Type of trial	BAL system				Subject
ID	Publication year	Type of trial	Type	Hybrid	Cell	Mass	Sample No.	Subtype	Age	Sex	Disease etiology
1	1994	Non-controlled trial	HepatAssist	Yes	Porcine hepatocytes	6 × 10⁹	7	FHF 6 PNF 1	10-58	4M:3F	PNF 1 ; Virus 1; AO 2; Indeterminate 3
2	1997	Non-controlled trial	HepatAssist	Yes	Porcine hepatocytes	5 × 10⁹	21	FHF 18	36.1 ± 3.4	7M:11F	Virus 4; Indeterminate 8; AO 4; Ischemic 2
2	1997	Non-controlled trial	HepatAssist	Yes	Porcine hepatocytes	5 × 10⁹	21	PNF 3	48.3 ± 11.2	1M:2F	Virus 1; Indeterminate 1; Autoimmune 1
3	2010	Non-controlled trial	HepatAssist	Yes	Porcine hepatocytes	5 × 10⁹	18	FHF 15	10-56	10M;5F	Indeterminate 7; Virus 3; AO 4; Ischemic 1
3	2010	Non-controlled trial	HepatAssist	Yes	Porcine hepatocytes	5 × 10⁹	18	PNF 3	26-58	1M:2F	Indeterminate 1; Virus 1; Autoimmune 1;
4	2002	Non-controlled trial	HepatAssist	Yes	Porcine hepatocytes	5 × 10⁹	10	FHF 10	31	4M:6F	Indeterminate 6; Virus 2; Wilson 1; Pyrazinamide 1
5	1994	Non-controlled trial	ELAD	No	C3A cells	200 g	11	FHF 10 PNF 1	38.5 ± 18.1	5M:6F	Idiopathic 1; Virus 3; AO 2; INH 1; FIAU 3; Anhepatic 1
6	2002	Non-controlled trial	ELAD	No	C3A cells	300-400g	5	FHF 5	22.2 ± 9.4	2M:3F	asparaginase toxicity 1; Indeterminate 3; Autoimmune 1
7	2002	Phase I trial	AMC-BAL	No	Porcine hepatocytes	11.9 × 10⁹	7	FHF 7	34.3 ± 15.2	2M:5F	Virus 4; AFLP 1; Indeterminate 2
8	2003	Case report	AMC-BAL	No	Porcine hepatocytes	10 × 10⁹	1	FHF	35	F	Virus 1
9	1996	Non-controlled trial	NR	No	Porcine hepatocytes	5 × 10⁹	12	FHF 11 PNF 1	37.2 ± 15.5	6M:6F	Indeterminate 4; AO 2; Virus 3; Ischemic Failure 1; Autoimmune 1; PNF 1
10	2003	Phase I trial	MELS	Yes	Porcine hepatocytes; non-parenchymal cells	(1.8-4.4) × 10¹⁰	8	FHF 8	34.3	1M:7F	Rug-related 2; Virus 3; Indeterminate 3
11	2003	Case report	MELS	Yes	Human hepatocytes	470 g	1	PNF	26	F	Intoxication with amanita phalloides
12	2002	Case report	BLSS	No	Porcine hepatocytes	70-100 g	1	FHF	41	F	Indeterminate 1
13	2002	Non-controlled trial	RFB-BAL	No	Porcine hepatocytes	200-230 g	7	FHF 4 PNF 3	37.4 ± 18.4	5M:2F	Virus 3; PNF 3; Liver trauma 1
14	2003	Non-controlled trial	HBAL	Yes	Porcine hepatocytes	1.0 × 10⁹	12	FHF 12	41.8 ± 13.0	9M:3F	Virus 12
15	1999	Non-controlled trial	HepatAssis	Yes	Porcine hepatocytes	5 × 10⁹	8	FHF 8	33.4 ± 11.0	1M:7F	AO 8
16¹	2018	Phase 1/2a Trial	LifeLiver BAL	NR	Porcine hepatocytes spheroids	NR	8	FHF 8	NR	NR	NR
17	1996	Pilot-Controlled Trial	ELAD	No	C3A cells	400 g	Group-1 17	FHF 17	30	6M:3F vs 3M:5F²	AO 5, Virus 3, ATB 5 vs AO 6, Virus 1²; ATB 1
17	1996	Pilot-Controlled Trial	ELAD	No	C3A cells	400 g	Group-2 7	FHF 7	30	0M:3F vs 3M:1F²	AO 3 vs AO 3, Virus 1²
18	2004	RCT	HepatAssist	Yes	Porcine hepatocytes	7 × 10⁹	171	FHF 147 PNF 24	37	26M:60F vs 25M:60F²	Known causes 83, Indeterminate 64

¹Data from abstract;

²Intervention vs control; NA: Not applicable; NR: Not reported; Sex: Male (M) and Female (F); ELAD: Extracorporeal liver assist device; BAL: Bioartificial liver; 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 bioartificial liver; HBALSS: Hybrid bioartificial liver support system; PNF: Primary nonfunction; FHF: Fulminant hepatic failure; AO: Acetaminophen; INH: Isoniazid; FIAU: Fialuridine; AFLP: Acute fatty liver of pregnancy; ATB: Anti-tuberculous hepatotoxicity; PERV: Porcine endogenous retrovirus; RCT: Randomized controlled trial.

