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Results for “Bioartificial Organs”

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PubMed2002

Clinical and laboratory evaluation of the safety of a bioartificial liver assist device for potential transmission of porcine endogenous retrovirus.

BACKGROUND: The potential risk of transmission of porcine endogenous retroviruses (PERV) from xenogeneic donors into humans has been widely debated. Because we were involved in a phase I/II clinical trial using a bioartificial liver support system (BLSS), we proceeded to evaluate the biosafety of this device. MATERIALS AND METHODS: The system being evaluated contains primary porcine hepatocytes freshly isolated from pathogen-free, purpose-raised herd. Isolated hepatocytes were installed in the shell, which is separated by a semipermeable membrane (100-kD nominal cutoff) from the lumen through which the patients' whole blood is circulated. Both before and at defined intervals posthemoperfusion, patients' blood was obtained for screening. Additionally, effluent collected from a clinical bioreactor was analyzed. The presence of viral particles was estimated by reverse transcriptase-polymerase chain reaction (RT-PCR) and RT assays. For the detection of pig genomic and mitochondrial DNA, sequence-specific PCR (SS-PCR) was used. Finally, the presence of infectious viral particles in the samples was ascertained by exposure to the PERV-susceptible human cell line HEK-293. RESULTS: PERV transcripts, RT activity, and infectious PERV particles were not detected in the luminal effluent of a bioreactor. Culture supernatant from untreated control or mitogen-treated porcine hepatocytes (cleared of cellular debris) also failed to infect HEK-293 cell lines. Finally, RT-PCR, SS-PCR, and PERV-specific RT assay detected no PERV infection in the blood samples obtained from five study patients both before and at various times post-hemoperfusion. CONCLUSION: Although longer patient follow-up is required and mandated to unequivocally establish the biosafety of this device and related bioartificial organ systems, these analyses support the conclusion that when used under standard operational conditions, the BLSS is safe.

Animals↗
PubMed1997

Packed-bed type reactor to attain high density culture of hepatocytes for use as a bioartificial liver.

In an attempt to develop a bioartificial liver using cultured hepatocytes, we investigated the short-term and long-term viability and metabolic functions of hepatocytes cultured in a new type of packed-bed type reactor using reticulated polyvinyl formal (PVF) resin as a supporting material. Perfusion culture experiments using this reactor, as well as monolayer cultures using conventional collagen-coated Petri dishes as control experiments, were performed. It was found that the highest density of immobilized hepatocytes attained with PVF resin was on the order of 10(7) cells/cm3 PVF and that hepatocytes cultured in this type of module for up to a week showed a sufficient level of liver-specific metabolic functions, such as ammonium metabolism, urea-N synthesis, and albumin secretion, to be comparable to those in the monolayer culture. It is concluded that the packed-bed reactor system utilizing PVF resin is a promising means to develop a bioartificial organ using hepatocytes.

Alanine Transaminase↗
PubMed1997

Factors determining hydrogel permeability.

Developing hydrogel membranes and coatings of appropriate permeability characteristics is key to the success of a number bioartificial organ technologies. Key principles relevant to the design and application of hydrogels for such applications were reviewed. The first key point is that permeability is a function of both transport and thermodynamic properties, the diffusion coefficient and partition coefficient, respectively, and that these parameters can be evaluated separately. Although the aspect of partitioning often emphasized is size exclusion, this review points out that many other relevant interactions come into play, especially hydrophobic and electrostatic interactions, and that these phenomena can dominate size exclusion. Similarly, while the diffusion coefficient also is strongly dependent upon size, other interactions can also cause diffusivity to deviate from theories which consider only solute size and gel swelling. For example, the heterogeneity of hydrogel networks can result in permeabilities that fail to decline as much as might be anticipated if networks were uniform.

Animals↗
PubMed1999

Artificial cells, encapsulation, and immobilization.

