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PubMedDate not supplied

Cellular control of membrane permeability. Implications for a bioartificial renal tubule.

A hemofiltrate processor, which consists of a cultured monolayer of renal epithelial cells on a permeable membrane, displayed transport functions that mimicked the renal tubule. Two cell lines, LLC-PK1 (a proximal tubule-like cell) and MDCK (a distal tubule-like cell), were cultured on microporous cellulose nitrate membranes and studied in a diffusion chamber. Dual-label tracer experiments revealed that inulin, glucose, and para-aminohippurate (PAH) moved across unseeded membranes with similar rates in either direction. Solute concentrations in both compartments reached equilibrium in less than 12 hours. MDCK cell-covered membranes were impermeable to all three solutes, as expected from a distal tubule-like cell. LLC-PK1 cell-covered membranes were impermeable to inulin and PAH, but demonstrated a net apical to basal glucose flux of 150 to 350 ng/cm2/min, depending on the conditions. This led within 72 hours to a zero glucose concentration in the compartment on the apical side of the cells, versus 4.6 mg/ml on the basal side. This glucose transport function was inhibited by 0.5 mmol/L phlorizin. Highest glucose flux was obtained using extracellular matrix as the cell attachment substrate on the membrane, suggesting the highest degree of cell differentiation. Based on estimates of the surface area of the normal kidney, the glucose reabsorption capacity of the LLC-PK1 cell line was about 20% that of the normal tubule. The absence of PAH secretion may have been due to the heterogeneity of cells derived from the proximal tubule. Different cell types, culture conditions, and attachment substrates may enhance the transport capacity of the bioartificial renal tubule.

Animals↗
PubMed2003

Maintenance of cold-preserved porcine hepatocyte function with UW solution and ascorbic acid-2 glucoside.

Normal human hepatocytes are an ideal source of liver-targeted cell therapies, such as hepatocyte transplantation and bioartificial livers, but availability of human donor livers for liver cell isolation is severely limited. To effectively utilize scarce donor organs for cell therapies, it is of extreme importance to establish an efficient isolation technique and an effective cold preservation solution for transportation of isolated cells. A lateral segment of the liver was surgically resected from pigs weighing 10 kg and a four-step collagenase and dispase digestion was conducted. Isolated hepatocytes were subjected to 8-h cold storage on ice. The following preservation solutions were tested: 1) University of Wisconsin (UW) solution, 2) UW with 100 microg/ml of ascorbic acid-2 glucoside (AA2G), 3) 100% fetal bovine serum (FBS), and 4) Dulbecco's modified Eagle's medium (DMEM) supplemented with 100% FBS. The mean viability of porcine hepatocytes was 95.5 +/- 2.5% when isolated in three independent experiments. Viability, plating efficiency, membrane stability, and ammonia metabolic capacity of cold-preserved hepatocytes were significantly better maintained by the use of UW solution. When AA2G (100 microg/ml) was combined with UW solution, such parameters were further improved. It was explained by inhibition of caspase-3 activation and retention of ATP at high levels of hepatocytes preserved with UW solution containing AA2G. The present work demonstrates that a combination of UW solution with AA2G (100 microg/ml) would be a useful cold preservation means for the development of cell therapies.

Adenosine↗
PubMed2003

Renal cell therapy is associated with dynamic and individualized responses in patients with acute renal failure.

BACKGROUND: Renal cell therapy in conjunction with continuous hemofiltration techniques may provide important cellular metabolic activities to patients with acute renal failure (ARF) and may thereby change the natural history of this disorder. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) human renal proximal tubule cells provides an opportunity to evaluate this form of therapy in patients with ARF in the intensive care unit. METHODS: Nine patients with ARF and multi-organ systems failure (MOSF) have been treated so far with a tissue-engineered kidney in an FDA-approved Phase I/II clinical study currently underway. Acute physiologic parameters and serum cytokine levels were assessed before, during and after treatment with a bioartificial kidney. RESULTS: Use of the RAD in this clinical setting demonstrates maintenance of cell viability and functionality. Cardiovascular stability appears to be maintained during RAD treatment. Human tubule cells in the RAD demonstrated differentiated metabolic and endocrinologic activity. Acute physiologic and plasma cytokine data demonstrate that renal cell therapy is associated with rapid and variable responses in patients with ARF and MOSF. CONCLUSION: The initial clinical experience with the bioartificial kidney and the RAD suggests that renal tubule cell therapy may provide a dynamic and individualized treatment program as assessed by acute physiologic and biochemical indices.

Acute Kidney Injury↗
PubMed1995

Analysis of glucose and insulin mass transfer in a novel 2-channel bioartificial pancreas.

