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At least 343 records · Page 19Linked to original sources
PubMed2001

Novel cell immobilization method utilizing centrifugal force to achieve high-density hepatocyte culture in porous scaffold.

Cell seeding is one of the key procedures in the construction of tissue-engineered organs. In our previous efforts to create a bioartificial liver, high-density cultures of hepatocytes (>1 x 10(7) cells/1 cm(3)-substrate) and long-term maintenance of metabolic function were achieved with a packed-bed reactor utilizing porous poly(vinyl formal) (PVF) resin as a scaffold. However, a low seeding efficiency of about 30% remains a major obstacle to the scaleup of the reactor. In the present study, a new cell seeding method, centrifugal cell immobilization (CCI), which is based on alternating centrifugation and resuspension, was used to achieve high-density seeding and improve the seeding efficiency. Using the CCI method, the maximum density of the immobilized hepatocytes reached 3.8 x 10(7) cells/1 cm(3)-PVF, and the seeding efficiency was improved to about 43% after a relatively short immobilization process (about 15 min). Moreover, further improvement of the seeding efficiency was obtained by serial immobilization procedures. Thus, we concluded that this method is useful and effective for seeding cells into 3-dimensional scaffolds.

Animals↗
PubMed2004

Artificial liver support systems.

Though artificial support systems for kidney failure have been widely available for the past several decades, it is only recently that they have become a promising treatment modality for liver failure. The various liver support systems include conventional dialysis, charcoal hemoperfusion, high volume plasma exchange, liver dialysis using sorbent technology, molecular readsorption recirculating system using albumin as the dialysate, bioartificial livers, extracorporeal liver assist device and extracorporeal organ perfusion. They are mainly used as a bridge to liver transplantation and occasionally in acute liver failure till the liver regenerates. The various methods of extracorporeal liver support that are available at present are assessed and those that appear to be promising are described.

Dialysis↗
PubMed2005

Bioartificial liver systems: current status and future perspective.

Because the liver is a multifunctional and a vital organ for survival, the management of acute liver failure requires the support of a huge number of metabolic functions performed by the organ. Many early detoxification-based artificial liver techniques failed to treat the patients owing to the inadequate support of the many essential hepatic functions. For this reason, a bioartificial liver (BAL) comprising of viable hepatocytes on a mechanical support is believed to more likely provide these essential functions than a purely mechanical device. From 1990, nine clinical studies of various BAL systems have been reported, most of which utilize a hollow fiber technology, and a much larger number of various BAL systems have been suggested to show an enhanced performance. Safety issues such as immunological reactions, zoonosis and tumorgenicity have been successfully addressed for regulatory approval, but a recent report from a large-scale, randomized, and controlled phase III trial of a leading BAL system (HepatAssist) failed to meet our expectation of efficacy in terms of the overall survival rate. In this paper, we review the current BAL systems actively studied and discuss critical issues such as the hepatocyte bioreactor configuration and the hepatocyte source. On the basis of the insights gained from previously developed BAL systems and the rapid progress in stem cell technology, the short-term and long-term future perspectives of BAL systems are suggested.

Animals↗
PubMed2000

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.

Acetaminophen↗
PubMed2003

Efficacy of an extracorporeal flat-plate bioartificial liver in treating fulminant hepatic failure.

