Liver-assist Devices Research Articles

Molecular Adsorbent Recirculating System (MARS)

Introduction: Molecular adsorbent recirculating system (MARS) for albumin liver dialysis has been used as a bridge to liver transplantation in patients with fulminant hepatic failure (FHF). This review examines the available data on its clinical use, its technical aspects and present gaps in knowledge. Methods: Peer-reviewed journals and monographs on the subject were covered. Results: FHF is associated with elevation in various substances including bilirubin, ammonia, lactate, free fatty acids and aromatic amino acids. Some of these toxic metabolites, such as ammonia and bilirubin, are believed to be central to the clinical manifestations of hepatic encephalopathy and acute renal failure. MARS ameliorates both biochemical and clinical manifestations of FHF by removing both water-soluble and protein-bound toxins. Among the benefits of MARS is the attenuation of severe cerebral oedema and raised intracranial pressure found in FHF, possibly through reduction in high concentrations of these toxins. Although MARS has been shown to be useful in FHF, its clinical efficacy in subfulminant hepatic failure and less severe forms of acute liver failure (ALF) remains uncertain. The current literature also suggests that it may be beneficial to treat cases of acute-on-chronic liver failure (AoCLF). Deranged systemic chemistries can be similarly ameliorated, but the impact of MARS on the natural history of AoCLF remains uncertain. The difficulty lies in being able to accurately quantify residual liver function and variability in the course of acute intercurrent events. The broader question is whether MARS can favourably change the natural history of ALF and FHF. For this, large multi-centre, randomised controlled trials are needed. Furthermore, it is also uncertain how hepatic excretory-assist devices, such as MARS, compare with bio-artificial liver-assist devices which have both synthetic and excretory hepatic functions in ALF treatment in intensive care unit patients. Nevertheless, MARS has proven to be a valuable homeostatic tool that may be useful in restoring the biochemical and clinical status quo in much the same way that continuous veno-venous haemofiltration and mechanical ventilation provide temporary artificial organ support while these organs are in distress. This is the evolving concept of multi-organ support therapy. Other major unresolved issues with MARS include the timing of initiation of albumin liver dialysis, the clinical and/or biochemical parameters to base this decision on, the intensity of MARS therapy (continuous versus intermittent) and the saturation capacity of the system for different metabolites in intermittent MARS. Conclusions: MARS is an effective and, thus far, safe homeostatic tool in treating FHF. More studies are needed to delineate its role as a homeostatic tool in less severe forms of ALF, including that which occurs in multi-organ failure and in AoCLF. Other studies need to focus on the optimal timing of initiation of and intensity of MARS albumin liver dialysis. The larger issue is to compare MARS with bio-assist liver devices in treating the whole spectrum of ALF.

Hepatic tissue engineering

Fulminant hepatic failure (FHF) attributes to rising medical cost and accounts for many deaths each year in the United States. Currently, the only solution is organ transplantation. Due to increasing donor organ shortage, many in need of transplantation continue to remain on the waiting list. Liver Assist Devices (LADs) are being used to temporarily sustain liver function and bridge the period between FHF and transplantation. Hepatic Tissue Engineering is a step toward alleviating the need for donor organs; yet many challenges must be overcome including scaffold choice, cell source and immunological barriers. Bioreactors have aided in hepatocyte survival and have proven to sustain viable cells for several weeks. Achieving the necessary functions required for hepatic replacement is aided by the incorporation of growth factors and mitogens many that now can be bound to the polymer scaffold and released in a timely manner. Utilizing concepts such as MicroElectroMechanical systems (MEMs) technology, our laboratory is able to mimic the natural vasculature of the liver and sustain functional and viable hepatocytes. Expanding and improving upon this platform technology, advancements made will continue toward the development of a fully functioning and implantable liver.

Hepatic tissue engineering

Fulminant hepatic failure (FHF) attributes to rising medical cost and accounts for many deaths each year in the United States. Currently, the only solution is organ transplantation. Due to increasing donor organ shortage, many in need of transplantation continue to remain on the waiting list. Liver Assist Devices (LADs) are being used to temporarily sustain liver function and bridge the period between FHF and transplantation. Hepatic Tissue Engineering is a step toward alleviating the need for donor organs; yet many challenges must be overcome including scaffold choice, cell source and immunological barriers. Bioreactors have aided in hepatocyte survival and have proven to sustain viable cells for several weeks. Achieving the necessary functions required for hepatic replacement is aided by the incorporation of growth factors and mitogens many that now can be bound to the polymer scaffold and released in a timely manner. Utilizing concepts such as MicroElectroMechanical systems (MEMs) technology, our laboratory is able to mimic the natural vasculature of the liver and sustain functional and viable hepatocytes. Expanding and improving upon this platform technology, advancements made will continue toward the development of a fully functioning and implantable liver.

