Bioartificial liver systems

There are artificial liver support devices available commercially with some evidence of efficacy with regard to secondary outcomes, such as improvements in encephalopathy and nephropathy, but no single device has clearly demonstrated convincing improvements in survival. Bioartificial liver systems continue to offer promise but are still in clinical trials. Systematic reviews combining the outcomes from several support devices have suggested reductions in mortality in AOCLF when compared to standard medical therapy, but a recent review evaluating more modern support devices found a benefit only in ALF. A number of large, multicenter randomized studies are currently underway. 

There have already been clinical trials of porcine hepatocyte-based bioartificial livers [5, 6]. However, we believe these systems to represent temporary and short-lived approaches. Compelling evidence from recent experiments show that primary porcine liver cells express and release endogenous retroviral particles that are able to infect human cells. However, long term in vivo investigations of patients previously exposed to porcine tissues over a period of 12 year did not show any porcine endogenous retrovirus (PERV) viremia [7]. Therefore, we consider the further pursuit of porcine bioartificial livers the only solution at present with regard to the cell source. However, as an intermediate term alternative human cell sources are in development [8]. Expansion technologies for human fetal cells may contribute to resolve these limitations in the future. 

To be useful to both, clinicians and the pharmaceutical industry, a bioartificial liver will need to maintain a large number of hepatocytes at high cell densities and in a fully differentiated state for prolonged periods of time. Development of such a system has been impeded by three principal problems a) a requirement for large numbers of cells (>25 10 ) b) loss of liver-specific functions in cultured cells (primary and immortalized) c) nutrient and waste product gradients in high density cultures leading to lowered cell viability and impaired function. 

One method of culturing anchorage-dependent tissue cells is to use a bed of packings, on the surface of which the cells grow and through which the culture medium can be passed. Hollow fibers can also be used in this role here, as the medium is passed through either the inside or the outside of the hollow fibers, the cells grow on the other side. These systems have been used to culture liver cells to create a bioartificial liver (Section 15.4.2). 

Mazariegos, G.. Kramer, D.. Lopez, R., Shjakil, A., Rosenbloom, A., DeVera, M., Giraldo, M., Grogan, T, Zhu. Y. Fulmer, M., Amiot, B., Patzer, J. Safety observations in phase I clini cal evaluation of Excorp medical bioartificial liver support system after the first four patients. ASAIO J. 47, 471, 2001. 

As liver performs multiple and complex functions, artificial organ or bioartifidal organ exploiting a synthetic cartridge to host biological components such as cells (hepatocytes in the case of a bioartificial liver) have been investigated. Among all of these potentialities, we only focus here on purely artificial systems. Membrane-based bioartificial livers (BAL) will not be described here, but could be found in other reviews [22-25] and in another chapter in the present book. 

As seen above, the artificial systems are only able to supply detoxication functions of the liver. In some cases, this might not be enough to save patients. An alternative is the design of bioartificial liver. A simplistic approach consists in considering such a device as a bioreactor based on synthetic elements able to offer an adequate environment to the liver cells. This environment would in turn lead to the maintenance of efficient functions of the cells aiming at liver supply, when placed in a bioreactor located in an extracorporeal circuit. The mandatory requirements for acceptable cell viability and functions in a bioartificial liver (BAL) are tentatively listed below, according to a biotechnological point of view ... 

Up to now, none of the presented system can claim its ability to fully replace all liver functions in an extracorporeal circuit. On the one hand, purely artificial techniques can only cover some detoxification aspects, which is already crucial in many clinical cases to save patients. On the other hand, bioartificial livers have not proven their full efficiency yet, mainly because both regulatory and logistic aspects limit, for the moment, the inclusion of significant numbers of patients to draw statistically relevant conclusions. 

First clinical use of a novel bioartificial liver support system (BLSS). Amer. X Transplant. 2002 2 260—266... 

Tsiaonssis, X, Newsome, P.N., Nelson, L.X, Hayes, P.C., Plevis, XN. Which hepatocyte will it be Hepatocyte choice for bioartificial liver support systems. Liver Transplant. 2001 7 2-10... 

In recent years, many investigations have been conducted, including clinical trials, with bioartificial liver devices using either animal or human liver cells. Likewise, many reports have been made with various designs of bioartificial liver device [19]. However, there are no established liver support systems that can be used routinely in the same way as hemodialyzers or blood oxygenators. Today, bioartificial liver devices can be used to assist the liver functions of patients with liver failure on only a partially and/or temporary basis. Moreover, none of these devices can excrete bile, as does the human liver. 

For certain applications it is necessary to maintain a large number of cells that transform an input of reactants into an output of products. This is the case for the bioartificial liver or pancreas and more recently for the production of blood cells from hematopoietic tissue. These systems require maintenance of the function of a large number of cells in a small volume. For example, a hypothetical bioar-... 

Over 50 types of cells, tissue constructs, and even tissue explants have been cultured in these bioreactors, which appear to be ideally suited to promote the expression of tissue-specific functions in the cultured cells and preserve the three-dimensional morphological characteristics of the native tissue. Thus, this system should be useful to create and maintain bioartificial tissues to be subsequently implanted in vivo. On the other hand, these devices would not be appropriate for tissue engineering applications requiring a combination of very high cell densities and very low liquid hold-up volumes, such as in the case of extracorporeal bioartificial livers. 

The bioartificial liver support devices that are under investigation include the extracorporeal liver assist device (ELAD, Vital Therapies, San Diego, Cahfornia, USA) and the HepatAssist Liver Support System (HepaLife Technologies, Boston, Massachusetts, USA). 

Other bioartificial liver devices under study include the bioartificial extracorporeal liver support (BELS) system, which uses porcine hepatocytes with separate capillary systems arranged to mimic hepatic architecture. 

Pless G. Bioartificial liver support systems. Methods Mol Biol 2010 640 511-23. 

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