BACKGROUND: Fulminant hepatic failure is associated with a high mortality rate. Orthotopic liver transplantation is the only established treatment for patients who do not respond to medical management. A major limitation of this treatment is a shortage of donor organs, resulting in many patients dying while waiting for a transplant. An extracorporeal bioartificial liver (BAL) has the potential to provide temporary support for patients with fulminant hepatic failure (FHF) and for patients awaiting orthotopic liver transplantation. We developed a flat-plate BAL with an internal membrane oxygenator in which porcine hepatocytes were cultured as a monolayer. MATERIALS AND METHODS: Twenty-four hours after cannulation of the left carotid artery and right jugular vein, FHF was induced in rats by administering 2 intraperitoneal injections of D-galactosamine (GalN) (1.2 g/kg) at a 12-h interval. The rats were connected to a BAL device 24 h after the first GalN injection and underwent extracorporeal perfusion for a duration of 10 h. Liver histology, liver-specific markers, and animal survival up to 168 h (7 days) were examined. RESULTS: Histologically, liver damage was reduced in the animal group treated with the hepatocyte-based BAL device. Significant reductions occurred in the plasma ammonia levels and prothrombin times in the group treated with the seeded BAL device. Animal survival in the group treated with the seeded BAL device was significantly higher (50.0%) than in the control animal group treated with an unseeded BAL device (11.1%). CONCLUSIONS: This flat-plate BAL with an internal membrane oxygenator and cultured porcine hepatocytes has yielded encouraging results in the treatment of rats with GalN-induced FHF.

Animals↗
PubMed2002

Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients.

Orthotopic liver transplantation (OLT) is the only effective therapeutic modality in severe acute hepatic failure (AHF). The scarcity of organs for transplantation leads to an urgent necessity for temporary liver support treatments in AHF patients. A hepatocyte-based bioartificial liver (BAL) is under investigation with the main purpose to serve as bridging treatment until a liver becomes available for OLT, or to promote spontaneous liver regeneration. We developed a novel radial-flow bioreactor (RFB) for three-dimensional, high-density hepatocyte culture and an integrated pumping apparatus in which, after plasmapheresis, the patient's plasma is recirculated through the hepatocyte-filled RFB. Two hundred thirty grams of freshly isolated porcine hepatocytes were loaded into the RFB for clinical liver support treatment. The BAL system was used 8 times in supporting 7 AHF patients in grade III-IV coma, all waiting for an urgent OLT Three patients with no history of previous liver diseases were affected by fulminant hepatic failure (FHF) due to hepatitis B virus, 3 by primary non-function (PNF) of the transplanted liver, and one by AHF due to previous abdominal trauma and liver surgery. Six out of 7 patients underwent OLT following BAL treatment(s), which lasted 6-24 hours. All patients tolerated the procedures well, as shown by an improvement in the level of encephalopathy, a decrease in serum ammonia, transaminases and an amelioration of the prothrombin time, with full neurological recovery after OLT Our initial clinical experience confirms the safety of this BAL configuration and suggests its clinical efficacy as a temporary liver support system in AHF patients.

Adolescent↗
PubMed2002

[Isolation and culture of pig hepatocyte in large scale for the application of bioartificial liver system].

BACKGROUND/AIMS: Acute hepatic failure is a serious problem. Its mortality reaches up to 80%. Only liver transplantation has been accepted as a definite treatment for patients with hepatic failure but shortage of donor organs is the main obstacle of this approach. A possible solution to this problem is a bioartificial liver system, perfusion of patients blood to isolated hepatocyte. In this study, we performed the isolation and culture of pig hepatocyte in large scale for the application of bioartificial liver system. METHODS: Hepatocyte isolation was performed by two-step collagenase method via portal vein perfusion in 10 kg female pigs. After that, we compared the functional differences of the spheroid culture to the monolayer culture of hepatocyte. The viability and the function of hepatocyte were assessed using trypan-blue exclusion test and the measurement of the rate of ureagenesis and ammonia removal. RESULTS: The average viability and yield of hepatocyte were 86.8 +/- 8.0 % and 7.8 +/- 5.4 X 10(9), respectively. The spheroid culture was superior to the monolayer culture in functional aspect of hepatocyte, and their differences, especially for ammonia removal, were more apparent in parallel with culture time. CONCLUSIONS: For hepatocyte isolation, we obtained sufficient viability and yield of hepatocyte for clinical usage of bioartificial liver system. The function of hepatocyte seems to be better in the spheroid culture than in the monolayer culture. Further studies are needed for application of bioartificial liver system in clinical setting.

Animals↗
PubMed2001

Contemporary immunosuppression in renal transplantation.

