Extracorporeal Liver Support Therapy Research Articles

Extracorporeal liver support: trending epidemiology and mortality - a nationwide database analysis 2007\u20132015

BackgroundExtracorporeal liver support therapies (ELS) are technical options (for bridge-to-recovery as well as bridge-to-transplant) in patients with acute liver dysfunction (e.g. acute liver failure (ALF), acute-on chronic liver failure (AoCLF) or decompensated chronic liver disease (decomp. CLD)) to reduce effects of failing hepatic detoxification functions. The present study investigates the real-life utilization of ELS (annual incidences), mortality rates as well as data regarding specific populations of liver transplantation in Germany.MethodsData on patient cases receiving extracorporeal liver support therapy were identified in a nationwide data set from the Federal statistical Office of Germany from 1 January 2007 through 31 December 2015 and analyzed regarding in-hospital mortality, age- and sex-specific distribution and use of ELS in the context of liver transplantation. Mortality rates in patients with primary acute liver dysfunction and secondary acute liver dysfunction (in the context of cardiothoracic surgery) were evaluated.ResultsAnnual incidences of ELS use remained stable between 0.39/100.000 in 2007 and 0.47/100.000 ELS in 2015. In-hospital mortality rate was 51.49% in the 2886 evaluated patient cases. Mortality was higher in men (56.04%) than in women (43.70) in the observed time period between 2007 and 2015. ELS utilization and case-related liver transplantation rates were low (12.47%). Since 2012, the annual numbers for ELS therapy in cardiosurgical patients exceeded the frequency of ELS utilization in cases of primary liver dysfunction (mortality rates: 68.39% versus 40.63%).ConclusionsELS utilization remained stable between 2007 and 2015. Mortality rates are high in this patient population of acute liver dysfunction, especially in combination with case-related cardiothoracic surgery. ELS is rarely used in the setting of liver transplantation. In 2015, more than 50% of all ELS cases in Germany were performed in the context of cardiothoracic surgery.

Acute Liver Failure, Acute-On-Chronic Liver Failure, Hepatorenal Syndrome, Hepatopulmonary Syndrome and Portopulmonary Hypertension, Artificial Liver Support on the ICU

Background Acute hepatic dysfunction in the form of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) is a disease with a high risk of mortality and requires interdisciplinary intensive care. Aim This article explains the nomenclature, pathophysiology, prognosis and possible treatment options of ALF and ACLF, including the possibilities of extracorporeal liver support therapy at the point of liver transplantation (LTx). Method Narrative review with a selective literature review and representative case studies. Results/Corner Points ALF and ACLF may have several causes and are associated with high mortality. The causes of ALF must be accurately diagnosed because targeted treatment options are available. Both ALF and ACLF may require a liver transplantation for the patient's survival. For ALF and ACLF there are different criteria for decision-making on liver transplantation and graft allocation. For extracorporeal liver support therapy, two methods have been established (MARS [molecuar adsorbent recirculating system] and FPSA [fractionated plasma separation and adsorption] Prometheus®). Both approaches may have the potential to increase the probability of survival of patients with ALF or ACLF. In some cases they can be used for bridging to liver transplantation, in individual cases also for primary poison elimination, e.g. after Amatoxin ingestion. Both methods are not suitable for long-term therapy. Conclusion Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are serious diseases with a high risk of mortality. Affected patients should receive immediate interdisciplinary intensive care in a (tertiary) centre with the aim to clarify the cause of the disease as well as possible treatment options with respect to available extracorporeal liver support therapy and liver transplantation.

Clinical effect of combined artificial extracorporeal liver support therapy for toxic hepatic failure

Objective: To investigate the clinical effect of plasma exchange (PE) versus double plasma molecular adsorption system combined with PE (DPMAS+PE) in the treatment of toxic hepatic failure. Methods: A total of 67 patients with toxic hepatic failure who were admitted during the same period of time were divided into PE group, DPMAS+ PE group, and control group. The 22 patients in the PE group were treated with PE alone, and the 24 patients in the DPMAS+PE group were given DPMAS combined with PE. The clinical out-come was compared between the three groups. Results: Both treatment groups had significantly higher clinical response rate and 24-week survival rate than the control group. After treatment, both treatment groups had significant reductions in the serum levels of total bilirubin (TBil) , direct bilirubin (DBil) , alanine aminotransfer-ase (ALT) , and aspartate aminotransferase (AST) , and the PE group had significant reductions in the albumin (Alb) level and activated partial thromboplastin time (APTT) (P<0.05) ; the DPMAS+PE group showed no sig-nificant changes in the Alb level and APTT (P>0.05). There were no significant differences in TBil, DBil, ALT, and AST between the two treatment groups after treatment (P>0.05). After treatment, the PE group had significantly higher Alb level and APTT than the DPMAS + PE group (P<0.05). Compared with the control group, both treatment groups had significant reductions in TBil, DBil, ALT and AST after treatment (P<0.05). Conclusion: The two artificial liver support techniques can significantly improve patients' liver function and in-crease their survival rate, and the combined artificial liver support technique can reduce the amount of plasma used.