Suppressed complement activation in human decay accelerating factor transgenic porcine liver cross-circulated with nonhuman primates.

We developed an extracorporeal liver perfusion (ECLP) system as a liver-assist device. In this study, we evaluated the safety of the ECLP using human decay accelerating factor (hDAF) transgenic porcine livers in healthy baboons. Livers were isolated from five hDAF transgenic pigs and five nontransgenic pigs for the ECLP. Ten cross-circulations between the ECLP and healthy baboons were performed without immunosuppressive agents. Cross-circulation was discontinued in any of the following circumstances: elevated hepatic arterial (>200 mm Hg) or portal (>60 mm Hg) perfusion pressure, massive exudate from the graft liver, mild macroscopic hemolysis, thrombocytopenia, or 24-hr well-conditioned cross-circulation. The cross-circulations with nontransgenic porcine livers were discontinued at 4.4+/-1.2 hr (mean+/-standard deviation) because of high perfusion pressure (n=2) or hemolysis (n=3). Three cross-circulations with hDAF transgenic porcine livers were performed for 24 hr; the other two cross-circulations were discontinued at 13 and 17 hr because of massive exudate and thrombocytopenia, respectively. The duration was 20.4+/-5.1 hr. Deposition of membrane attack complex in the hDAF transgenic porcine liver was less than that in the nontransgenic liver, although immunoglobulin-M deposition was comparable. The porcine livers showed no apparent interlobular bleeding or lobular necrosis. All porcine livers maintained bile production during the cross-circulation. No baboons showed any serious complications after the cross-circulation. The hDAF transgenic porcine liver reduced complement activation in xenoperfusion with healthy nonhuman primate blood and led to extended duration of cross-circulation.

A PERFUSED ROTATING WALL VESSEL BIOARTIFICIAL LIVER

A novel bioartificial liver is being developed based on the rotating wall vessel (RWV) technology of NASA. We discovered that preaggregated primary rat hepatocytes retained high viability and drug metabolizing enzyme activities in the High Aspect Ratio Vessel (HARV), suggesting that a bioartificial liver could be developed using hepatocytes cultured in a RWV. The Perfused Rotating Wall Vessel (PKWV) was selected as it allowed the continuous perfusion of plasma from a patient. Porcine hepatocytes were used. The original RWV design allowed only short-term culturing of the hepatocytes, with viability dropping to less than 50% in 1 hr. Modificiation of the bioreactor via the addition of a more efficient oxygenator increased the viability to over 50% for a duration of 5 hrs. A hollow fiber column was used as a filter to prevent the entry of hepatocytes from the SLAD to the patient's systemic circulation. The efficacy of this novel bioartificial liver (Stelsys Liver Assist Device, SLAD) was demonstrated by its ability to efficiently detoxify ammonia (using 1–5 billion porcine hepatocytes, the ammonia level of a phantom patient was decreased from 130 μM to 40 μM after a 5 hr treatment period). A comparison was made between the SLAD and the conventional hollow fiber bioartificial liver. We discovered that a significantly higher mass transfer could be achieved via cross-flow than the conventional parallel flow. Ammonia detoxification as well as acetaminophen metabolism were demonstrated with the cross-flow hollow fiber bioartificial liver (SLAD-CHF).

Auxiliary liver transplantation and bioartificial bridging procedures in treatment of acute liver failure.