This paper introduces a newly developed 2-channel bioartificial pancreas for the treatment of type I diabetes. In this device, insulin secreting cells (islets of Langerhans) are placed between 2 semi-permeable membranes that form a flat rectangular chamber. One side of the chamber is in contact with blood from an artery and the other side with blood from a vein. In addition to the diffusive transfer of glucose and insulin, the pressure difference between the artery and the vein creates an ultrafiltration flux through the islet chamber. This diffusion and ultrafiltration flux carries glucose from the artery to the islets, and insulin from the islets to the vein. The bioartificial pancreas has a compact geometry and the blood channels were designed to prevent blood clotting. The predicted insulin release in response to a square-wave and a triangular-wave glucose stimulation is given for the bioartificial pancreas of dimensions necessary for implantation in diabetic patients.

Artificial Organs↗
PubMed1996

Mass transfer limitations to the performance of membrane bioartificial liver support devices.

A number of membrane bioartificial devices have been proposed for liver support. However, their design does not yet ensure the successful treatment of acute liver insufficiency. In this paper, the Author reviews the limitations of the mass transport phenomena to the performance of a membrane bioartificial liver support device. First of all the requirements that an optimal membrane bioartificial liver support device has to meet for the therapy to be effective are presented. On these grounds, the issues that are still to be addressed to optimize the performance of such devices are discussed: particular attention is devoted to the mass transport phenomena in each region of the membrane bioartificial device. Finally, the main transport features of the membrane bioartificial liver support devices proposed so far are illustrated and examined.

Animals↗
PubMed2003

Bioartificial liver support for fulminant hepatic failure.

Mortality from fulminant hepatic failure (FHF) is high (50%-80%), although survivors have absolutely normal liver function. The only treatment option that is curative is liver transplantation. However, because of shortage of cadaveric organ donors and/or delay in their availability, only 10% of FHF patients ultimately receive a transplant. This has led to development of artificial liver support systems with an idea to bridge the time to transplantation and/or recovery from FHF. Initial support systems were based on the principles of hemodialysis, hemofiltration, plasma-exchange, and hemoperfusion through adsorbent media (e.g., charcoal). However, lack of clinical efficacy, problems of bioincompatibility and fear of loss of circulating hepatocyte-regeneration factors led to the search for alternate strategies. With the successful long-term propagation and culturing of human and pig hepatocytes, and the development of adequate biocompatible microcarrier modules, it is now possible to achieve sufficient density of hepatocytes per unit volume to develop bioartificial liver systems. These can be implanted transperitoneally but are subject to early destruction because of inadequate vascularization and immune attack from the host. Thus the major thrust is now to develop bioreactors, e.g., Extracorporeal Liver Assist Device (ELAD), Bioartificial Liver (BAL), etc. These contain human or pig hepatocytes implanted on hollow-fiber ultrafiltration cartridges. The patient's blood or plasma circulates through these bioreactors and after clearance of toxic compounds (via ultrafiltration and metabolism in hepatocytes) and addition of synthesized products, is returned to the patient. This article reviews the genesis, the pros and cons, and the clinical experience of BAL support for FHF.

Animals↗
PubMedDate not supplied

[Hybrid (bioartificial) systems for liver support. History and current developments].

Attempts to develop liver support systems for the treatment of acute liver failure patients have ranged in the past, from the use of hemodialysis, or plasma exchange, or activated charcoal particles and synthetic resins, as well as the use of bioreactors loaded with liver tissue. However, no system demonstrated a significant improvement of patient survival, nor has achieved a wide clinical use. Liver transplantation remains the only treatment for severe hepatic failure that can improve patient survival. On the other hands, the chronic scarcity of organs for transplantation, leads to an urgent necessity of liver support systems. In this paper, we reviewed the historical experience and current status of artificial liver support systems, with particular emphasis on the so-called hybrid or bioartificial liver, in which to the traditional artificial components, such as selective membranes, charcoal particles and resins, isolated hepatocytes are used.

Animals↗
PubMed1997

Semipermeable hollow fiber membranes in hepatocyte bioreactors: a prerequisite for a successful bioartificial liver?

Recent studies have shown that liver support systems based on viable hepatocytes can prolong life in animal models of acute liver failure. Now the time has come to elucidate the design characteristics that are essential to construct an efficient bioreactor. The gold standard remains the intact liver. Despite the very high cell density in this organ, individual cell perfusion is guaranteed resulting in low diffusional gradients which are essential for optimal mass transfer. These conditions are not met in bioreactors based on hollow fiber membranes. Moreover, the semipermeable membranes can foul and act as a diffusional barrier between the hepatocytes and the blood or plasma of the recipient. We devised a novel bioreactor for use as a bioartificial liver that does not include hollow fiber membranes for blood or plasma perfusion. The device is based on an integral oxygenator and a nonwoven polyester matrix material for hepatocyte culture as small aggregates. The efficacy of this original design was tested in rats with liver ischemia. Preliminary results show statistically significantly improved survival; life was prolonged 100% compared to the control experiments.

