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PubMed2006

Physical-chemical and biological characterization of silk fibroin-coated porous membranes for medical applications.

Membranes in artificial organs and scaffolds for tissue engineering are often coated with biomimetic molecules (e.g., collagen) to improve their biocompatibility and promote primary cell adhesion and differentiation. However, animal proteins are expensive and may be contaminated with prions. Silk fibroin (SF) made by Bombyx Mori silk worms, used as a scaffold or grafted to other polymers, reportedly promotes the adhesion and growth of many human cell types. This paper describes how commercial porous membranes were physically coated with SF, and their physical-chemical properties were characterized by SEM, AFM, tensile stress analysis and dynamic contact angle measurements. The effect of the SF coating on membrane biocompatibility and resistance to bacterial colonization is also examined. The proposed technique yields SF coats of different thickness that strengthen the membranes and make their surface remarkably more wettable. The SF coat is not cytotoxic, and promotes the adhesion and proliferation of an immortalized fibroblast cell line. Similarly to collagen, SF-coated membranes also exhibit a much better resistance to the adhesion of S. epidermidis bacteria than uncoated membranes. These preliminary results suggest that SF is a feasible alternative to collagen as a biomimetic coating for 3D scaffolds for tissue engineering or bioartificial (as well as artificial) prosthesis.

Chemical Phenomena↗
PubMed2006

[Structural and functional polarity of porcine hepatocyte cultured spheroids].

Hepatocytes are epithelial cells that show a complex polarity in vivo. However, hepatocytes isolated and cultured in vitro normally lose both their differentiated properties and polarity. Culturing hepatocyte spheroids seems to be the accurate approach to maintain tissue level of organization. The structural and functionalpolarities of pig liver spheroids were analyzed in this work. Swine liver cells were isolated and cultured as spheroids. Their metabolic activity was proved through the metabolism of diazepam, ammonium and synthesis of albumin. Several structural features show the presence of polarity in the cells inside the spheroids. Reticular and collagen fibers, as well as Ck19(+) cells forming duct-like structures were found. _eta and _-catenins and pancadherins were positive in different regions of the spheroids, mainly in the outer cell layers, which have cuboidal epithelia features. The scanning electron microscopy showed a tightly compacted architecture, with smooth surface. The transmission electron microscopy analysis showed bile canaliculi with microvilli, tight junctions, zonula adherens and desmosome-like junctions. Well-maintained cellular organelles, as mitochondria, nucleus, nucleolus, peroxisomes, endoplasmic reticulum, were seen in the spheroids. A complex inner bile canaliculi network was shown by using a fluorescent bile acid analogue incorporated and excreted by the spheroids. Furthermore, excretion of a normal pattern of bile acids was demonstrated. The morphology and functionality of the spheroids may provide an appropriate model for applications where the maintenance of liver-specific functions is crucial, as a bioartificial liver device.

Albumins↗
PubMed1994

[Development of a hybrid bio-artificial liver].

Despite recent advances in medical management, fulminant hepatic failure (FHF) is still associated with high mortality. Liver transplantation is currently the only effective therapy for patients with FHF in many countries, but not yet in Japan. Thus, it is needed to introduce a bioartificial liver (BAL) support system using hepatocytes that substitutes for insufficient metabolism until the liver can recover. To function as a surrogate liver, BAL must meet two metabolic criteria: the first criterion requires highly differentiated liver cells; the second requires a mass sufficient to support the needs of the patients. Cell-extracellular matrix interaction is biologically relevant to regulating gene expression and maintaining cell differentiation of hepatocyte through activating liver-enriched transcriptional factors, including hepatocyte nuclear factor-1 (HNF-1) and HNF-4. With the advance of biotechnology, clinical trials of BAL using porcine primary hepatocytes or human hepatoblastoma cell lines have been successfully performed in the United States. In the near future, a hybrid liver support system is expected to be widely used for treating patients with FHF.

Animals↗
PubMed2002

Regenerative biology and medicine.