The aim of this review is to discuss the place of auxiliary liver transplantation (ALT) and other cellular based bridging procedures such as hepatocyte transplantation, ex vivo liver perfusion, and bioartificial livers, in the treatment of acute liver failure, vis à vis conventional orthotopic liver transplantation. Hepacocyte transplantation, and ex vivo pig or human liver perfusion are still experimental procedures. Bioartificial livers using human tumoral hepatocytes or porcine hepatocytes have been used in clinical situations as a bridge to transplantation, i.e. to gain the time required to find a high-quality graft for conventional or auxiliary liver transplantation. None of these techniques have yet proved capable of keeping a patient alive long enough for the native liver to recover. Conversely, ALT has been shown to be effective in the treatment of acute liver failure and now appears to be a satisfactory bridging procedure pending native liver (NL) regeneration. We report personal experience of 18 ALT procedures performed in 17 patients between October 1992 and December 1999. The ALT procedure was indicated when patients met criteria for conventional transplantation; it was ultimately selected when a fresh frozen biopsy of the NL did no show any fibrosis. Six patients died within the first 2 postoperative months. The remaining 11 patients are alive, with a follow-up ranging from 2 to 7 years. Regeneration of the NL occurred in 11 of the 17 patients (65%) and in 8 of the 11 survivors (72%), 6 of whom have permanently stopped immunosuppressive therapy. We conclude that liver failure should no longer be handled outside centers where all types of transplantation can be offered, and where innovative therapies such as hepatocyte transplantation and extracorporeal liver-assist devices are being developed and evaluated.

Powdered sorbent liver dialysis and pheresis in treatment of hepatic failure.

The Liver Dialysis Unit (the Unit) is a liver-assist device that employs hemodiabsorption (dialysis of blood against powdered sorbents) to selectively remove numerous small molecular weight toxins of hepatic failure. The Unit has been cleared by the Food and Drug Administration and is indicated and marketed for treatment of acute hepatic encephalopathy (AHE) due to decompensation of chronic liver disease (A-on-C) or fulminant hepatic failure (FHF). Controlled, prospective, and randomized studies of liver dialysis were conducted at several centers, enrolling 56 patients with AHE, grades II-IV with or without renal and respiratory insufficiency or failure. Liver dialysis treatments were for 6 h daily, 1-5 days with similar observation periods for control patients. Physiologic status, neurologic status, and outcome (recovery of hepatic function, improvement for transplant, or death) were measured, and results were compared for treated patients versus controls for patients with A-on-C and patients with FHF. Liver dialysis resulted in physiologic and neurologic improvement of patients with AHE, regardless of etiology. Liver dialysis significantly improved the incidence of positive outcomes (recovery of hepatic function or improvement for transplant) of A-on-C patients versus controls (71.5% treated, 35.7% control, p = 0.036), but had an insignificant improvement in the outcome of patients with FHF as compared with the control group. Among the overall 31 treated patients, 51.6% survived. Outcome was not negatively affected by the presence of kidney failure or respiratory failure. The plasmafilter unit (PF-Unit) combines hemodiabsorption with push-pull sorbent-based pheresis (the PF add-on module, with powdered sorbent surrounding plasmafilters). At blood flow rates of 200 ml/min, the system clears creatinine and aromatic amino acids at 120-160 ml/min, unconjugated bilirubin at 20-40 ml/min, and cytokines at 15-25 ml/min. The PF-Unit has been tested in a few patients with hepatic failure with Grades III and IV encephalopathy, and respiratory, and kidney insufficiency. Treatment appeared to be safe, and there were no significant hematologic changes. Physiologic changes included improved blood pressure, and encephalopathy, and stable urine output. Chemical changes included a decrease in the plasma levels of bilirubin, aromatic amino acids, ammonium, creatinine, and IL-1beta. The PF add-on module adds the capability to the Unit to remove bilirubin and other strongly protein-bound toxins from treated patients and may be of clinical benefit in the management of patients with the most severe hepatic failure and encephalopathy, including patients with FHF or concomitant sepsis.

Biological extracorporeal liver assist devices: A minireview

During the past decade, whole organ transplantation has become the primary method of treating fulminant hepatic failure and chronic liver failure due to specific genetic, hepatocellular, and anatomic defects of liver function. However, wider application of liver transplantation is restricted by shortage of organ donors, high cost, relatively high morbidity, and need for lifelong immunosuppression. As a result, investigators have attempted to develop alternative methods to treat liver insufficiency. These ranged from use of plasma exchange to utilization of detoxification columns and extracorporeal devices loaded with various liver tissue preparations. Recent advances in hepatocyte isolation and culture techniques, improved understanding of hepatocyte-matrix interactions, availability of new biomaterials, improved hollow-fiber technology, and better understanding of flow and mass transport across semipermeable membranes have resulted in the development of a new generation of liver assist devices. Some of these devices, including the one we developed, are currently being tested in the clinical setting. In this article, past experience with biological liver-assist devices is reviewed, the field's present status is examined, and our own experience with a hepatocyte-based bioartificial liver is summarized. Areas in which further research efforts are particularly needed are briefly characterized.