The basic principles of artificial cells, encapsulation and immobilization form the basis for a number of bioartificial organs. Hemoperfusion based on encapsulated adsorbent has been in routine clinical uses for many years to remove toxins or drugs from the circulating blood. Blood substitutes based on crosslinked hemoglobin or encapsulated hemoglobin are being developed and tested in phase II and Phase III clinical trials. Enzyme therapy using microencapsulated enzymes have been studied in animal studies and in a preliminary human study. Encapsulation or other ways of immobilization of cells are being developed extensively by many groups. This includes the encapsulation or immobilization of islets, hepatocytes and genetically engineered cells.

Animals↗
PubMed2001

Present status of modified hemoglobin as blood substitutes and oral therapy for end stage renal failure using artificial cells containing genetically engineered cells.

Artificial cell or bioencapsulation has been developed for use in bioartificial organs, drug delivery, blood substitutes, and other areas. Recent rapid advances in modified hemoglobin blood substitutes have resulted in advance stages of Phase III clinical trials. Another area of use is in oral therapy, using artificial cells microencapsulated with genetically engineered cells for use in end stage renal failure and other conditions.

Administration, Oral↗
PubMed1998

Two-dimensional manipulation of confluently cultured vascular endothelial cells using temperature-responsive poly(N-isopropylacrylamide)-grafted surfaces.

Temperature-responsive hydration/dehydration changes in surface-grafted poly(N-isopropylacrylamide) (PIPAAm) were utilized for hydrophilic/hydrophobic surface property alterations in cell culture. In this report, we utilized PIPAAm-grafted surfaces to recover confluently-cultured vascular endothelial cells as coherent monolayers from this cell culture substrate and to transfer to new cell culture substrates. For this purpose, we used two different methods to recover and transfer cell monolayer cultures: (1) chitin membranes used as an apical side cell support during cultured cell transfer, allowing cell basal side reattachment to new culture substrates after transfer; and (2) a cell culture insert (porous PET) used as both a support as well as new substrate, allowing basal surfaces of cultured cells to be exposed to the medium after transfer. In both cases, all cells grown on PIPAAm-grafted surfaces detach completely with maintenance of basement membrane-like structure. Recovered cells attach to the second culture surfaces, covering more than 60% of the new substrate, and retain approximately 90% viability and their original function as judged from tissue-type plasminogen activator secretion. This technique could be utilized to prepare novel bioartificial organs as well as cell co-culture systems by multi-layering different cell types to mimic tissue structures for tissue engineering.

Acrylic Resins↗
PubMed2002

Cultivation of porcine hepatocytes in polyurethane nonwovens as part of a biohybrid liver support system.

Many patients suffering from end-stage liver disease cannot be transplanted within reasonable time due to the shortage of donor organs. Bioartificial liver support systems may contribute to the liver regeneration or bridging the time until a liver graft for transplantation becomes available. Nonwovens with integrated oxygenation capacity have been developed and manufactured by melt blow technology using thermoplastic polyurethane. Capillary membranes for oxygenation were integrated into the nonwoven during the processing. The polyurethane nonwoven structures with adapted pore size and high pore volume allow high cell densities in the hepatocyte culture. The three-dimensional cell culture was housed by a flow bioreactor system and was integrated in a closed loop circulation with monitoring possibilities for pressure, pH, temperature, ammonia, and oxygen. Hepatocytes were isolated from rats or pigs by collagenase perfusion and infused into the medium-perfused circulation. Cells showed high viability and hepatocyte specific cytochrome P450-dependent metabolic function in culture (MEGX test).

Albumins↗
PubMed2006

Mechanical properties of alginate beads hosting hepatocytes in a fluidized bed bioreactor.