Table 2 Outcomes and adverse events after treating by bioartificial liver support system in clinical trials

ID	Treating time	Bridgingtime	OLT /total		SR of OLT	SR of no OLT	Recovery without OLT	Follow-up time	Hemodynamics	Liver and renal function	Hematologic and coagulation	Encephalopathy index	Neurologic	Adverse events	PERV test
1	1.6 × 6 h	24 h	7/7		100%	NA	NA	NR	Stable	Decreased: ammonia; transaminases	Decreased: Fibrinogen	Improved	Decreased: ICP Increased: CPP	None	NR
2	2.1 × 6 h	45.3 h	16/18		100%	50%	1	NR	Stable	Decreased: ammonia; ALB; transaminases; bilirubin; BUN; creatinine Increased: glucose	Not improved	Improved	Decreased: ICP; Increased: CPP; GCS; CLOCS	Transient hypotension	NR
2	1.6 × 6 h	83.0 h	3/3		100%	NA	NA	NR	Stable	Decreased: transaminases; bilirubin; ALB Increased: glucose	Not improved	Not improved	Not improved	Transient hypotension	NR
3	1.8 × 6 h	38.6 h	14/15		100%	100%	1	2-62 m	Stable	Decreased: ammonia; bilirubin; transaminases; ALB; BUN; creatinine; Increased: Glucose	Not improved	Improved	Decreased: ICP; Increased: CLOCS	None	Negative (5 y)
3	1.7 × 6 h	21 h-8 d	3/3		100%	NA	NA	2-62 m	Stable	Not improved	Not improved	Improved	Not improved	None	Negative (5 y)
4	1.9 × 6 h	46 h	10/10		80%	NA	NA	24.5m	Stable	Decreased: bilirubin; transaminases	Decreased: Platelets; Fibrinogen	Improved	Increased: GCS; CLOCS	Bleeding; transitory hypotension	Negative
5	52.6 h	40.8 h	4/11		100%	14%	1	10 d	Stable	Improved	NR	Improved	Improved	Transitory hypotension	NA
6	50.8 h	50.8 h	5/5		80%	NA	NA	30 d	Stable	Improved	NR	Not improved	Not improved	None	NA
7	18.9 h	NR	6/7		100%	100%	1	18 m	Stable	Decreased: bilirubin; ammonia	NR	NR	Improved	Transitory hypotension	Negative -18 m
8	35 h	35 h	1/1		100%	NA	NA	15 m	Stable	Decreased: bilirubin; ammonia; lactate	Not improved	NR	Improved	NR	Negative 12 m
9	1.7 × 6 h	39.3 h	12/12		100%	NR	NR	NR	Stable	Decreased: bilirubin; ammonia; transaminases; Increased: glucose	Not improved	Improved	Decreased: ICP; Increased: CPP; CLOCS	None	NR
10	27.3 h	NR	8/8		100%	NR	NR	3y	Stable	Decreased: bilirubin; ALB	Decreased: platelets	Improved	NA	Decreased body temperature	Negative 3 y
11	79 h	79 h	1/1		100%	NR	NR	1y	Stable	Decreased: lactate; BUN; creatinine	Improved	Improved	Improved	Decreased body temperature	NA
12	12 h	7 d	NA¹	NA¹		NA¹	NA¹	7d	Stable	Decreased: lactate; ammonia; transaminases	Improved	NR	Not improved	Hypoglycemia	NR
13	11.7 h	11.7 h	6/7		83%	0%	0	NA	Stable	Decreased: bilirubin; transaminase; ammonia; lactate; urea	Improved	NR	Improved	None	Negative 180 d
14	1.1 × 6 h	NR	NA²	NA²		NR	NR	1 m	Stable	Decreased: bilirubin; transaminase; ammonia	Improved	NR	Improved	None	NR
15	2.9 × 6 h	NR	3/8		100%	100%	5	NR	Stable	Decreased: ammonia; bilirubin; transaminases; BUN; creatinine	Improved	Improved	Decreased: ICP Increased: CLOCS	None	NR
16	NR	NR	2/6		100%	75%	3	NR	NR	Decreased: ammonia	Not improved	NR	Improved	Coagulopathy pneumonia, sepsis, and diseased progression	Negative
17	72 (3-168) h	NR	2/9 vs 2/8³		50% vs 50%³	6/7 vs 5/6³	6 vs 5³	NR	Stable	Decreased ammonia	Improved	NR	NR	Tachypnoeic; tachycardic; pyrexial; disseminated intravascular coagulation	NA
17	72 (3-168) h	NR	1/3 vs 1/4³		100% vs 100%³	0% vs 0%³	0 vs 0³	NR	Stable	Decreased ammonia	Improved	NR	NR		NA
18	17.4 h	5 d vs 3 d	45/85 vs 49/86³		89% vs 80%³	50% vs 38%³	20 vs 14³	30 d	Stable	Decreased bilirubin	Not improved	NR	Not improved	None	Negative 12 m

¹Suitable liver was available for OLTx during that time.

²Simultaneous HBAL 1/7 died; nonsimultaneous HBAL 2/5 died.

³Intervention vs control. NA: Not applicable; NR: Not reported; SR: Survival rate; OLT: Orthotopic liver transplantation; ALB: Albumin; BUN: Blood urea nitroge; ICP: Intracranial pressure; CPP: Cerebral perfusion pressure; GCS: Glasgow coma score; CLOCS: Comprehensive level of consciousness score; PERV: Porcine endogenous retrovirus.

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

ID	Year	Animal					BAL system					Outcomes		Test for PERV
ID	Year	Species	No	Sex	Weight(kg)	Inducer	Type	Cell	Mass	Bioreactor	Treatment time	Survival	Other	Test for PERV
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.

Citation: He YT, Qi YN, Zhang BQ, Li JB, Bao J. Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature. World J Gastroenterol 2019; 25(27): 3634-3648
URL: https://www.wjgnet.com/1007-9327/full/v25/i27/3634.htm
DOI: https://dx.doi.org/10.3748/wjg.v25.i27.3634