Effects of prostaglandin E(1) on the efficacy of xenogeneic extracorporeal pig liver perfusion in a canine model of acute liver failure.

Xenogeneic extracorporeal liver perfusion (ECLP) has the potential to become an important tool in the management of patients with severe liver failure. We previously showed that xenogeneic pig liver perfusion may be prolonged for up to 9 hours by the administration of prostaglandin E(1) (PGE(1)). In this study, we used a canine model of acute liver failure to evaluate the effects of PGE(1) on the efficacy of ECLP as a liver-assist device. Liver failure was surgically induced in 12 beagle dogs, with a control group (group 1, n = 4) not connected to the ECLP circuit. Direct cross-circulation between the dogs and the ECLP circuit using a pig liver was performed without (group 2, n = 4) or with (group 3, n = 4) continuous administration of PGE(1) through the portal vein of the pig liver. The duration of cross-circulation in group 3 (9.4 +/- 1.2 hours) was significantly longer than in group 2 (4.3 +/- 1.0 hours). In addition, elevation of blood ammonia, total bile acid, and hyaluronic acid levels was less marked in group 3 compared with the other 2 groups. The ratio of branched-chain amino acids to aromatic amino acids was also improved in group 3. The mean survival time in group 3 (26.6 +/- 0.4 hours) was significantly longer than in group 1 (15.5 +/- 1.3 hours) or group 2 (17.1 +/- 2.9 hours). Continuous administration of PGE(1) to xenogeneic ECLP resulted in a significant improvement in both liver function and survival time of dogs with surgically induced liver failure.

ARTIFICIAL LIVER SUPPORT DEVICES FOR FULMINANT LIVER FAILURE

Artificial liver-support devices attempt to bridge patients with fulminant hepatic failure until either a suitable liver allograft is obtained for transplantation or the patient's own liver regenerates sufficiently to resume normal function. It is thought that toxins contribute to the clinical picture of fulminant hepatic failure. The earliest reports of successful toxin removal were blood- and plasma-exchange transfusions. Given these successful case reports, mechanical liver-support devices were designed to filter toxins. These mechanical devices used hemodialysis, charcoal hemoperfusion, hemoperfusion through cation-exchange resins, hemodiabsorption, and combinations of all of these techniques as in the MARS liver-support device. Despite promising case reports and small series, no controlled studies of mechanical devices have ever showed a long-term survival benefit. Thus, the removal of presumed toxins seems to be insufficient to support patients with fulminant hepatic failure, and the biologic function of the liver must also be replaced. Attempts at replacing the biologic function have included extracorporeal liver perfusion, cross-circulation, and hepatocyte transplantation. Current technologies have combined mechanical and biologic support systems in hybrid liver-support devices. The mechanical component of these hybrid devices serves both to remove toxins and to create a barrier between the patient's serum and the biologic component of the liver-support device. The biologic component of these hybrid liver support devices may consist of liver slices, granulated liver, or hepatocytes from low-grade tumor cells or porcine hepatocytes. These biologic components are housed within bioreactors. Currently the most clinically studied bioreactors are those that use capillary hollow-fiber systems. Both the bioartificial liver by Demetrious and the extracorporeal liver-assist device by Sussman and Kelly are in clinical trials. Although the trials seemed to have yielded good survival data when the devices are used as a bridge to transplantation, the type and degree of liver support provided by these devices remains uncertain. Thus, despite decades of great progress in the field of artificial liver support, no one technique alone yet provides sufficient liver support. A hybrid system seems to be the best option at present. Still to be determined is the best tissue to use, how much liver tissue should be used, and the optimal design of the bioreactor.

Treating Acute Liver Failure with an Extracorporeal Liver-Assist Device

Treating Acute Liver Failure with an Extracorporeal Liver-Assist Device

Management of drug-induced liver disease.