Fluidized bed bioartificial liver has been proposed as a temporary support to bridge patients suffering from acute liver failure to transplantation. In such a bioreactor, alginate beads hosting hepatocytes are in continuous motion during at least six hours. After having shown in vitro the functionality of such a device, the present study aims at analyzing the potential mechanical alterations of the beads in the bioreactor, perfused by different surrounding media. Compression experiments are performed and coupled for analysis with Hertz theory. They provide qualitative and quantitative data. The average value of the shear modulus, calculated for the different cases studied varied from 2.4 to 10.4 kPa, and could therefore be considered as a quantitative measure of the beads mechanical properties. From the compression experiments and the estimated values of the shear modulus, we could now evaluate the effect of different operating conditions (fluidization, presence of cells, surrounding medium) on the mechanical behavior of alginate beads. On the one hand, the motion during six hours in the bioreactor does not alter the beads significantly. On the other hand, the presence of different substances in the fluid phase might change their mechanical strength. These results can be considered as new encouragements to use such a device as a bioartificial organ.

Alginates↗
PubMed2000

The impact of tissue engineering on dentistry.

BACKGROUND: Tissue engineering is a novel and highly exciting field of research that aims to repair damaged tissues as well as create replacement (bioartificial) organs. OVERVIEW: The authors provide a general review of the principles underlying key tissue engineering strategies, as well as the typical components used. Several examples of preclinical and clinical progress are presented. These include passive approaches, such as dental implants, and inductive approaches that activate cells with specific molecular signals. PRACTICE IMPLICATIONS: Tissue engineering will have a considerable effect on dental practice during the next 25 years. The greatest effects will likely be related to the repair and replacement of mineralized tissues, the promotion of oral wound healing and the use of gene transfer adjunctively.

Animals↗
PubMedDate not supplied

In vitro diffusion in polyacrylamide embedded agarose microbeads.

125I Sodium iodide, 125I insulin, 125I albumin, and 111indium IGG were employed to investigate release from, and penetration of different sized molecules into agarose/polyacrylamide microcapsules. The microcapsules were formed by photopolymerization of an acrylamide solution round agarose beads. The indium-chelated antibody gave a particular low background count. The different release times were explained in terms of differences in diffusion coefficient. By retarding in vitro penetration of antibodies, these microcapsules could be of value for the encapsulation of living cells in bioartificial organs.

Acrylic Resins↗
PubMed1987

Applications of artificial cells in medicine and biotechnology.

This article summarizes those research activities in the area of artificial cells which are related to medicine and biotechnology. This includes the applications of artificial cells in: (1) chronic renal failure, (2) drug poisoning, (3) aluminium and iron removal, (4) fulminant hepatic failure, (5) immunosorbent for direct blood perfusion, (6) enzyme therapy and metabolic function replacement, (7) immobilized cell cultures for Bioartificial Organs, (8) blood substitutes, (9) microencapsulation, (10) biotechnology and other areas.

Artificial Organs↗
PubMed2003

Progress on regulations for human-derived therapeutic products.

Several European work programmes are building a unified regulatory framework for therapeutic products that utilise material of human origin, that is, substances, derivatives or tissues of human origin or viable cells of human origin. This is a report on progress to date.

Artificial Organs↗
PubMed1994

The concept of application of immobilized and perfused mammalian cells (a bioreactor model) in biomedical research.

An overview of the concept of cellular immobilization and perfusion as a small laboratory bioreactor model is presented. The cellular systems currently used may be described as static. This is due to conditions of hypoxia and waste product build-up that affect cell physiology. Cellular immobilization and perfusion is, therefore, expected to maintain the cells for very long periods of time under approximately physiological conditions. A number of applications of immobilized perfused hepatocytes and other cellular systems such as adipocytes and Sertoli cells are described in addition to various other cell lines. Moreover, it is suggested that the bioreactor may have potential use as a bioartificial organ.

Adipocytes↗
PubMed1997

[Stem cell-fed maturational lineages and epithelial organogenesis].

Stem cell-fed maturational lineages have long known to exist in rapidly proliferating tissues such as bone marrow, gut and epidermis. Recent studies support the hypothesis that stem cell-fed maturational lineages occur also in quiescent tissues. In this review is presented evidence for this hypothesis using liver as one of the model systems representative of quiescent tissues. In addition, studies are summarized indicating that control of growth and tissue-specific gene expression is dependent on maturational lineage mechanisms operating dynamically and sometimes synergistically in combination with gradients of regulatory signals that include hormones, growth factors and extracellular matrix components. Tissue engineering for optimal maintenance of cells and tissues ex vivo and for the development of bioartificial organs will depend on use of cells at specific maturational lineage stages, seeding them onto substrata of specific mixtures of extracellular matrix components, and culturing them in hormonally and nutritionally defined media.

