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At least 253 records · Page 14Linked to original sources
PubMed2001

Newly developed aminopropyl-silicate immunoisolation membrane for a microcapsule-shaped bioartificial pancreas.

An aminopropyl-silicate membrane, synthesized from tetramethoxysilane (TMOS) and 3-aminopropyltrimethoxysilane (APTrMOS) by the sol-gel method, was formed onto Ca-alginate gel beads via electrostatic interactions. The permeability of the membrane could be controlled easily by changing the molar ratio of both the precursors ([APTrMOS]/[TMOS]). The aminopropyl-silicate membrane prepared at a molar ratio of 2.40 rejected gamma-globulin and BSA successfully, whereas it permeated ovalbumin. This result indicates that the molecular weight cutoff point of this newly developed aminopropyl-silicate membrane is approximately 60 kDa.

Bioartificial Organs↗
PubMed2001

The role of a bioengineered artificial kidney in renal failure.

Renal failure continues to carry substantial burden of morbidity and mortality in both acute and chronic forms, despite advances in transplantation and dialysis. There is evidence to suggest that the kidney has metabolic, endocrine, and immune effects transcending its filtration functions, even beyond secretion of renin and erythropoietin. Our laboratory has developed experience in the tissue culture of renal parenchymal cells, and has now been able to demonstrate the metabolic activity of these cells in an extracorporeal circuit recapitulating glomerulotubular anatomy. We have observed active transport of sodium, glucose, and glutathione. We describe the design and initial preclinical testing of the bioartificial kidney, as well as future directions of our research.

Animals↗
PubMed2001

Derivation of pharmacokinetics equations for quantitative evaluation of bioartificial liver functions.

A bioartificial liver (BAL) is an extracorporeal medical device incorporating living hepatocytes in a cartridge. A variety of BALs have been developed and new devices are being introduced. Some of them have been clinically applied and from the results obtained they are claimed to be useful devices for assisting the liver functions of patients. However, there is still uncertainty as to their efficacy and their limitations are not clear. It is important to establish methods to quantitatively evaluate the metabolic and synthetic functions of BAL. In this paper, we derive simple equations for the quantitative evaluation of BAL functions on the basis of pharmacokinetics. Pharmacokinetics was originally developed to understand the processes of absorption, distribution, and elimination of administered drugs. Metabolic functions of the natural liver have been analyzed using pharmacokinetics and values of the useful parameters, clearance (CL) and intrinsic clearance (CLint), have been reported. The metabolic functions of the BAL expressed using values of CL and CLint are easily compared with those of the normal human liver. We believe that our method provides a useful basis for estimating the clinical effectiveness of BAL.

Bioartificial Organs↗
PubMed2001

Advances in bioartificial liver assist devices.

Rapid advances in development of bioartificial liver assist devices (BLADs) are exciting clinical interest in the application of BLAD technology for support of patients with acute liver failure. Four devices (Circe Biomedical HepatAssist, Vitagen ELAD, Gerlach BELS, and Excorp Medical BLSS) that rely on hepatocytes cultured in hollow-fiber membrane technology are currently in various stages of clinical evaluation. Several alternative approaches for culture and perfusion of hepatocytes have been evaluated in preclinical, large animal models of liver failure, or at a laboratory scale. Engineering design issues with respect to xenotransplantation, BLAD perfusion, hepatocyte functionality and culture maintenance, and ultimate distribution of a BLAD to a clinical site are delineated.

Animals↗
PubMed2001

Effect of flow configuration and membrane characteristics on membrane fouling in a novel multicoaxial hollow-fiber bioartificial liver.

A novel "multicoaxial hollow fiber bioreactor" has been developed consisting of four concentric tubes, the two innermost tubes are called hollow fibers. Bioartificial livers are created by culturing liver progenitors in the space between the two innermost hollow fibers and with culture media contained in the two compartments (intracapillary and extracapillary) sandwiching the cell compartment. The outermost compartment is used for gas exchange. A hydrodynamic model has recently been established to predict the optimum hydraulic permeability and bioreactor operational parameters to create the physicochemical environment found in the liver acinus. However, perfusion with serum-free hormonally-defined media and inoculation of cells introduces membrane fouling into the equation, and this parameter must be incorporated into the model. Using commercially available semipermeable hollow fibers (1 mm [0.65 microm pores] and 3 mm [0.1 microm pores] outer diameters [o.d]), the primary cause of resistance is the middle hollow fiber. Preliminary studies using bioreactors inoculated with isolated rat hepatocytes and perfused with serum-containing culture media demonstrated that the middle hollow fiber is the primary site of fouling, and this fouling ultimately causes cell mortality by blocking the transfer of nutrients. Experiments were performed to determine the best commercially available middle hollow fiber for construction of bioreactors and two 3-mm outer-diameter middle hollow fibers were compared: polypropylene and polysulfone, with 0.2 microm and 0.1 microm pore sizes, respectively. Dead-ended and cross flow configurations were compared for their effectiveness at reducing membrane fouling in the middle hollow fiber by determining the change in resistance with time. The results demonstrate that the 0.2-microm pore size polypropylene hollow fiber is the best choice for construction of the multicoaxial hollow-fiber bioreactor, and that cross flow results in two orders of magnitude lower resistance than dead-ended flow after 36 h.