Over the past 3 decades, renal allograft survival has improved significantly as a result of the development of powerful immunosuppressive agents. Nevertheless, the overall half-life of renal allografts has increased marginally during that time period, owing to drug-related nephrotoxicity and chronic rejection. New immunosuppressive agents are being evaluated because of the need for a reduction in the dose of nephrotoxic calcineurin inhibitors and corticosteroids. Additional agents have demonstrated the ability to retard the onset of chronic rejection in preclinical transplant models. In concert with these efforts, approaches are in development to alleviate the ever increasing shortage of donor organs, including the as yet unrealized goals of successful and practical xenotransplantation and the bioartificial kidney. Further identification and development of novel agents that target the specific components of the allograft response will provide the key to the achievement of donor-specific tolerance, the "Holy Grail" of solid organ transplantation.

Graft Rejection↗
PubMed1998

Does hepatocyte transplantation in a chemically induced acute hepatic failure make sense?

PURPOSE: Acute hepatic insufficiency (AHF) is one of the major challenges of intensive care medicine. Liver transplantation is the current solution to unsuccessful medical management. Owing to the lack of organ donors, other methods such as hepatocyte transplantation (HcTX) and bioartificial livers need to be explored. The aim of our experimental study is to evaluate the effect of hepatocyte transplantation on the survival in AHF animals intoxicated with D-Galactosamine (D-Gal). METHODS: The first step consists of the determination of the dose of D-Gal needed to induce at least 80% mortality between 48 and 72 hours. Two groups of a single strain of male Wistar rats are then compared, one being intoxicated with D-Gal (control group), the other receiving and HcTX in the splenic parenchyma 48 hours after intoxication. RESULTS: The required dose to achieve AHF is 3 gr/kg body weight (Gr. 0). Survival rates are as follow: Gr. 1: D0: 93%; from D1 to D28: 13%. Gr. 2: D0: 80%; D1 and D2: 33%; D3: 20%; D4: 13%, from D5 to D28: 6%. (D0 = Day of transplantation). Liver enzymes show a peak of deterioration at 24 hours, then return to normal values in both groups. Histological examination of those animals still alive and sacrificed on day 28 demonstrates a restitutio ad integrum of hepatic structure. In Group 2, it is possible to observe remaining living hepatocytes in the splenic parenchyma. CONCLUSIONS: When HcTX is performed 48 hours after D-Gal intoxication, i.e., when the animals begin to develop AHF symptoms, animal survival only significantly improves between days 0 and 3. Unlike other trials, we cannot demonstrate an improvement in long-term survival. Thus, according to this particular experimental model, HcTX is not an alternative for the treatment of AHF.

Animals↗
PubMed1999

Overview of extracorporeal liver support systems and clinical results.

Patients with acute liver failure (ALF) continue to have an almost 50% mortality rate despite improvements associated with the use of orthotopic liver transplantation (OLT). Numerous ex vivo methods have been developed in attempts to improve patient survival. These methods can be divided into three groups: detoxification (e.g., dialysis, charcoal adsorption, plasma exchange), which only provides excretory function; ex vivo liver perfusion (e.g., whole organ or tissue perfusion), which provides some metabolic function; and bioartificial or cell-based systems, which combine elements of the first two methods. Clinical trials have shown minimal efficacy of the various detoxification methods in terms of ALF patient survival, while the relative success of OLT has shown the importance of providing metabolic as well as excretory functions. Attempts to provide those additional functions with ex vivo tissue perfusion have been fraught with complications such as clotting and acute tissue rejection, leading to the conceptual development of cell-based bioreactor systems. A number of these bioartificial systems have been clinically evaluated, and the preliminary patient survival rates have encouraged further work in this area.

Animals↗
PubMed1997

Porcine islet xenotransplantation utilizing a vascularized bioartificial pancreas.

