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PubMed1998

[Use of normal human hepatocytes in a hybrid organ system].

Using the bioreactor model developed by J. Gerlach, we examined the potential of normal human hepatocytes for application in bioartificial liver devices. From normal human donor livers 1.5 x 10(8) hepatocytes were isolated. Hepatocytes were perfused in a woven multi-compartment capillary system in serum-free culture medium containing ammoniachloride over a period of 2 weeks. These cells demonstrated a well differentiated ultrastructure with formation of junctional complexes and bile canaliculi between adjacent cells. During reactor run, a constant albumin synthesis with levels above 11 mg/ml and maintenance of urea production and lignocaine metabolism (MEGX-test) were detected. These initial results indicate that normal human hepatocytes express typical morphology and ultrastructure and are able to keep differentiated functions in suitable perfusion models. Combination of the distinct human liver cell populations might enable promotion of further specific functions (clotting factors) and induction of liver cell proliferation.

Cell Survival↗
PubMed1997

Prospects for a bioartificial kidney.

The developing technologies of cell therapy and tissue engineering may, in the next two decades, provide alternatives to current methods of renal replacement therapy. First, suitable organs for xenotransplantation from animals to humans may be developed, or second, as described in this report, application of tissue engineering may result in development of a range of devices to aid care of patients with renal failure. The simplest and easiest achievable devices could replace a specific aspect of renal function, such as an implantable device to produce erythropoietin. Both a bioartificial hemofilter and a renal tubule device may be developed. Ultimately this work may result in an implantable bioartificial kidney.

Animals↗
PubMed1996

Neurological and psychological sequelae in transplant recipients after bridging with the bioartificial liver.

Prior to the advent of the bioartificial liver there was little hope to offer the families of comatose patients unless an organ could be found immediately, or xenografting was attempted. The elevated intracranial pressure that develops is more life-threatening than prolonged bleeding times. Over a 2-year period, nine patients were bridged to transplantation using the BAL to keep them neurologically intact prior to surgery. The goal is to maintain the ICP less than 20 mmHg in adults and between 10 and 15 mmHg in children, so that the cerebral perfusion pressure remains above 50 mmHg. The first patients, a 35-year-old woman, arrived in stage II coma. The second patient, a 10-year-old boy in stage IV coma, had decerebrate posturing and anisocoria. The third patient, an 18-year-old girl, had an ICP of 28 mmHg with decerebrate posturing and disconjugate gaze. The fourth patient, a 34-year-old male, had an ICP of > 38 mmHg. The fifth patient, a 24-year-old male, had fixed dilated pupils. The sixth patient, a 50-year-old woman, had readings to 52 mmHg. The seventh patient, a 48-year-old male, had postoperative numbness in his fingertips that remitted. The eighth patient, a 31-year-old female, had decerebrate posturing and an ICP of 64 mmHg transiently. The ninth patient, a 52-year-old woman, had decerebrate posturing with a peak ICP of 50 mmHg. All nine patients survived.

Adolescent↗
PubMedDate not supplied

[Clinical experience in treatment of Amanita phalloides poisoning].

BACKGROUND: The management of patients suffering from Amanita Phalloides poisoning (APP) may be very challenging. Furthermore, the treatment often includes depurative techniques and Orthotopic Liver Transplantation (OLTx) must be started timely to be effective. We report our experience in severe APP treatment. PATIENTS AND METHODS: We retrospectively evaluated five patients suffering from APP and hospitalized within our Intensive Care Unit, assessing different kinds of treatment: two different dialytic techniques, namely Continuous Renal Replacement Therapy (CRRT), and Charcoal Plasmaperfusion (CRRT+CPP), and OLTx. RESULTS: Two patients treated with CRRT+CPP, one patient treated with CRRT only and the patient treated by OLTx recovered. One patient, undergoing CRRT only, died after 14 days of treatment. During the CRRT+CPP treatment no relevant complication occurred. The transplanted patient received dialytic treatment for 7 days after transplantation in order to support renal function impairment and to enhance liver function recovery. CONCLUSIONS: Clinical management of patients suffering from APP requires multi-disciplinary intervention; therefore it is recommended to treat these patients in an Intensive Care Unit with specialized nephrological and toxicological consultancy, in collaboration with an organ transplantation team. In the near future we wish to associate dialytic treatment with a bioartificial liver device, which could bridge the time gap to liver transplantation.