One case of type II heparin-induced thrombocytopenia occurring in artificial extracorporeal liver support therapy

One case of type II heparin-induced thrombocytopenia occurring in artificial extracorporeal liver support therapy

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

No sustained impact of intermittent extracorporeal liver support on thrombocyte time course in a randomized controlled albumin dialysis trial.

Reduction of platelets is a common finding in patients with liver disease and can be aggravated by extracorporeal therapies, e.g. artificial liver support. The impact of extracorporeal albumin dialysis on the time count and time course of platelets in liver failure patients was evaluated in a randomized controlled clinical trial. Mean thrombocyte reduction during a single extracorporeal liver support therapy was -15.1% [95%CI: -17.7; -12.5]. No differences were found between treatments of patients with a more reduced platelet count (<100 GPT/L: -15.6% [-19.5; -11.7%]; n = 43) compared to patients with normal or slightly decreased thrombocytes (-14.6% [-18.3%; -11.0%]; n = 43; P = 0.719). The variation of platelet count within 24 h after onset of extracorporeal therapy treatment was less, albeit significant (-3.5% [-6.3%; -0.7%], P < 0.016). Absolute thrombocyte variability was comparable between both groups (with extracorporeal therapy -5.6 GPT/L [-9.7; -1.4], without extracorporeal therapy -1.3 GPT/L [-7.3; 4.7]; P = 0.243), whereas relative decrease of thrombocytes within a 24-h period of extracorporeal therapy was greater than the changes in patients without extracorporeal therapy (-3.5% [-6.3%; -0.7%] vs. 2.0% [-2.0%; 5.9%]; P = 0.026]. Within a period of two weeks after enrollment, no significant differences of platelet count were observed either between the two groups or in the time course (P(group) = 0.337, P(time) = 0.277). Reduction of platelets during intermittent extracorporeal liver support was less pronounced within a 24-h period as before and after a single treatment and was comparable to variations in the control group without extracorporeal therapy.

Artificial extracorporeal liver support therapy in patients with severe liver failure

Severe liver failure is common and carries a high mortality risk in patients with both acute and acute-on-chronic liver failure. The failing liver constitutes a medical emergency, and in many cases liver transplantation is the only definite treatment. Extracorporeal liver support can be employed as a strategy for bridging to transplantation or recovery. This article focuses on options for artificial (nonbiological) extracorporeal treatment: single-pass albumin dialysis, fractionated plasma separation and adsorption (Prometheus®) and the molecular adsorbent recirculatory system. Their different principles, potential advantages and indications are discussed. Despite proven biochemical efficacy, there are little data regarding clinical end points. Thus far, molecular adsorbent recirculatory system therapy in acute and acute-on-chronic liver failure showed no survival benefit compared with standard medical therapy. Prometheus therapy showed reduced mortality in subgroups of higher severity of disease compared with standard medical therapy. Nevertheless, the value of extracorporeal liver support remains to be corroborated by further clinical studies that include the optimal timing, mode, intensity and duration of this treatment.

New insights into the management of hepato‐renal syndrome

Hepato-renal syndrome (HRS) is a serious complication in patients with advanced liver disease indicating a very poor prognosis. Nevertheless, effective treatment strategies have been introduced into clinical practice over the last decade. The combined treatment with terlipressin/albumin has been proven to be effective in most published studies and should be regarded as the standard of care. Norepinephrine or midodrine are possible alternatives when terlipressin is not available. Although there is presently not enough evidence to recommend extracorporeal liver support therapy as a standard procedure in patients with HRS, these concepts constitute promising options that need to be studied in prospective clinical trials.