Animals↗
PubMed2005

What are the relevant parameters for the geometrical optimization of an implantable bioartificial pancreas?

A sphere within a cylinder representing the islet encapsulated in a hollow fiber can model an implantable bioartificial pancreas. Based on a finite element model for insulin response to a glucose load in the presence of various oxygen supplies, the present study aimed at pointing out the major parameters influencing this secretion. The computational results treated with the Taguchi method clearly demonstrated that geometrical parameters (fiber length and islet density) should be precisely optimized for an enhanced insulin response. This requires the collection of more relevant experimental data concerning the islet oxygen consumption. Moreover, the relative errors on glucose consumption or insulin secretion by the islets do not seem to affect the whole optimization process, which should focus on the oxygen supply to islets.

Bioartificial Organs↗
PubMed1994

An extracorporeal microscopy perfusion chamber for on-line studies of environmental effects on cultured hepatocytes.

The development of bioartificial-hybrid organ support systems is hampered by the lack of knowledge on the effects of different (in vivo) environments on cells during extracorporeal perfusion. In the present study, a perfusion chamber was designed for continuous monitoring of cultured cells during perfusion with media, as well as during plasma perfusion in an extracorporeal circuit. Chamber characterization showed satisfactory thermal and perfusion profiles and no major pH fluctuations. Further testing was performed with hepatocytes that were cultured in between two collagen layers, a configuration which was previously shown to preserve hepatocyte morphology and function for over six weeks of culture. Perfusion of the hepatocytes with culture media did not adversely affect cell morphology and function, provided the perfusion time was < or = 48 hours. Perfusion of the cultures during connection of the chamber to an extracorporeal circuit involving normal rats for six hours resulted in reversible cytoplasmic changes, unaltered cell shapes indices, and a 40 percent increase in albumin secretion rate during the first post-perfusion day, followed by a return to stable control levels. We expect that this chamber will be a valuable tool for on-line studies of cells under (extracorporeal) perfusion conditions and could be used for a large variety of studies on regeneration, reperfusion damage, and detoxification.

Albumins↗
PubMed2001

Self-assembly and mineralization of peptide-amphiphile nanofibers.

We have used the pH-induced self-assembly of a peptide-amphiphile to make a nanostructured fibrous scaffold reminiscent of extracellular matrix. The design of this peptide-amphiphile allows the nanofibers to be reversibly cross-linked to enhance or decrease their structural integrity. After cross-linking, the fibers are able to direct mineralization of hydroxyapatite to form a composite material in which the crystallographic c axes of hydroxyapatite are aligned with the long axes of the fibers. This alignment is the same as that observed between collagen fibrils and hydroxyapatite crystals in bone.

Bioartificial Organs↗
PubMed2001

Excitability and contractility of skeletal muscle engineered from primary cultures and cell lines.

The purpose of this study was to compare the excitability and contractility of three-dimensional skeletal muscle constructs, termed myooids, engineered from C2C12 myoblast and 10T1/2 fibroblast cell lines, primary muscle cultures from adult C3H mice, and neonatal and adult Sprague-Dawley rats. Myooids were 12 mm long, with diameters of 0.1-1 mm, were excitable by transverse electrical stimulation, and contracted to produce force. After approximately 30 days in culture, myooid cross-sectional area, rheobase, chronaxie, resting baseline force, twitch force, time to peak tension, one-half relaxation time, and peak isometric force were measured. Specific force was calculated by dividing peak isometric force by cross-sectional area. The specific force generated by the myooids was 2-8% of that generated by skeletal muscles of control adult rodents. Myooids engineered from C2C12-10T1/2 cells exhibited greater rheobase, time to peak tension, and one-half relaxation time than myooids engineered from adult rodent cultures, and myooids from C2C12-10T1/2 and neonatal rat cells had greater resting baseline forces than myooids from adult rodent cultures.