Animals↗
PubMed2004

Evaluation of effect of hybrid bioartificial liver using end-stage liver disease model.

AIM: To study the role of hybrid bioartificial liver (HBL) in clearing proinflammatory cytokines and endotoxin in patients with acute and sub-acute liver failure and the effects of HBL on systemic inflammatory syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). METHODS: Five cases with severe liver failure (3 acute and 2 subacute) were treated with HBL. The clinical signs and symptoms, total bilirubin (TBIL), serum ammonia, endotoxin TNF-alpha, IL-6 and prothrombin activity (PTA),cholinesterase (CHE) were recorded before, during and after treatment. The end-stage liver disease (MELD) was used for the study. RESULTS: Two patients were bridged for spontaneous recovery and 1 patient was bridged for OLT successfully. Another 2 patients died on d 8 and d 21. The spontaneous recovery rate was 30.0%. PTA and CHE in all patients were significantly increased (P<0.01), while the serum TBIL, endotoxin, TNF-alpha, IL-6 were decreased. MELD score (mean 43.6) predicted 100% deaths within 3 mo before treatment with HBL. After treatment with HBL, four out of 5 patients had decreased MELD scores (mean 36.6). The MELD score predicted 66% mortalities. CONCLUSION: The proinflammatory cytokines (TNFalpha, IL-6 and endotoxin)can be significantly removed by hybrid bioartificial liver and HBL appears to be effective in blocking SIRS and MODS in patients with acute and sub-acute liver failure. MELD is a reliable measure for predicting short-term mortality risk in patients with end-stage liver disease. The prognostic result also corresponds to clinical outcome.

Adult↗
PubMed2002

Bioengineering of liver assist devices.

Over 30 000 patients die annually in the United States from liver failure. In fulminant hepatic failure, a clinical syndrome associated with high mortality, orthotopic liver transplantation is the primary therapeutic option for patients not responding to supportive therapy. However, the persistent scarcity of donor organs has limited this therapeutic modality, resulting in a continued increase in the number of patients who die waiting for a donor liver. An extracorporeal bioartificial liver device could provide vital support to a liver failure patient until a donor liver was available or until the patient's own liver regenerated. Although it is unclear which liver-specific functions must be provided by such a device to be effective, a constant challenge has been to obtain stable, well-differentiated, and normally functioning hepatocytes that can be cultured at high cell densities. Many of the devices currently undergoing clinical trials are limited by designs which are prone to substrate limitations, resulting in compromised hepatocyte function. In devices that avoid substrate limitations, hepatocyte functions can be optimized, thereby leading to increased device efficiency. In this overview, the authors describe the critical issues involved in bioartificial liver development and discuss their experiences in hepatocyte culture optimization within the context of a microchannel, flat-plate bioartificial liver device with an internal membrane oxygenator.

Animals↗
PubMed1995

General surgery.

Ambulatory surgery now accounts for approximately 50% of all surgery in the United States. Minimally invasive procedures have entered the vascular arena with transfemoral endovascular graft replacement. A bioartificial liver support system was tested in seven patients with the use of porcine hepatocytes.

General Surgery↗
PubMed2003

Porcine endogenous retroviruses: no infection in patients treated with a bioreactor based on porcine liver cells.

BACKGROUND: Acute liver failure (ALF) remains a disease with high mortality. Bioartificial liver support systems, which combine living cells of the liver in an extracorporeal circuit, have been successfully used in first clinical trials. The shortage of human organs to be used for bioreactors and the lack of safe and effective human liver cell lines have resulted in pigs becoming an important hepatic cell source. However, using these cells may be associated with the risk of transmission of porcine endogenous retroviruses (PERVs). PERVs are present in the genome of all pigs and are able to infect human cells in vitro. However, it remains unclear whether PERVs infect transplant recipients in vivo and, if so, whether they are pathogenic. OBJECTIVES: To detect antibodies directed against specific epitopes from PERVs in seven individuals who were treated with porcine liver cell bioreactor therapy prior to liver transplantation. METHODS: Sera from seven patients treated with a hybrid liver support system based on porcine liver cells for ALF who survived the treatment and were discharged from hospital were investigated for antibodies against PERV. For this in addition to methods already reported (Xenotransplantation (2001) 125), new immunological detection methods were developed. RESULTS: PERV-specific antibodies were found in none of the patients using Western blot assays based on purified virus or recombinant viral core and envelope proteins or ELISA based on synthetic diagnostic peptides. CONCLUSION: The assays used are specific and sensitive, and correlated in their diagnostic value. The data indicate that no PERV infection had occurred in none of the patients treated with the CellModule bioreactor containing porcine cells.

Adult↗