Successful pancreas/islet transplantation restores normal glucose metabolism in patients with insulin dependent diabetes mellitus (IDDM) but requires chronic immunosuppression which is associated with morbidity and mortality. Immune exclusion devices containing pancreatic islets (bioartificial pancreas) are designed to provide glycemic control without immunosuppression. The immune exclusion is achieved by separating islets from the host by semipermeable membranes. Small molecules such as glucose, insulin and nutrients pass through, whereas immune lymphocytes and immunoglobulins are excluded by the membrane and unable to cause destruction of the islets. Use of xenogeneic islets (i.e., porcine islets) in the device also circumvents the shortage of human donor organs. This report provides a brief summary of our experience with vascularized bioartificial pancreas (VBAP) containing allogeneic and xenogeneic islets for treatment of experimental diabetes in dogs and describes our plans for a clinical trial of the VBAP in patients with IDDM.

Animals↗
PubMedDate not supplied

Establishment of highly differentiated immortalized human hepatocyte line with simian virus 40 large tumor antigen for liver based cell therapy.

Acute liver failure and metabolic liver disorder animal models have demonstrated that hepatocytes transplanted into the liver or spleen survive and participate in the liver repopulation process, and recent studies have documented the usefulness of hepatocyte transplantation in humans. However, despite the promising cell therapy, there are still many restrictions, such as the shortage of donor human livers and the limited lifespan and the functional insufficiency of primary cultured hepatocytes. The immortalized and highly differentiated human hepatocyte could provide an unlimited supply of transplantable cells. In this study, we established an efficient and highly differentiated immortalized human hepatocyte line for bioartificial liver and hepatocyte transplantation research. Hepatocytes isolated from the liver of a 25 year old, brain dead male were transfected with pcDNA3.1 (-) recombinant plasmid containing the genes encoding simian virus 40 (SV40) large tumor antigen. One of the hepatocyte clones, HepLL, displayed highly differentiated liver functions with immortalized characteristics and was selected with a 700-300 microg/ml of G418 technique in 42 days. To characterize this immortalized cell line for cell therapy in the near future, HepLL cells were studied with immunohistochemistry, reverse transcription-polymerase chain reactions, immunoblotting, and tumorigenicity tests. The results revealed that HepLL cells displayed morphologic characteristics of liver parenchymal cells, secreted albumin, synthesized urea and glycogen, and expressed liver enriched functional markers, but there were no tumorigenic qualities after transplantation into severe combined immunodeficiency mice. Thus this immortalized human hepatocyte line is expected to be a useful tool for studying the functions of differentiated human hepatocyte and a promising strategy to resolve the shortages of donor organs and the limits of primary human hepatocyte for transplantation and bioartificial liver support systems.

Albumins↗
PubMed2003

Isolation of human hepatocytes from livers rejected for liver transplantation on a national basis: results of a 2-year experience.

The offer of liver transplantation to many patients affected by liver failure is limited by organ shortage. Clinical application of human-based liver cell therapies, such as bioartificial liver and hepatocyte transplantation, might support liver transplantation, allowing more patients to be treated and decreasing mortality in the waiting list. The development of a standardized method of hepatocyte isolation is a mainstay for large-scale application of liver cell therapy. The aim of this study is to analyze retrospectively a 2-year experience of human hepatocyte isolation from livers rejected from transplantation at organ harvesting, performed on a national basis in Italy. All the livers judged unsuitable for transplantation were considered for hepatocyte isolation. Macrosteatosis greater than 60% was the most common reason of refusal, followed by nonviral cirrhosis. Fifty-four organs were used. Human hepatocyte isolation resulted in more that 7 million liver cells/g of tissue digested with 73% +/- 14% viability. Steatotic organs gave better results in terms of cell yield than cirrhotic livers. Isolated hepatocytes were able to perform specific liver functions, and evidence of factor IX and albumin messenger RNA (mRNA) production was reported when cells were plated in culture. Modifications of the traditional method of hepatocyte isolation, aimed at reducing ischemia-reperfusion damage and improving post-isolation cell conditions, showed improvements in post-isolation viability. In conclusion, we show that it is possible to use the vast majority of livers not suitable for transplantation on a national basis for human hepatocyte isolation, obtaining a large amount of viable functioning human hepatocytes that might be used for cell transplantation and therapy.