The replacement of damaged tissues and organs with tissue and organ transplants or bionic implants has serious drawbacks. There is now emerging a new approach to tissue and organ replacement, regenerative biology and medicine. Regenerative biology seeks to understand the cellular and molecular differences between regenerating and non-regenerating tissues. Regenerative medicine seeks to apply this understanding to restore tissue structure and function in damaged, non-regenerating tissues. Regeneration is accomplished by three mechanisms, each of which uses or produces a different kind of regeneration-competent cell. Compensatory hyperplasia is regeneration by the proliferation of cells which maintain all or most of their differentiated functions (e.g., liver). The urodele amphibians regenerate a variety of tissues by the dedifferentiation of mature cells to produce progenitor cells capable of division. Many tissues contain reserve stem or progenitor cells that are activated by injury to restore the tissue while simultaneously renewing themselves. All regeneration-competent cells have two features in common. First, they are not terminally differentiated and can re-enter the cell cycle in response to signals in the injury environment. Second, their activation is invariably accompanied by the dissolution of the extracellular matrix (ECM) surrounding the cells, suggesting that the ECM is an important regulator of their state of differentiation. Regenerative medicine uses three approaches. First is the transplantation of cells into the damaged area. Second is the construction of bioartificial tissues by seeding cells into a biodegradable scaffold where they produce a normal matrix. Third is the use of a biomaterial scaffold or drug delivery system to stimulate regeneration in vivo from regeneration-competent cells. There is substantial evidence that non-regenerating mammalian tissues harbor regeneration-competent cells that are forced into a pathway of scar tissue formation. Regeneration can be induced if the factors leading to scar formation are inhibited and the appropriate signaling environment is supplied. An overview of regenerative mechanisms, approaches of regenerative medicine, research directions, and research issues will be given.

Journal Article↗
PubMedDate not supplied

Sustaining a bioartificial liver under hypothermic conditions.

Bioartificial liver (BAL) devices employing xenogeneic hepatocytes are being developed as a temporary support of liver failure. For clinical applications, transporting such a device from the manufacturing site to the hospital is necessary. We investigated the effect of hypothermic treatment on the performance of the collagen-entrapment BAL device developed at the University of Minnesota. A number of chemical protectants were examined for their effectiveness in minimizing damage to hepatocytes. Preincubation with protectant (tauroursodeoxycholic acid, TUDCA) before hypothermic treatment improved posttreatment BAL performance. Oxygen consumption and albumin and urea synthesis all resumed at levels comparable to pretreatment levels. The method described will facilitate the application of BAL in the treatment of liver failure.

Animals↗
PubMed2003

Inactivation of porcine endogenous retrovirus by human serum as a function of complement activated through the classical pathway.

BACKGROUND: The clinical use of organs and cells of pig donors as a source of tissue for xenotransplantation and extracorporeal therapies has been problematic due to the risk for zoonotic infection of porcine endogenous retroviruses (PERV). METHODS: The effect of human serum on PERV was evaluated using an infectivity assay and virolysis assay. Cell-free PERV infection to human 293 cells was determined by the presence of proviruses 5 days post-infection by a highly sensitive nested PCR, and the lysis of PERV virions was determined by the reverse transcriptase activities released into the supernatant. RESULTS: Treatment of PERV-PK, the culture supernatant of a pig kidney cell line containing the virus titer of 10(2.8) TCID(50) units/ml, with a quarter volume of human serum completely inactivated the infectivity. This activity was heat-labile and sensitive to an anti-complement agent, nafamostat mesilate, and a Ca(2+)-chelator, EGTA, indicating the crucial involvement of complement activated through the classical pathway. Since a synthetic galactosyl alpha1-3 galalactose (Galalpha1-3Gal) largely absorbed the activity from the serum, natural antibodies to the Galalpha1-3Gal epitopes are likely to trigger the complement activation. CONCLUSION: Cell-free PERV seems no longer be infectious in human serum. This greatly encourages the clinical application of pig tissues in particular for extracorporeal therapies such as a bioartificial liver, in which pig cells do not come in direct contact with a recipient.