Animals↗
PubMed2004

Rapid formation of functional muscle in vitro using fibrin gels.

The transition of a muscle cell from a differentiated myotube into an adult myofiber is largely unstudied. This is primarily due to the difficulty of isolating specific developmental stimuli in vivo and the inability to maintain viable myotubes in culture for sufficient lengths of time. To address these limitations, a novel method for rapidly generating three-dimensional engineered muscles using fibrin gel casting has been developed. Myoblasts were seeded and differentiated on top of a fibrin gel. Cell-mediated contraction of the gel around artificial anchors placed 12 mm apart culminates 10 days after plating in a tubular structure of small myotubes (10-microm diameter) surrounded by a fibrin gel matrix. These tissues can be connected to a force transducer and electrically stimulated between parallel platinum electrodes to monitor physiological function. Three weeks after plating, the three-dimensional engineered muscle generated a maximum twitch force of 329 +/- 26.3 microN and a maximal tetanic force of 805.8 +/- 55 microN. The engineered muscles demonstrated normal physiological function including length-tension and force-frequency relationships. Treatment with IGF-I resulted in a 50% increase in force production, demonstrating that these muscles responded to hormonal interventions. Although the force production was maximal at 3 wk, constructs can be maintained in culture for up to 6 wk with no intervention. We conclude that fibrin-based gels provide a novel method to engineer three-dimensional functional muscle tissue and that these tissues may be used to model the development of skeletal muscle in vitro.

Animals↗
PubMed2005

Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury.

BACKGROUND: Implantation of bioartificial patches distorts myocardial geometry, and functional improvement of the recipient heart is usually attributed to reactive angiogenesis around the graft. With the liquid bioartificial tissue compound used in this study, we achieved targeted large-scale support of the infarcted left ventricular wall and improvement of heart function. METHODS AND RESULTS: A liquid compound consisting of growth factor-free Matrigel and 10(6) green fluorescent protein (GFP)-positive mouse (129sv) embryonic stem cells (ESCs) was generated and injected into the area of ischemia after ligation of the left anterior descending artery in BALB/c mice (group I). Left anterior descending artery-ligated mice (group II) and mice with Matrigel (group III) or ESC treatment alone (group IV) were used as the control groups (n=5 in all groups). The hearts were harvested for histology 2 weeks later after echocardiographic assessment with a 15-MHz probe. The liquid injectable tissue solidified at body temperature and retained the geometry of the infarcted lateral wall. Immunofluorescence stains revealed voluminous GFP grafts. The quality of restoration (graft/infarct area ratio) was 45.5+/-10.8% in group I and 29.1+/-6.7% in group IV (P=0.034). ESCs expressed connexin 43 at intercellular contact sites. The mice treated with the compound had a superior heart function compared with the controls (P<0.0001 by ANOVA/Bonferroni test; group I: 27.1+/-5.4, group II:11.9+/-2.4, group III:16.2+/-2.8, group IV: 19.1+/-2.7). CONCLUSIONS: Injectable bioartificial tissue restores the heart's geometry and function in a targeted and nondistorting fashion. This new method paves the way for novel interventional approaches to myocardial repair, using both stem cells and matrices.

Animals↗
PubMed2006

Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN Channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model.

BACKGROUND: The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo. METHODS AND RESULTS: Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-DeltaDeltaDelta, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1-DeltaDeltaDelta in vivo uniquely exhibited automaticity with a normal firing rate (237+/-12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-DeltaDeltaDelta-injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1-DeltaDeltaDelta in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo "bioartificial node" that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing. CONCLUSIONS: The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene-based therapy for correcting defects in cardiac impulse generation.

Animals↗
PubMed2003

Development of a cultured dermal substitute composed of a spongy matrix of hyaluronic acid and atelo-collagen combined with fibroblasts: fundamental evaluation.

We have developed an allogeneic cultured dermal substitute (CDS) by cultivating fibroblasts on a 2-layered spongy matrix of hyaluronic acid (HA) and atelo-collagen (Col). The HA sponge was designed to have a honeycomb structure with many holes (0.5 mm diameter) separated by a distance of 4 mm. Part of the Col sponge was able to penetrate into these holes, and the resulting anchoring structure allows binding of a HA spongy layer with a Col spongy layer. The preparation of the CDS consists of two steps: (i) attachment of cells to the Col surface of the hydrated 2-layered spongy matrix and (ii) proliferation of cells on this sponge immersed in culture medium. The aim of the present study was to assess properties of fresh and cryopreserved CDS. Fibroblasts seeded on the Col surface of the 2-layered spongy matrix attached, proliferated and released vascular endothelial growth factor (VEGF) and fibronectin. The amount of VEGF released from cryopreserved CDS after thawing slowly in an incubator at 37 degrees C and re-cultivation for 1 week was about 300 pg/ml. After thawing quickly in a water bath at 37 degrees C and re-cultivation for 1 week, the amount of VEGF released was about 600 pg/ml. These findings indicate that the cryopreserved CDS maintained its ability to release a significant amount of VEGF. Retention of the therapeutic properties of CDS after cryopreservation is important for clinical use.