The treatment and prevention of drug-induced liver injury starts with the recognition of hepatotoxicity at the earliest possible time so that the suspected drug can be discontinued expeditiously. Both liver enzyme monitoring and vigilance for signs of hypersensitivity involving the liver are useful strategies for many agents known to cause hepatocellular necrosis leading to liver failure. Specific antidotes to prevent or limit hepatic damage exist for only a few drugs, the most important being N-acetylcysteine for the treatment of acetaminophen hepatotoxicity. Corticosteroids are of unproven benefit in the setting of fulminant failure. Ursodiol may be helpful in instances of cholestatic injury. For other agents, supportive measures and the increasing use of liver-assist devices as well as emergency liver transplantation are available when drug injury evolves into irreversible liver failure. It is hoped that a better understanding of hepatotoxicity mechanisms will lead to the development of more specific and effective forms of therapy in the near future.

Postthaw Viability of Precultured Hepatocytes

Hepatocytes are being studied for a wide variety of applications, including drug metabolism studies, gene therapy, and use in liver-assist devices for temporary liver support. The ability to cryopreserve isolated hepatocytes would permit the pooling of cells to reach the required therapeutic coordination of the cell supply with patient care regimes and the completion of safety and quality-control testing. The objective of this investigation was to develop a method of cryopreserving isolated hepatocytes that will retain high levels of function and facilitate the use of the cells in different applications. Freshly isolated hepatocytes were cultured in a spinner flask for different periods of time, up to 48 h. The cells were cryopreserved by use of a range of solution concentrations and cooling rates. For fresh, nonfrozen hepatocytes precultured for 24 h prior to being plated on collagen, the albumin secretion rate was 0.88 ± 0.62 mg/ml/h. When the cells were precultured for 24 h, frozen in a solution containing 10% Me2SO with a cooling rate of 1°C/min, thawed, plated on collagen, and cultured, the albumin secretion rate was 0.21 ± 0.24 μg/ml/h. In contrast, freshly isolated hepatocytes cryopreserved without preculture and cultured on collagen had an albumin secretion rate of 0.07 ± 0.08 mg/ml/h. The influences of different solution compositions and cooling rates on postthaw function of precultured hepatocytes were also determined. These results indicate that the use of a preliminary culture step prior to cryopreservation can enhance the postthaw function of hepatocytes.

A novel stable reproducible model of hepatic failure in canines.

Stable and reproducible large animal models of hepatic failure, which allow the assessment of liver-assist devices, are not available. Our objective was to develop a physiologically stable animal model of hepatic failure on which the safety and efficacy of an extracorporeal liver-assist device can be tested. We hypothesized that a surgical model which consists of an end-to-side portocaval shunt combined with common bile duct ligation and transection would create hepatic failure with: (1) elevations in amino transferases, total bilirubin, and ammonia; (2) a decrease in the ratio of branched chain to aromatic amino acids; and (3) histologic evidence of hepatic injury. Eleven mongrel dogs underwent common bile duct transection and an end-to-side portocaval shunt. Aminotransferases (AST, ALT), total bilirubin, ammonia, and branched chain and aromatic amino acids were measured prior to operation (baseline) and after 9 days. A necropsy was performed on Postoperative Day 9 and liver biopsies were obtained for histology. By Postoperative Day 9, AST, ALT, total bilirubin, and ammonia values were significantly elevated compared to baseline (P < 0.02). The ratio of branched chain to aromatic amino acids was significantly reduced compared to baseline (P < 0.003). There was histologic evidence of cholestasis and inflammation. Portocaval shunt with common bile duct transection produces liver failure with elevations in aminotransferases, total bilirubin, and ammonia, a decreased branched chain to aromatic amino acid ratio, and histologic inflammation. Unlike ischemic or chemically induced models of liver failure, the dogs were hemodynamically and neurologically stable. This model can be used to test the safety and efficacy of liver-assist devices aimed at temporizing the detoxification functions of the failing liver.

Extracorporeal tissue engineered liver-assist devices.

The treatment of acute liver failure has evolved to the current concept of hybrid bioartificial liver (BAL) support, because wholly artificial systems have not proved efficacious. BAL devices are still in their infancy. The properties that these devices must possess are unclear because of our lack of understanding of the pathophysiology of liver failure. The considerations that attend the development of BAL devices are herein reviewed. These considerations include choice of cellular component, choice of membrane component, and choice of BAL system configuration. Mass transfer efficiency plays a role in the design of BAL devices, but the complexity of the systems renders detailed mass transfer analysis difficult. BAL devices based on hollow-fiber bioreactors currently show the most promise, and available results are reviewed herein. BAL treatment is designed to support patients with acute liver failure until an organ becomes available for transplantation. The results obtained to date, in this relatively young field, point to a bright future. The risks of using xenogeneic treatments have yet to be defined. Finally, the experience gained from the past and current BAL systems can be used as a basis for improvement of future BAL technology.