Journal Article↗
PubMed1999

Bioartificial pancreas: alternative supply of insulin-secreting cells.

In this study, insulin secretion function of INS-1 cells immunoisolated in microcapsules was evaluated. Following encapsulation, the immunoisolated INS-1 cells continued to propagate and flourish within the microcapsules during the entire two-month in vitro incubation period. The insulin secretion from encapsulated INS-1 cells following seven days of in vitro culture increased from 1.6 +/- 0.2 ng/2h/10(6) cells in a glucose-free medium to 11.5 +/- 2.1 ng/2h/10(6) cells at 16.7 mM glucose. In vivo, transplants of 1.2 x 10(7) cells into each of six diabetic C57BL/6 mice resulted in the restoration of normoglycemia in all graft recipients for up to 60 days post transplantation. Most capsules recovered from two animals 30 days post transplantation were free of cell overgrowth and physically intact. Immunostaining for insulin of the cells within the recovered capsules clearly indicated the presence of insulin. The presented data demonstrate the potential use of an immunoisolated beta-cell line for the treatment of diabetes.

Animals↗
PubMed1990

Large-scale production and cultivation of hepatocytes on Biosilon microcarriers.

A method for large-scale production of hepatocytes on microcarriers have been developed for the purpose of bioartificial liver support system. Hepatocytes obtained by collagenase treatment of rat liver were efficiently attached and spread on a microcarrier surface in the presence of O2-saturated perfluorodecalin. In order to compare the metabolic activities of hepatocytes under long-term cultivation on microcarriers with those of cells under conventional monolayer culture, some liver-specific functions were investigated. Microcarrier-attached hepatocytes cultured in the absence of serum for 8 days synthesized and secreted albumin and fibronectin. Moreover, hepatocytes on microcarriers retained the ability to conjugate bilirubin for 4-5 days. With respect to these specific metabolic properties, microcarrier-attached hepatocytes were comparable to those from routine dish culture. These results suggest that this method developed for large-scale production of hepatocytes on microcarriers will allow one to obtain metabolically active cells suitable for extracorporeal liver support systems.

Animals↗
PubMed1998

[The artificial liver--an interim report].

A Bioartificial Liver (BAL) is not available to date. Human therapeutic applications of different systems of BAL as of 1998 are presented and discussed. It is concluded that--as for now--no artificial liver device has gained any importance for the treatment of liver failure, and that some critical issues in this field of research have not been sufficiently investigated and/or are not resolved. This review analyzes reports of clinical applications of BAL from the following research groups (numbers in brackets indicate patients treated with an artificial liver device): Demetriou/Rozga, Los Angeles (31 patients), Williams, London (1 patient); Gerlach, Berlin (1 patient); Strom, Virginia (5 patients). The BAL systems used in these studies cannot be directly compared because there are considerable differences in the quality and in quantity of the functional unit employed in bioreactors, the experimental design, patient selection, to mention just a few points. None of the systems investigated so far could convincingly prove its effectivity in replacing impaired liver function neither in animal models nor in a clinical application. It remains to be shown, whether liver cells cultured in bioreactors remain stable, i.e. viable and functionally active, for a sufficient period of treatment. Selected metabolic or detoxifying functions of the bioreactor are difficult to assess, since these functions do not necessarily serve as pars pro toto for the complex clinical presentation of liver failure and therefore cannot sufficiently validate any organ replacement system. Furthermore, since some applications combine biological units with other components, such as active charcoal, it be-comes even more difficult to assess the role of hepatocytes in these settings. Case reports of patients treated with BAL usually refer to BAL as a "successful bridge to transplant", thereby demonstrating the positive effect of orthotopic/auxiliary liver transplants in the treatment of acute liver failure rather than the potential benefit derived from an artificial liver device. Randomised studies have been proposed and urged for years in order to prove the effectivity of these systems which, in part, are already available for clinical use. Because of the heterogeneous patient group in question the design of such protocols will be a difficult task. It must be asked, whether currently used artificial liver systems have left basic science research too early; the use of "black box" applications in humans cannot draw its legitimation merely from the fact that an effective conservative treatment of liver failure is not available so far.