Bioartificial Organs↗
PubMed2003

Modification of porous aminopropyl-silicate microcapsule membrane by electrically-bonded external anionic polymers.

Biocompatibility and permeability of a microcapsule membrane governs the function of a microcapsule-shaped bioartificial pancreas. We have previously developed an alginate/sol-gel-synthesized aminopropyl-silicate/alginate microcapsule (Alg/AS/Alg), which had insufficient biocompatibility. The purpose of this study was to investigate whether the biocompatibility could improve by modifying the external surface with other anionic polymers and to investigate an influence of the modification on the permeability of the membrane. Four kinds of anionic polymers, poly(oxyethylene)diglycolic acid (3 kDa), heparin (15 kDa), Alg (54 kDa) and carboxymethylcellulose (CMC, 60 kDa) were used as the external anionic polymers. The heparin-bonded gel bead had the largest resistance to the diffusion of small molecules. The molecular mass cut-off point of 150 kDa required for immunoisolation was maintained for all anionic polymers. Cellular overgrowth to the implanted islet-enclosing microcapsule, a sign of insufficient biocompatibility, was suppressed by altering the external surface material from Alg to CMC. These results suggest that the biocompatibility of the Alg/AS/anionic polymer membrane can be improved by using a biocompatible anionic polymer. At the same time, it is suggested the influence on the permeability has to be investigated to develop an optimal microcapsule for bioartificial pancreas.

Animals↗
PubMed2003

Dextran sulfate as a material for the preparation of a membrane for immunoisolation.

Bioartificial pancreas, in which the islets of Langerhans (islets) are enclosed in an artificial membrane to be protected from the host immune system, is expected to be a promising medical device to treat patients who suffer from insulin-dependent diabetes. Our strategy for preparation of a bioartificial pancreas involves utilizing a membrane including polymeric materials that can inhibit the complement. In our series of studies, we have examined interactions of various polyanions with the complement system to search for potential complement inhibitors. In this study, we concentrated our efforts to clarify the effects of dextran sulfate on the complement system. All of the dextran sulfates examined inhibited the complement activation through both classical and alternative pathways as previously reported. In addition to their inhibitory effects, a certain species of dextran sulfate (molecular mass 10 kDa, degree of sulfonation in a pyranose ring 1.99) specifically degraded C3 without complement activation and, thus, anaphylatoxins that trigger inflammatory reactions were not generated. These facts suggest that a membrane including dextran sulfate effectively protects the islet cells from humoral immunity in addition to not triggering inflammatory reactions. These properties of the membrane make it suitable for a bioratificial pancreas.

Bioartificial Organs↗
PubMed2005

Membranes for biohybrid liver support: the behaviour of C3A hepatoblastoma cells is dependent on the composition of acrylonitrile copolymers.

Co-polymers based on acrylonitrile, N-vinylpyrrolidone, aminoethylmethacrylate and sodium methallylsulfonate were used to prepare flat membranes by phase inversion. The surface properties of membranes were characterised by water contact angle measurements, atomic force microscopy and X-ray photoelectron spectroscopy (XPS). Membrane permeability was estimated by porosity measurements with water as test liquid. Human C3A hepatoblastoma cells were plated on these materials. Cell-material interaction was characterised by overall cell morphology, formation of focal adhesion contacts and intercellular junctions. Furthermore, cell proliferation was measured and compared with the functional activity of cells as indicated by 7-ethoxycoumarin-O-deethylation. More hydrophilic materials reduced spreading of cells, formation of focal adhesion and subsequent proliferation while homotypic cell adhesion was facilitated in correlation with stronger expressions of intercellular junctions and improved functional activity. In contrast, membranes with stronger adhesivity enhanced cell proliferation but reduced the functional activity of cells. It was concluded that the co-polymerisation of acrylonitrile with hydrophilic co-monomers, such as N-vinylpyrrolidone, could be used to tailor membrane materials for the application in biohybrid liver support systems.

Acrylonitrile↗