Cell Differentiation↗
PubMed2005

Technology insight: Applications of tissue engineering and biological substitutes in urology.

Patients suffering from diseased or injured organs may be treated with transplanted organs. However, there is a severe shortage of donor organs, which is worsening yearly owing to the ageing population. Scientists in the field of regenerative medicine and tissue engineering apply the principles of cell transplantation, materials science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. This article reviews recent advances in regenerative medicine and describes applications of biological substitutes that may offer novel therapies for patients with end-stage organ failure.

Bioartificial Organs↗
PubMed2001

Historical perspectives of hybrid hepatic assist devices: tissue sourcing, immunoisolation, and clinical trial.

A hybrid hepatic assist device using canine liver tissues was developed and clinically applied 38 years ago. However, for many years practical hybrid hepatic assist devices were not clinically introduced owing to the many difficulties encountered in employing cultured hepatocytes. These problems include: (1) maintenance of viable cultured cells, (2) maintenance of normal hepatocyte function with these cells, (3) elimination of toxic substances generated by non-viable cultured and/or stored cells, (4) elimination of immunological factors generated by cultured cells and by the patient, and (5) difficulties of the biocompatible immunological barrier for cells against the patient. Fortunately, recent progress in apheresis and biomaterial technologies enable us to isolate cultured cells immunologically and yet maintain effective metabolic functions for the patient. These technologies generate an immunological barrier of a hybrid hepatic assist device for the patients. Proper adsorption columns developed for apheresis procedures enable us to remove the toxic substances released by non-viable cells. Recent development of oxygen-carrying macromolecules enable us to provide sufficient oxygen supply to the cultured cells and to maintain their normal cellular function, not only during the cultured period of time, but also during their actual clinical application. Together with the advancement of cell culture technologies, including the proper cultured environments and cellular seeding environments, these technologies, primarily developed for therapeutic apheresis, should be able to provide more effective and safe hybrid artificial organs.

Animals↗
PubMedDate not supplied

Porcine hepatocytes from slaughterhouse organs. An unlimited resource for bioartificial liver devices.

Most recent strategies for the development of hybrid artificial liver devices focus on the use of parenchymal liver cells (hepatocytes). For clinical application of these devices, a sufficient cell supply is mandatory. Because human liver tissue is rarely available, isolated porcine hepatocytes from laboratory animals have been suggested for use in bioartificial livers. The authors introduce a modified isolation protocol to yield large scale numbers of viable porcine hepatocytes from slaughterhouse organs. Perfusion and enzymatic digestion of the left medial liver lobe (n = 74) resulted in 1.0 +/- 0.3 x 10(7) viable hepatocytes per gram of tissue, and an overall yield of 1.92 +/- 0.5 x 10(9) viable cells per isolation (viability: 93 +/- 2%). Collagen gel immobilization maintained morphologic integrity and functional activity of hepatocyte cultures over long-term periods. Cell morphology, as assessed by light microscopic evaluation, was maintained for 2 weeks. Stable DNA content (51 +/- 5 micrograms) and low values of alanine aminotransferase release (8 microU/hr/micrograms DNA) indicated structural stability of cultures after a short period of post isolational adaptation. Albumin secretion (4.5 micrograms/hr/micrograms DNA) and persistent Cytochrome P450 IA1 dependent deethylation of 7-ethoxycoumarin (4.5 nmol/hr/micrograms DNA) indicated long-term metabolic activity of cultured hepatocytes. Hepatocytes from livers of slaughtered pigs represent an unlimited resource of viable material for cell culture, and their usefulness as functional units of bioartificial liver support devices should be tested.

7-Alkoxycoumarin O-Dealkylase↗