Animals↗
PubMed2006

Future direction of renal positron emission tomography.

Positron emission tomography (PET) is perfectly suited for quantitative imaging of the kidneys, and the recent improvements in detector technology, computer hardware, and image processing software add to its appeal. Multiple positron emitting radioisotopes can be used for renal imaging. Some, including carbon-11, nitrogen-13, and oxygen-15, can be used at institutions with an on-site cyclotron. Other radioisotopes that may be even more useful in a clinical setting are those that either can be obtained from radionuclide generators (rubidium-82, copper-62) or have a sufficiently long half-life for transportation (fluorine-18). The clinical use of functional renal PET studies (blood flow, glomerular filtration rate) has been slow, in part because of the success of concurrent technologies, including single-photon emission computed tomography (SPECT) and planar gamma camera imaging. Renal blood flow studies can be performed with O-15-labeled water, N-13-labeled ammonia, rubidium-82, and copper-labeled PTSM. With these tracers, renal blood flow can be quantified using a modified microsphere kinetic model. Glomerular filtration can be imaged and quantified with gallium-68 EDTA or cobalt-55 EDTA. Measurements of renal blood flow with PET have potential applications in renovascular disease, in transplant rejection or acute tubular necrosis, in drug-induced nephropathies, ureteral obstruction, before and after revascularization, and before and after the placement of ureteral stents. The most important clinical application for imaging glomerular function with PET would be renovascular hypertension. Molecular imaging of the kidneys with PET is rather limited. At present, research is focused on the investigation of metabolism (acetate), membrane transporters (organic cation and anion transporters, pepT1 and pepT2, GLUT, SGLT), enzymes (ACE), and receptors (AT1R). Because many nephrological and urological disorders are initiated at the molecular and organelle levels and may remain localized at their origin for an extended period of time, new disease-specific molecular probes for PET studies of the kidneys need to be developed. Future applications of molecular renal imaging are likely to involve studies of tissue hypoxia and apoptosis in renovascular renal disease, renal cancer, and obstructive nephropathy, monitoring the molecular signatures of atherosclerotic plaques, measuring endothelial dysfunction and response to balloon revascularization and restenosis, molecular assessment of the nephrotoxic effects of cyclosporine, anticancer drugs, and radiation therapy. New radioligands will enhance the staging and follow-up of renal and prostate cancer. Methods will be developed for investigation of the kinetics of drug-delivery systems and delivery and deposition of prodrugs, reporter gene technology, delivery of gene therapy (nuclear and mitochondrial), assessment of the delivery of cellular, viral, and nonviral vectors (liposomes, polycations, fusion proteins, electroporation, hematopoietic stems cells). Of particular importance will be investigations of stem cell kinetics, including local presence, bloodborne migration, activation, seeding, and its role in renal remodeling (psychological, pathological, and therapy induced). Methods also could be established for investigating the role of receptors and oncoproteins in cellular proliferation, apoptosis, tubular atrophy, and interstitial fibrosis; monitoring ras gene targeting in kidney diseases, assessing cell therapy devices (bioartificial filters, renal tubule assist devices, and bioarticial kidneys), and targeting of signal transduction moleculas with growth factors and cytokines. These potential new approaches are, at best, in an experimental stage, and more research will be needed for their implementation.

Forecasting↗
PubMed2003

Review article: a medicine based on cell transplantation -- is there a future for treating liver diseases?