Cell Separation↗
PubMed2000

Bioartificial kidney for full renal replacement therapy.

The rapid understanding of the cellular and molecular basis of organ function and disease processes will be translated in the next millennium into new therapeutic approaches to a wide range of clinical disorders, including acute and chronic renal failure. Central to these new therapies are the developing fields of gene therapy, cell therapy, and tissue engineering. These new technologies are based on the ability to expand stem or progenitor cells in tissue culture to perform differentiated tasks and to introduce these cells into the patient either in extracorporeal circuits or as implantable constructs. Cell therapy devices are currently being developed to replace the filtrative, metabolic, and endocrinologic functions of the kidney lost in both acute and chronic renal failure. This article summarizes the current state of device development for a renal tubule assist device, a bioartificial hemofilter, and a regulatable erythropoietin cell therapy device. These individual devices have the promise to be combined to produce a wearable or implantable bioartificial kidney for full renal replacement therapy. These new approaches may result in therapeutic modalities that significantly diminish the morbidity and mortality in patients with acute renal failure or end-stage renal disease.

Animals↗
PubMed2005

Galactose-carrying polymers as extracellular matrices for liver tissue engineering.

Extracellular matrix (ECM) plays important roles in tissue engineering because cellular growth and differentiation, in the two-dimensional cell culture as well as in the three-dimensional space of the developing organism, require ECM with which the cells can interact. Especially, the bioartificial liver-assist device or regeneration of the liver-tissue substitutes for liver tissue engineering requires a suitable ECM for hepatocyte culture because hepatocytes are anchorage-dependent cells and are highly sensitive to the ECM milieu for the maintenance of their viability and differentiated functions. Galactose-carrying synthetic ECMs derived from synthetic polymers and natural polymers bind hepatocytes through a receptor-mediated mechanism, resulting in enhanced hepatocyte functions. Attachment and functions of hepatocytes were affected by physico-chemical properties including ECM geometry as well as the type, density and orientation of galactose. Also, cellular environment, medium composition and dynamic culture system influenced liver-specific functions of hepatocytes beside ECM.

Animals↗
PubMedDate not supplied

Ice formation in isolated human hepatocytes and human liver tissue.

Cryopreservation of isolated cells and tissue slices of human liver is required to furnish extracorporeal bioartificial liver devices with a ready supply of hepatocytes, and to create in vitro drug metabolism and toxicity models. Although both the bioartificial liver and many current biotoxicity models are based on reconstructing organ functions from single isolated hepatocytes, tissue slices offer an in vitro system that may more closely resemble the in vivo situation of the cells because of cell-cell and cell-extracellular matrix interactions. However, successful cryopreservation of both cellular and tissue level systems requires an increased understanding of the fundamental mechanisms involved in the response of the liver and its cells to freezing stress. This study investigates the biophysical mechanisms of water transport and intracellular ice formation during freezing in both isolated human hepatocytes and whole liver tissue. The effects of cooling rate on individual cells were measured using a cryomicroscope. Biophysical parameters governing water transport (Lpg = 2.8 microns/min-atm and ELp = 79 kcal/mole) and intracellular heterogeneous ice nucleation (omega het = 1.08 x 10(9) m-2s-1 and kappa het = 1.04 x 10(9) K5) were determined. These parameters were then incorporated into a theoretical Krogh cylinder model developed to simulate water transport and ice formation in intact liver tissue. Model simulations indicated that the cellular compartment of the Krogh model maintained more water than isolated cells under the same freezing conditions. As a result, intracellular ice nucleation occurred at lower cooling rates in the Krogh model than in isolated cells. Furthermore, very rapid cooling rates (1000 degrees C/min) showed a depression of heterogeneous nucleation and a shift toward homogeneous nucleation. The results of this study are in qualitative agreement with the findings of a previous experimental study of the response to freezing of intact human liver.

Cell Communication↗