Relationship between kinetics of albumin-bound bilirubin and water-soluble urea in extracorporeal blood purification

The purpose of the study was to examine the relationship between urea and conjugated bilirubin kinetics during extracorporeal liver support (ELS) therapy and to determine the dose of therapy for urea and conjugated bilirubin as markers for water-soluble and protein-bound solutes, respectively. Kinetics of urea and bilirubin were described by standard two-compartment models with central clearance, constant intercompartment clearance, constant generation rate and constant volume. While the concentration of urea was assumed as equilibrated between compartments at the beginning of ELS therapy, the concentration of conjugated bilirubin between compartments was assumed to follow the partition of albumin between plasma and interstitial spaces. Treatment dose was calculated as removed solute mass and fractional solute removal. Seven patients were studied during 15 treatments lasting at least 6 h. Bilirubin distribution volume of 14.8 ± 5.4 L was not different from urea extracellular water volume of 15.0 ± 2.8 L. The correspondence between models was used to predict the mass of bilirubin removed based on extracellular volume obtained from urea kinetics, average data from bilirubin kinetics, as well as selected treatment and patient information. The prediction of bilirubin mass removed based on this reduced information was not different from the mass of solute removed based on complete bilirubin kinetic analysis. The correspondence between kinetics of urea and conjugated bilirubin can be used to identify the bilirubin distribution volume from urea kinetic analysis. This information is then useful to estimate and predict the solute removal of conjugated bilirubin in ELS.

Extracorporeal Liver Support Therapy With Prometheus in Patients With Liver Failure in the Intensive Care Unit

Acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF) are associated with a high mortality. In these patients an accumulation of both water-soluble and water-insoluble, protein-bound, metabolic waste products occurs. Conventional extracorporeal blood purification techniques based on diffusion and/or convection such as hemodialysis or hemofiltration may only eliminate small molecular weight, water-soluble compounds. In recent years, fractionated plasma separation and adsorption (FPSA) with the Prometheus system has been introduced for extracorporeal liver support therapy. To date, however, only limited data is available regarding the effect of this treatment on mortality and outcome of patients with advanced liver disease. Here we report on our experience with 23 patients with severe liver failure who were treated with Prometheus in our medical intensive care unit. Fourteen patients had AoCLF, and nine patients experienced ALF. The median bilirubin level at the start of Prometheus therapy was 30.5 mg/dL and the median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 26. During 40 individual treatment sessions lasting 5-6 h, Prometheus therapy reduced serum bilirubin levels from 23.7 mg/dL to 15.0 mg/dL (median values) (P < 0.001), and the overall survival was 26%. ALF patients had a better survival compared to AoCLF patients (44% vs. 22%; P = 0.022). Apart from one patient who developed hemodynamic instability during a treatment session, Prometheus therapy was well tolerated without relevant side-effects. In conclusion, extracorporeal liver support therapy with Prometheus is a novel and safe treatment option in patients with severe liver failure. In this series, patients with ALF showed a significantly better outcome with Prometheus therapy compared to AoCLF patients.

Usefulness and Safety of Extracorporeal Liver Support Therapy Using MARS® for Patients with Liver Failure: A Preliminary Report

The molecular adsorbent recirculating system (MARSR) is a form of artificial extracorporeal liver support and can be used for a bridge to spontaneous recovery of hepatic function or liver transplantation in patients with liver failure. This study evaluated the usefulness of MARSR in patients with liver failure. Between January 2004 and July 2007, 30 patients (21 males and 7 females; age 48.9+/-12.9 years) with acute or acute-on-chronic liver failure were managed using MARSR. We assessed laboratory data, the grade of hepatic encephalopathy, Child-Turcotte-Pugh class, and Model for End-Stage Liver Disease (MELD) score. The number of patients with acute liver failure and acute-on-chronic liver failure was 16 and 14, respectively. The mean cycle of MARSR in patients with liver failure was 2.2 sessions. After MARSR had been performed, serum total bilirubin, alanine aminotransferase (ALT), BUN, creatinine, ammonia level, daily urine output, and MELD score were improved (p<0.05). In contrast, MARSR failed to improve Child-Turcotte-Pugh score and the grade of hepatic encephalopathy. Liver transplantation was performed in 8 patients. Among them, 5 (62.5%) patients survived and 3 (37.5%) patients died. Twenty two patients underwent MARSR without liver transplantation and 4 (18.2%) of them survived. In patients with liver failure, MARSR improved the laboratory data and hepatic and renal function associated clinical characteristics. However, MARSR without liver transplantation did not improve survival. MARSR may be useful as a bridge therapy to liver transplantation in patients with liver failure.