Cell-based therapies, comprising isolated hepatocyte transplantation, ex vivo gene therapy and bioartificial liver devices, may actually design a new scenario in the treatment of patients with liver failure. Recent advances in the liver repopulation field and the considerable excitement surrounding the use of haematopoietic stem cells for a 'regenerative medicine', allow us to see under a new light the alternative cell sources actually under investigation. In particular, the major drawbacks and the most important advantages of xenogenic primary cells, tumour-derived cell lines, immortalised hepatocytes and stem cells in the wide range of experimental and clinical applications are presented. Even if up to now none of them represent a 'gold standard' in the clinical practice, the intersecting advances in the development of mechanical components of artificial devices and in the liver biology and bioengineering will open tantalising possibilities to treat patients with liver failure, by tailoring the therapeutic choice on the basis of the aetiology and the stage of liver disease.

Artificial Organs↗
PubMed1992

Hepatocyte function in a hollow fiber bioreactor: a potential bioartificial liver.

We have developed a novel hepatocyte loaded hollow fiber bioreactor as a potential bioartificial liver. Freshly harvested rat hepatocytes were entrapped in a three-dimensional gel matrix within hollow fibers in a perfused bioreactor. Gel entrapment allowed cells to be cultured at high density while maintaining tissue-specific function. Hepatocyte function was evaluated in 10 bioreactors, each containing approximately 5 x 10(7) cells. Oxygen consumption averaged 0.32 pmole/cell/hr, albumin appearance averaged 0.60 pg/cell/hr, and lidocaine clearance (a measure of the P-450 activity) averaged 0.74 pg/cell/hr. Function persisted for the 7 days of the study. Electron microscopy at 7 days showed the distinctive ultrastructure of viable, differentiated hepatocytes: bile canaliculi, intercellular junctions, peroxisomes, abundant mitochondria, and glycogen granules. Maintenance of tissue specific function and ultrastructure suggests that this bioreactor configuration has potential as a device to support patients in liver failure, as well as to study hepatocytes in vitro.

Amino Acids↗
PubMed1996

Functional stability of porcine hepatocyte spheroids in various culture systems under 100% porcine and human plasma conditions.

To select an immobilization method suitable for bioartificial liver (BAL) modules utilizing porcine hepatocyte spheroids, functional activities were compared in various systems in 100% porcine and human plasma together with a synthesized medium. The spheroids, continuously suspended in rotating dishes or entrapped in collagen (CN) gel, expressed approximately two times higher ammonium detoxification abilities over conventional monolayers during 8 days of direct contact with 100% human or porcine plasma with a standardized inoculum cell number. No significant deterioration was observed in the abilities as compared with that in a synthesized medium. Although the cell number gradually decreased in rotational culture, the abilities per cells remaining on Day 10 were two times higher than in the CN-gel entrapped spheroids in all the media examined, presumably due to the diffusion limitation by the gel. Thus, in utilizing porcine hepatocyte spheroids in BAL modules, immobilization allowing direct contact of spheroids with perfused patient plasma was concluded to be possible and suitable.

Animals↗
PubMed2003

Bridging a patient with acute liver failure to liver transplantation by the AMC-bioartificial liver.

Recently a phase I clinical trial has been started in Italy to bridge patients with acute liver failure (ALF) to orthotopic liver transplantation (OLT) by the AMC-bioartificial liver (AMC-BAL). The AMC-BAL is charged with 10 x 10(9) viable primary porcine hepatocytes isolated from a specified pathogen-free (SPF) pig. Here we report a patient with ALF due to acute HBV infection. This patient was treated for 35 h by two AMC-BAL treatments and was bridged to OLT. There was improvement of biochemical and clinical parameters during the treatment. No severe adverse events were observed during treatment and follow-up of 15 months after hospital discharge. Possible porcine endogenous retrovirus (PERV) activity could not be detected in the patient's blood or blood cells up to 12 months after treatment.

Adult↗
PubMed1998

Entrapment of islets into reversible disulfide hydrogels.