Acute Disease↗
PubMed2003

Bioartificial liver support. Review and personal experience.

End-stage liver disease is treated successfully by liver transplantation. In spite of the recent advances in transplantation techniques, donor organ shortage remains a serious problem. Conditions such as fulminant hepatic failure are still burdened by a high mortality rate. This has prompted the design of an extracorporeal liver assist device, to "bridge" patients over until they either recover or receive a liver transplant. In these devices, various types of liver cells are inserted and different device designs have been proposed. The paper will review different models of bioartificial liver and will describe ongoing clinical trials. At the end we will report our experimental experience with a newly designed bioartificial liver, evaluating its beneficial effect on acute liver failure.

Bioreactors↗
PubMed1996

[Liver transplantation. Current aspects].

The development of liver transplantation has led to technical refinements such as liver graft reduction or splitting for transplantation in two recipients, the use of living related donors, and the temporary orthotopic transplantation of auxiliary liver grafts. Regarding immuno-suppression, new drugs are currently under evaluation, such as tacrolimus (FK 506) which could be effective on some severe rejections. On the other hand, the indications of liver transplantation have been revisited according to clinical results. In France, the increasing development of organ and tissue transplantation has led to the creation of the Etablissement Français des Greffes, which has the following missions: managing the waiting lists, supporting organ donation, ensuring sanitary safety, and evaluating transplantation activities. Future alternatives to allogenic liver transplantation are mainly represented by xenografting with monkey or pig livers, hepatic assistance and bioartificial liver, and gene therapy.

Genetic Therapy↗
PubMed2004

Controlling the cellular organization of tissue-engineered cardiac constructs.

There are currently no effective treatments to restore the cardiac muscle lost because of ischemia for the millions of people who suffer heart attacks annually. Cell therapy procedures have emerged as novel therapeutic strategies for treatment of heart failure after myocardial infarction but have been hampered by the lack of adequate cell sources of cardiomyocytes and by the inability to integrate cell grafts into cardiac muscle. A cardiac patch composed of organized and functional cardiomyocytes could drastically enhance the efficacy of this important clinical approach. Here, we report our ongoing efforts to develop a bioartificial cardiac muscle capable of synchronized multidirectional contraction within a three-dimensional hydrogel scaffold. Neonatal rat cardiomyocytes, smooth muscle cells, and reconstituted polymeric collagen enriched with growth factors and hormones are used. A bioreactor system is used to impart precise strains onto the developing tissue constructs in vitro. The results demonstrate that cell-mediated collagen compaction is significantly enhanced by strain preconditioning, resulting in a more favorable cellular organization. Furthermore, the results demonstrate that strain stimulation guides cellular orientation in the direction of applied strain (i.e., in the circumferential direction). Hence, we demonstrate the importance of mechanical preconditioning as a means of promoting the in vitro development of engineered cardiac muscle for use with myocardial regeneration therapies.

Animals↗
PubMed2004

[Bioartificial liver support system: state of the art].

The temporary function replacement and intensive support play a pivotal role in the treatment of patients with acute or chronic end-stage organ failure. The hemodialysis and peritoneal dialysis have become routine techniques in the management of acute or chronic renal failure. But for the complexity of hepatic function, e.g. metabolism, biosynthesis and biotransformation for endogenous or exogenous substrates, the simulation or partial replacement of hepatic function is a great dream of bionic technologists. With the development of cell biology and biomedical material, the combination of biomaterial and the hepatocyte cultured ex vivo could provide a range of human liver-specific functions. The combination of biomaterial and viable cell was called hybrid or bioartificial liver support system (BALSS). It is a chimera of biomaterials and hepatocytes. The bionic technologists study the cell and its culture in vitro, which is the main component of BASLL. Many types of BALSS were translated into the early clinical stage. In this overview, we review the hepatocyte culture and the design of different bioreactors. It includes the immune obstacles in xeno-hemoperfusion and how to assess pre-clinical and clinical effectiveness.