Association Rule Mining to Analyze the Performance of Human Liver Cell Bioreactors Based on Donor Organ Data

Aim: Human liver cell bioreactors are used in extracorporeal liver support therapy (1). To optimize and standardize bioreactor operation, an early detection of the long-term culture performance is of interest. Recently, 25 variables characterizing donor organ properties, organ preservation, cell isolation and inoculation prior to bioreactor operation were analyzed in this respect using statistical and machine learning methods (2). Here, a further analysis based on association rule mining is described that also includes data characterizing the liver injury that led to the exclusion of the organ from transplantation and to the use of its cells in the bioreactor. Material and Methods: Data from 73 liver cell bioreactor runs labeled as performing 'Low' (n=19), 'Medium' (n=36) and 'High' (n=18) were analyzed by mining for association rules of the kind 'IF Premiss, THEN Conclusion'. The premiss consists of one to four conditions linked by up to three AND operators. Each condition contains one of the 29 variables analyzed with their respective categorical or numerical values. The conclusion designates one of the bioreactor performance levels 'Low', 'Medium' or 'High'. The rules' importance was assessed using the 'Confidence' and the 'Support'. Rules confirmed with 'Confidence=1', i.e. without any opposing run, were subsequently ranked by the 'Support', i.e. the ratio of supporting runs to all runs. Due to the practical interest in primarily detecting badly performing runs, rules for the conclusion 'Performance=Low' were further analyzed. Results: No other uni-conditional rule than 'IF Liver Injury=Arteriosclerosis, THEN Performance=Low' had a 'Support' of 4/73 or higher without any opposing run. However, two rules with the following more complex premisses for the conclusion 'Performance=Low' obtained a maximum 'Support' of 6/73: a) 'Inoculated Volume=Low AND AST (aspartate aminotransferase)=High'; b) 'Liver Injury=Fatty Liver AND ALT (alanine aminotransferase)=High AND GGT (gamma glutamyltranspeptidase)=High AND Donor Weight=Medium'. Conclusion: A fatty liver as exclusion cause of the organ from transplantation was found to be associated with a low liver cell bioreactor performance only when other conditions, e.g. high 'ALT', are also met. The finding that a low 'Inoculated Volume' together with other conditions is associated with a low performance supports results previously obtained (2)

HUMAN LIVER CELLS IN A 3-D HIGH DENSITY FOUR-COMPARTMENT COCULTURE BIOREACTOR FOR A MODULAR EXTRACORPOREAL LIVER SUPPORT CONCEPT

The development of a bioreactor providing a three-dimensional network of interwoven capillary membranes with integrated oxygenation enables the culture of primary human liver cells from discarded donor organs for extracorporeal liver support. Primary liver cells from n=104 discarded organs (donor age: 56+/− 13 years) were isolated and 2.8 to 6.4 x 1010 parenchymal hepatocytes (PC) were co-cultured with non-parenchymal cells (NPC) of the same organ in bioreactors (n=47). Some of the bioreactors were used clinically, utilizing a modular liver support technology including a detoxification and a dialysis module, after a stand-by period of 1–3 weeks in order to bridge patients with liver failure to Ltx (n=8). Cell metabolism was stable over a period of at least 2-3 weeks. By transmission electron microscopy (TEM) and immunohistochemistry it was demonstrated that PC and NPC spontaneously re-built tissue-like structures. Vascular cavities and bile-duct-like channels, both exhibiting proliferation activities (Ki-67 immunoreactivity [IR]), were regularly distributed. Some of the bile-duct-like channels showed ultrastructural similarities to the Canals of Hering found in the natural liver. Cells with morphological and antigenic characteristics of adult liver stem cells, i.e. CD 34 IR and c-kit IR, were regularly observed. The results indicate that primary human liver cells from transplant discards can be maintained in bioreactors and enable cell-based extracorporeal liver support therapy.