Currently, there are three types of devices for a bioartificial pancreas; microencapsulation, an extravascular diffusion chamber, and an intravascular diffusion chamber. The purpose of the present study was to provide a new extracellular matrix hydrogel for the devices of extra- and intravascular diffusion chamber types. As the sol-gel transition of this hydrogel is reversible, refilling of islets in vivo will be possible without a severe traumatic procedure. The hydrogel was produced from a polyacrylamide derivative carrying thiol groups synthesized by radical copolymerization of acrylamide and N,N'-bis-acrylcystamine, followed by reduction of the disulfide bonds in the copolymer. This water-soluble copolymer was used to entrap hamster islets by re-formation of disulfide bonds on the copolymer to produce a hydrogel. The formed hydrogel was easily reliquefied by reduction of the disulfide crosslinks to thiols. Insulin release from the islet-entrapped hydrogel continued for more than 1 month when examined in vitro. A static glucose stimulation test for the entrapped islets exhibited an increased insulin release.

Animals↗
PubMed1996

Development of a bioartificial liver with sandwiched-cultured hepatocytes between two collagen gel layers.

We have been developing a multiplate type of bioartificial liver (BAL) using primary cultured hepatocyte monolayers since 1987. This BAL has been shown to prolong the survival time of anhepatic dogs and rabbits. Initially, hepatocytes were cultivated on collagen-coated plates. To increase the multiplated BAL function, a sandwich cultivation method was employed in which rat hepatocytes were cultured between two collagen gel layers and were then evaluated in both stationary and perfusion cultures. In the stationary culture, the sandwich method showed a higher activity in urea synthesis than in the other culture methods (culture on a collagen coating, culture on a collagen gel, and culture between a collagen coating and a collagen gel) for 14 days. In the perfusion culture, a BAL housing cultured hepatocytes (6.5 x 10(7) cells) in the sandwich system showed urea synthesis activity ranging from 17.5 to 22.6 micrograms/2 x 10(6) cells/90 min. This activity was maintained for 5 days in the perfusion culture. The sandwich type of cultivation is applicable to the multiplated BAL.

Ammonia↗
PubMed2000

[Engineering of osseous cells and bioartificial tissues].

The association of osteogenic stem cells to a synthetic carrier makes possible the elaboration of bioartificial tissue. Numerous phosphocalcic ceramics does not trigger a foreign body reaction when implanted in bone tissue and thus, a number of materials are available osteogenic stem cell carriers to replace the bone tissue. Several methods can be used to harvest these cells. Their multiplication in vitro can lead to the appearance of anomalies of their metabolism or their karyotype. The culture method also seems to have a major influence on their appearance. The presence of these anomalies could explain the variability of results in terms of bone extracellular matrix synthesis after cell reimplantation. The surgical technique used for the implantation is also of influence. A method suppressing the in vitro period has been developed to avoid any cell metabolism modification. This method allows for a very reproducible bone synthesis in ectopic site. The availability of human embryonic stem cells could help to develop cell graft techniques for bone reconstruction.

Biocompatible Materials↗
PubMedDate not supplied

Short-term hypothermic preservation of porcine hepatocyte spheroids using UW solution.

The feasibility of University of Wisconsin (UW) solution in short-term hypothermic preservation of porcine hepatocyte spheroids was investigated, because they have great potential in bioartificial liver (BAL) systems. Porcine hepatocyte spheroids preserved for 3 days expressed almost comparable levels of albumin secretion as those without preservation, during 8 subsequent days of recultivation in continuous rotational culture, whereas isolated single cells did not reorganize into spheroids and completely lost their function in recultivation. Although for 3-day-preserved spheroids, the albumin secretion was lowered immediately after recultivation (Days 0-2), it was completely restored to that of nonpreserved ones. The function was completely lost in recultivation for 7-day-preserved ones. These results demonstrate that reorganization into spheroids is effective in preventing the functional loss of porcine hepatocytes occurring in hypothermic preservation, and that spheroid formation should precede the preservation as long as spheroid culture is finally used in BAL systems. Also, porcine hepatocyte spheroids are shown to be satisfactory stored in UW solution up to 3 days without significant cellular or functional loss.

Adenosine↗