Bioreactors↗
PubMed2002

Critical issues in bioartificial liver development.

End-stage liver disease accounts for over 30,000 deaths annually in the United States. Orthotopic liver transplantation is the only clinically proven treatment for patients with end-stage liver failure. A limitation of this therapy is a shortage of donor organs available. This donor organ shortage is exacerbated by the fact that the number of patients listed for transplantation has continued to increase. As a result, there has been a continuing increase in the number of patients who die waiting for a donor liver. Extracorporeal bioartificial liver devices consisting of viable hepatocytes have the potential to provide temporary support for patients with fulminant hepatic failure, thereby serving as a "bridge" to transplantation. In some patients, this temporary support would allow the native liver to regenerate function, eliminating the need for transplantation and the resulting life-long immunosuppressive therapy, all of which translates into a cost savings to the health care system. Although the bioartificial liver device is a promising technology for the treatment of liver failure, significant technical challenges remain in order to develop systems with sufficient processing capacity and of manageable size. An overview of the critical issues in the development of bioartificial liver devices is discussed.

Animals↗
PubMed2000

Immunologic considerations for therapeutic strategies utilizing allogeneic hepatocytes: hepatocyte-expressed membrane-bound major histocompatibility complex class I antigen sensitizes while soluble antigen suppresses the immune response in rats.

Understanding the immunologic effects of hepatocytes is critical because of the potential to use these cells for bioartificial livers, as a vehicle for gene transfer, and as a means to induce donor-specific immunosuppression in organ transplantation. However, this understanding is complicated by the fact that hepatocytes express membrane-bound and soluble forms of major histocompatibility complex (MHC) class I antigen, each with the potential to induce different immune responses. In the present study we first determined the immunologic effect of normal donor-derived hepatocytes in a rat heart transplant model. We then used ex vivo hepatocyte gene transfer to examine the immunologic effects of different forms of hepatocyte-expressed MHC class I antigen. Results showed that intrasplenic injection of purified, donor-strain-specific hepatocytes into recipients primes alloimmunity, as evidenced by acceleration of heart allograft rejection. Interestingly, injection of autologous hepatocytes transfected ex vivo with DNA encoding only membrane-bound donor MHC class I antigen (RT1.A(a)) also accelerated allograft rejection. However, hepatocytes transfected to express only secreted donor MHC antigen prolonged transplant survival. Limiting-dilution analysis of lymphocytes from animals treated with hepatocytes producing only secreted alloantigen showed an antigen-specific reduction in cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) precursors. Further analysis of CTL populations by flow cytometry revealed a relatively high percentage of nonviable cells, implying that soluble antigen promotes allospecific CTL death. In summary, this study suggests that hepatocyte-expressed MHC class I molecules have opposing immunologic effects, with the membrane-bound antigen inducing immunologic sensitization, and the soluble antigen promoting donor-specific immunosuppression.

Animals↗
PubMed1999

The human antibody response to porcine xenoantigens is encoded by IGHV3-11 and IGHV3-74 IgVH germline progenitors.

