Artificial Liver Devices and Bioartificial Liver Systems: Current Status

Hyuck David Kwon Choon; Suk-Koo Lee; Jung-Keug Park; Doo-Hoon Lee; Ji-Hyun Lee

doi:10.4285/jkstn.2011.25.1.15

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Choon, Lee, Park, Lee, and Lee: Artificial Liver Devices and Bioartificial Liver Systems: Current Status

Review Article

J Korean Soc Transplant 2011;25(1):15-21.

Published online: 10 March 2011

DOI: https://doi.org/10.4285/jkstn.2011.25.1.15

Artificial Liver Devices and Bioartificial Liver Systems: Current Status

Hyuck David Kwon Choon, M.D.¹, Suk-Koo Lee, M.D.¹, Jung-Keug Park, Ph.D.², Doo-Hoon Lee, Ph.D.³, Ji-Hyun Lee, Ph.D.⁴

¹Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine Korea

²Department of Medical Biotechnology, Dongguk University Korea

³Department of Biomedical Research Institute, Lifeliver Co. Ltd. Korea

⁴Department of Samsung Biomedical Research Institute, Seoul Korea

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Acute liver failure is a rapidly progressive disease of the liver associated with high morbidity and mortality without liver transplantation. Although good survival after transplantation can be achieved, due to the disparity between patients awaiting transplantation and available organs, many patients die due to progression of the disease while waiting for a liver graft. To reduce the high morbidity and mortality associated with acute liver failure, attempts have been made during the last several decades to develop a temporary liver support system, such as artificial and bioartificial livers. The artificial liver is a non-biological device mainly aimed at the removal of accumulated toxins during liver failure, and the bioartificial liver is a biological device that has bioreactors containing living hepatocytes which provide both biotransformation and synthetic liver functions. There are currently 3 artificial livers available in the market that have been actively used in the clinical field, and 11 bioartificial livers that have been developed and have undergone clinical trials. In this article, we will discuss about the 3 artificial liver devices and 5 bioartificial liver systems that are the most advanced and have been widely evaluated clinically. Also, the characteristics and the preclinical data of the first bioartificial liver system developed in Korea that is currently under clinical investigation, will be discussed.

Keywords: Bioartificial liver, Artificial liver, Acute liver failure, Calcium alginate, Hepatic transplantation

References

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Fig. 1.

Schematic illustration of Molecular Absorbent Recirculating System (MARS) (A) and Prometh-eus (B).

Fig. 2.

Schematic illustration of Extracorporeal Liver Assist Device (ELAD). The plasma is separated using ultrafiltrate generator and the ultrafiltrate is circulated to 4 parallel cartilages containing C3A cells.

Fig. 3.

Schematic illustration of Modular Extracorporeal Liver Support (MELS) device. It consists of a detoxification module performing single pass albumin dialysis, hemofiltration module and a bioreactor that contains 3 bundles of hollow fiber membrane interwoven into a three-dimensional capillary network.

Fig. 4.

Structural characteristics of LifeLiver. The 70 μ m sized spheroids are encapsulated using calcium alginate beads of 800 μ m size and immobilized in the bioreactor (A, B). The calcium alginate bead acts as a semipermeable barrier protecting the hepatocytes from immunological reaction of the host (C).

Fig. 5.

Results of preclinical trial of LifeLiver. Decreased blood ammonia level is seen in the bioartificial (BAL) group (A) resulting in increased survival compared to both the control and blank group (B).

Table 1.

Characteristics of bioartificial liver devices

Device	Bioreactor type	Hepatocyte source	Cell amount	Membrane cut-off	Perfusion (plasma separation rate, mL/min)	Bioreactor flow rate (mL/min)
ELAD (Vitagen/	Hollow fiber	Human, tumor cell line (C3A)	60/400 g	70/120 kD	Blood (NA)	200/2,000
Hepatix)					/plasma
HepatAssist/	Hollow fiber	Cryopreserved porcine	5∼7×10⁹	3,000 kD	Plasma (50)	400/800
HepatAssist2			/15×10⁹
BLSS	Hollow fiber	Freshly isolated porcine	70∼120 g	100 kD	Blood (NA)	100∼250
MELS	Hollow fiber	Freshly isolated porcine/human	∼600 g	400 kD	Plasma (31)	100∼200
AMC-BAL	Porous matrix	Freshly isolated porcine,	10×10⁹	Direct contact	Plasma	150
		immortalized human fetal			(40∼50)
LifeLiver	Encapsulation	Freshly isolated porcine	20×10⁹	600 kD	Plasma (40)	300

Abbreviations: ELAD, Extracorporeal Liver Assist Device; BLSS, Bioartificial Liver Support System; MELS, Modular Extracorporeal Liver Support; AMC-BAL, Academic Medical Center-Bioartificial Liver; NA, not available. Adapted from Table 30.1 of reference [14].

Table 2.

Results of clinical studies of bioartificial liver devices

Device	Liver disease	No. of patients	Clinical phase	Treatment	Outcome	References
ELAD	Acute liver failure	24	I/II; one center;	Median 72 hours	↓ Encephalopathy,	Ellis et al.(6)
			RCT		↓ NH4, ↓ Bilirubin
	Fulminant liver failure	24	I/II; one center	Approx 50 hours	↑ Survival	Millis et al.(15)
HepatAssist/	Acute liver failure	171	II/III; multicenter;	6 hours daily;	↓ Risk of pretransplant	Demetriou et al.(8)
HepatAssist2			RCT		death
BLSS	Acute liver failure and acute-on-chronic liver failure	4	I/II; one center	12 hours	↓ NH4, ↓ Bilirubin	Mazariegos et al.(9)
MELS	Acute liver failure	8	I/II; one center	Porcine, Mean 27	↓ Encephalopathy,	Sauer et al.(10)
				hours	↑ coagulation, OLT
	Acute liver failure	8	I/II; one center	Human, Mean 79	↓ Encephalopathy,	Sauer et al.(11)
				hours	↑ coagulation, OLT
AMC-BAL	Acute liver failure	12	I/II; one center	8∼5 hours	↓ Encephalopathy,	van de Kerkhove
					↓ NH4, ↓ Bilirubin and improvement of hemodynamic status	et al.(13)

Abbreviations: ELAD, Extracorporeal Liver Assist Device; BLSS, Bioartificial Liver Support System; MELS, Modular Extracorporeal Liver Support; AMC-BAL, Academic Medical Center-Bioartificial Liver; RCT, randomized controlled trial; No., number; approx, approximately. Adapted from Table 2 of reference [16].

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