Recovery of Preservation-Injured Primary Human Hepatocytes and Nonparenchymal Cells to Tissuelike Structures in Large-Scale Bioreactors for Liver Support: An Initial Transmission Electron Microscopy Study

This study investigated large-scale regeneration and tissue reorganization of adult human liver cells from preservation injured transplant organs. The use of basement membrane protein gels and growth factor enriched culture medium in standard culture flasks promotes liver tissue formation in isolated rat and pig hepatocytes, resulting in prolongation of phenotypic stability and metabolic competence of primary cells in vitro. A special bioreactor construction for high-density three-dimensional cell recovery was developed and isolation of cells from discarded human donor livers was enabled. In vitro regeneration of adult human liver cells isolated from preservation-injured organs took place over a period of 2 weeks in a purpose-built bioreactor. Basement membrane protein and growth factors were avoided. Reorganization of tissue structures was studied using transmission electron microscopy (TEM). This showed regeneration and tissue reorganization of adult human cells from preservation-injured organs by coculture with nonparenchymal cells in the bioreactor. The majority of the aggregated hepatocytes in the bioreactors showed morphological similarities to those in vivo (although not re-formed to hepatocyte plates), exhibiting cell-cell junctions and reconstituted bile canaliculi-like spaces between neighboring hepatocytes. Perfusion channels appeared regularly between cell aggregates. The arrangement of nonparenchymal cells between the hepatocyte aggregates exhibited similarities to liver sinusoids. Endothelial cells often covered the aggregates and formed a borderline to the perfusion channels between the capillaries. Similar to the space of Disse, further nonparenchymal cells were located between the endothelial cells and the parenchymal aggregates. Deposits of biomatrix fibers occurred spontaneously. The regenerated cell mass was close to that of a single liver lobe. In conclusion, the further optimization of bioreactors that enable cell recovery from preservation injury may lead to the utilization of cells from discarded whole or split transplants for extracorporeal temporary liver support therapy or hepatocyte transplantation.

Extracorporeal liver support: porcine or human cell based systems?

Initial results of the clinical use of primary porcine liver cells for extracorporeal liver support are being reviewed as the cell source is controversial. According to Eurotransplant data 20-25% of explanted donor livers are not transplanted, due to factors such as steatosis or cirrhosis. This number corresponds to the number of patients with acute liver failure who require bridging therapy to transplantation. Primary human liver cells from transplant discards can be isolated, purified and maintained in bioreactors and provide an alternative for cell-based extracorporeal liver support therapy. A four-compartment bioreactor enables recovery from preservation and isolation injury in a three-dimensional network of interwoven capillary membranes with integrated oxygenation, rendering the liver cells from these discarded donor organs viable for clinical utilization. Patient contact with additional animal-derived biomatrix and fetal calf serum can be avoided. The initiation of an in vitro cultivation phase allows cell stabilization, quality control, and immediate availability of a characterized system without cryopreservation. The hypothesis of this paper is that with appropriate logistics and four-compartment bioreactor technology, cells from human liver transplant discards can serve the demand for cell-based therapy, including extracorporeal liver support.

Concept for modular extracorporeal liver support for the treatment of acute hepatic failure.

Acute liver failure has a poor prognosis. The introduction of liver transplantation as a therapeutic option reduced mortality to 20-40%.With the growing disparity between the number of organ donations and the number of patients waiting for liver transplantation, efforts have been made to optimize the allocation of organs and to design extracorporeal methods to support the failing liver. The modular extracorporeal liver support is a concept for the treatment of hepatic failure. The CellModule is a multicompartment bioreactor for extracorporeal liver support therapy. The construction provides efficient integrated oxygenator functions and decentralized mass transfer is effected by a woven array of capillary systems. The bioreactor promotes primary human liver cells to spontaneous neo-formation of liver sinusoidal structures in vitro. Small capillary subunits, in which interwoven membrane links represent the liver lobuli, are simultaneously perfused. The used cell mass of 400-600 g enabled the clinical application of a liver lobe equivalent hybrid organ. The DetoxModule enables albumin-dialysis for removal of albumin-bound toxins; a DialysisModule for continuous veno-venous hemofiltration can be added to the system, in the case of hepato-renal failure.

Development of a hybrid liver support system.