Preformed and induced Ab responses present a major immunological barrier to the use of pig organs for human xenotransplantation. We generated IgM and IgG gene libraries established from lymphocytes of patients treated with a bioartificial liver (BAL) containing pig hepatocytes and used these libraries to identify IgVH genes that encode human Ab responses to pig xenoantigens. Genes encoded by the VH3 family are increased in expression in patients following BAL treatment. cDNA libraries representing the VH3 gene family were generated, and the relative frequency of expression of genes used to encode the Ab response was determined at days 0, 10, and 21. Ig genes derived from the IGHV3-11 and IGHV3-74 germline progenitors increase in frequency post-BAL. The IGHV3-11 gene encodes 12% of VH3 cDNA clones expressed as IgM Abs at day 0 and 32.4-39.0% of cDNA clones encoding IgM Abs in two patients at day 10. IGHV3-11 and IGHV3-74 genes encoding IgM Abs in these patients are expressed without evidence of somatic mutation. By day 21, an isotype switch occurs and IGHV3-11 IgVH progenitors encode IgG Abs that demonstrate somatic mutation. We cloned these genes into a phagemid vector, expressed these clones as single-chain Abs, and demonstrated that the IGHV3-11 gene encodes Abs with the ability to bind to the gal alpha (1,3) gal epitope. Our results demonstrate that the xenoantibody response in humans is encoded by IgVH genes restricted to IGHV3-11 and IGHV3-74 germline progenitors. IgM Abs are expressed in germline configuration and IgG Abs demonstrate somatic mutations by day 21.

Adult↗
PubMed2003

Function of a new internal bioartificial liver: an in vitro study.

The goal of this study was to determine whether a new internal bioartificial liver utilizing porcine hepatocytes can perform detoxification and other metabolic functions. Such a system might aid in treating patients with moderate to severe liver failure and prolong patient survival until a matching organ is found for transplantation. Porcine hepatocytes were attached to a microcarrier and an internal artificial liver was constructed by perfusing the hepatocytes into a polysulfon hollow fiber. The 4 experimental groups were: (a) control group, (b) microcarrier group, (c) hollow fiber group, and (d) internal bioartificial liver group. Viability of hepatocytes, alanine aminotransferase (ALT) and lactate dehydrogenase (LD) activities in the medium, urea production, diazepam transformation, protein synthesis, and glucose-6-phosphatase activity of cells were monitored during a 7-day culture period. Viability of porcine hepatocytes in the internal bioartificial liver group was maintained at >80% during the culture period, and alanine aminotransferase and lactate dehydrogenase activities did not fluctuate significantly. These enzyme activities were significantly lower in the internal bioartificial liver group than in the control or microcarrier groups. Urea production, diazepam transformation, [3H]-leucine incorporation, and glucose-6-phosphatase activity were significantly higher in the internal bioartificial liver group than in the control and hollow fiber groups. These results show that the new internal bioartificial liver produces small amounts of ALT and LD and exhibits detoxification and protein synthetic functions.

Alanine Transaminase↗
PubMedDate not supplied

Control of molecular weight cut-off for immunoisolation by multilayering glycol chitosan-alginate polyion complex on alginate-based microcapsules.

Glycol chitosan is a positively charged polysaccharide which is water-soluble at pH 7.4, and is able to form a polyion complex (PIC) with anionic polymers, such as alginate. The authors attempt to develop a novel type of alginate-based microcapsule using this glycol chitosan for a islets-encapsulated bioartificial pancreas. The number of layers composed of glycol chitosan-alginate (GC-Alg) PIC were optimized, in order to cut off immunoglobulin transport and to protect encapsulated islets from the host immune reaction, and the transport characteristics were evaluated of glucose, bovine serum albumin (BSA) and gamma-globulin. To add mechanical stability to the microcapsule, calcium ions, which crosslinked the alginate polymers close to the interface between core Ca-alginate and multilayered membrane, were partially substituted with barium ions after the formation of multilayered Ca-alginate gel beads. The partition coefficients of BSA and gamma-globulin were decreased with the increasing number of layers. The immunoisolation was achieved against gamma-globulin with four layers of the GC-Alg PIC membrane, while BSA could permeate the membrane. The four-layered Ba-alginate gel bead had a good permeability for glucose, giving a diffusion coefficient corresponding to 80% of that in pure water. Insulin secretion from the islets in the four-layered Ba-alginate microcapsule was satisfactorily observed with the fractional stimulation ratio of 2.17. This result indicates that the encapsulated islets maintained their viability even after encapsulation. It was, thus, shown that the Ba-alginate microcapsule with four layers of the GC-Alg PIC membrane is promising as the microencapsulation material for a bioartificial pancreas.

Alginates↗