Acute hepatic failure: a Western perspective.

Acute hepatic failure (AHF) is an uncommon, devastating syndrome, which results in death or the need for liver transplantation in more than 50% of cases. While AHF has numerous causes, most cases are due to viral hepatitis and drug toxicity or idiosyncratic reactions. A significant group with indeterminate causation remains, despite careful investigation. In many of these cases a viral aetiology is suspected, although yet not proven. Major differences exist in the aetiology of AHF between the West and Eastern countries. A wider range of aetiologies exists in the West. Common causes include acetaminophen toxicity and idiosyncratic drug reactions, while viral hepatitis is less frequent. Hepatitis E infection is rarely seen in Western countries in contrast to its high prevalence in the East. The mainstay of AHF management is supportive care in an intensive care unit. Liver transplantation is now the standard of care in many Western liver units for individuals who have a less than 20% probability of survival. Lack of availability of donor livers at short notice remains a significant problem. Methods of liver support used while waiting for a donor liver or for the native liver to regenerate include bioartificial livers, extracorporeal liver-assist devices, extracorporeal whole organ perfusion (human and transgenic pig) and hepatocyte transplantation. The effectiveness of these methods remains unproven and awaits controlled clinical trials. Both transplantation and liver-support methods require specialized units and expensive and complicated equipment. Further research is necessary to identify modalities of therapy that would be effective as well as widely accessible.

Is there a future for liver-assist devices?

Patients with fulminant hepatic failure fall into two categories: those who will not recover without hepatic replacement, and those with severe but potentially reversible liver injury whose livers have the potential to recover and/or regenerate. Liver support systems must provide physiologic support, rendering the patient hemodynamically stable and "bridging" the patient to transplantation, or allowing the native liver to recover and/or regenerate. Recent limited successes with bioartificial liver support for patients with fulminant liver failure are encouraging. However, these preliminary results come without randomization or control groups and without stratification by disease etiology or severity. It is hoped that randomized, controlled trials will answer important questions about the efficacy of these systems.

Extracorporeal Xenoperfusion of the Pig Liver As a Liver Assist Device: Effects of Prostaglandin E 1 and Soluble Complement Receptor Type 1

Extracorporeal Xenoperfusion of the Pig Liver As a Liver Assist Device: Effects of Prostaglandin E 1 and Soluble Complement Receptor Type 1

New approaches to supporting the failing liver.

With the continued, growing disparity between the numbers of organ donations and patients waiting for liver transplantation, various efforts have been made to optimize the allocation of organs, as well as to devise means to support the failing liver. Over the years, the development of bioartificial liver-assist devices has aimed at replacing the three main functions of hepatocytes, which are synthetic, metabolic, and excretory. The application of porcine hepatocytes in humans to carry out biotransformation, as well as other metabolic functions and refinement of the membrane separator, have yielded some promising results in supporting patients with acute liver failure. Further advances will need to be made before these bioartificial devices can be considered for routine application in clinical settings.

Extracorporeal liver support: Cell-based therapy for the failing liver

It is perhaps self-evident to state that a liver support device is possible as long as the artificial organ provides liver function. This basic concept has received woefully little attention, mainly because “liver function” escapes precise definition. We have seen a variety of liver-assist devices that have little to do with liver function over the past 30 years. Recent work has focused on the liver as a biochemical reactor, rather than an excretory organ, and the paradigm has shifted away from blood purification and toward metabolic support. This new generation of devices includes viable liver cells, which provide the necessary biochemical function without needing to identify the numerous metabolic pathways necessary to support the patient with a failing liver. This approach is the most effective and least invasive method available with current technology, and it has yielded exciting data. Questions about the mass of cells required to provide adequate support, the timing and length of treatment, and the source of cellular material continue to be debated. Here we address theoretical and practical problems in developing an extracorporeal liver-assist device (ELAD) and suggest the future role of extracorporeal liver support in the management of liver failure.