Hybrid liver systems are being developed as temporary extracorporeal liver support therapy. The overview given here emphasizes the development of both hepatocyte culture models for bioreactors and of systems for clinical therapy. In vitro studies demonstrate long term external metabolic function in isolated primary hepatocytes within bioreactors. These systems are capable of supporting essential liver functions. Animal experiments verify the possibility of upscaling bioreactors for clinical treatment. However, since there is no reliable animal model for investigating the treatment of acute liver failure, the promising results obtained from these studies have limited relevance to human beings. The small number of clinical studies performed thus far are not sufficient to enable any conclusions concerning improvements in the therapy of acute liver failure. Although important progress has been made in the development of these systems, multiple hepatocyte culture models and bioreactor constructions are being discussed in the literature, indicating competition in this field of medical research. For the use of hepatocytes and sinusoidal endothelial cells in coculture, a bioreactor has been designed. The construction is based on capillaries for hepatocyte aggregate immobilization. Four separate capillary membrane systems, each permitting a different function, are woven in order to create a three-dimensional network. Cells are perfused via independent capillary membrane compartments. Decentralized oxygen supply and carbon dioxide removal with low gradients is possible. The parallel use of identical units enables easy upscaling. Initial studies on the use of discarded organs that are unsuitable for transplantation as a source for primary human liver cells seem to be promising.

In vitro evaluation of a novel bioreactor based on an integral oxygenator and a spirally wound nonwoven polyester matrix for hepatocyte culture as small aggregates

Background/Aims: The development of custom-made bioreactors for use as a bioartificial liver (BAL) is considered to be one of the last challenges on the road to successful temporary extracorporeal liver support therapy. We devised a novel bioreactor (patent pending) which allows individual perfusion of high density cultured hepatocytes with low diffusional gradients, thereby more closely resembling the conditions in the intact liver lobuli. Methods: The bioreactor consists of a spirally wound nonwoven polyester matrix, i.e. a sheet-shaped, three-dimensional framework for hepatocyte immobilization and aggregation, and of integrated hydrophobic hollow-fiber membranes for decentralized oxygen supply and CO 2 removal. Medium (plasma in vivo) was perfused through the extrafiber space and therefore in direct hepatocyte contact. Various parameters were assessed over a period of 4 days including galactose elimination, urea synthesis, lidocaine elimination, lactate/pyruvate ratios, amino acid metabolism, pH, the last day being reserved exclusively for determination of protein secretion. Results: Microscopic examination of the hepatocytes revealed cytoarchitectural characteristics as found in vivo. The biochemical performance of the bioreactor remained stable over the investigated period. The urea synthesizing capacity of hepatocytes in the bioreactor was twice that of hepatocytes in monolayer cultures. Flow sensitive magnetic resonance imaging (MRI) revealed that the bioreactor construction ensured medium flow through all parts of the device irrespective of its size. Conclusions: The novel bioreactor showed encouraging efficiency. The device is easy to manufacture with scale-up to the liver mass required for possible short-term support of patients in hepatic failure.

Long-term liver cell cultures in bioreactors and possible application for liver support.

Hybrid artificial liver systems are being developed as a temporary extracorporeal liver support therapy. A short overview is given which emphasizes the development of hepatocyte culture models for bioreactors, subsequent in vitro studies, animal studies and the clinical application of hybrid liver support systems. An own bioreactor construction has been designed for the utilization of hepatocytes and sinusoidal endothelial cells. The reactor is based on capillaries for hepatocyte aggregate immobilization, coated with biomatrix. Four separate capillary membrane systems, each permitting a different function, are woven in order to create a three-dimensional network. Cells are perfused via independent capillary membrane compartments. Decentralized oxygen supply and carbon dioxide removal with low gradients is possible. There is a decentralized co-culture compartment for nonparenchymal liver cells. The use of identical parallel units to supply a few hepatocytes facilitates scale-up.

Use of hepatocyte cultures for liver support bioreactors.

Hybrid artificial liver systems are being developed as extracorporeal temporary liver support therapy. Here, an overview is given with emphasis on hepatocyte culture models for bioreactors, in vitro studies, animal studies and the clinical application of hybrid liver support systems. In vitro studies show long term external metabolic functions of primary isolated hepatocytes in bioreactors. These systems are capable of supporting essential liver functions. Animal experiments show the possibility of upscaling the bioreactors for clinical treatment. Since there is no reliable animal model for investigations on the treatment of acute liver failure, the promising results of these studies have limited relevance. The small number of clinical studies are not sufficient to give statements about a clinical improvement of therapy of acute liver failure. Although important progress has been made in the development of the systems, multiple different hepatocyte culture models and bioreactor constructions are discussed in the literature, indicating competition in this field of medical research.