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Augustinus Bader - One of the best experts on this subject based on the ideXlab platform.
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Large animal models for testing bioartificial liver support systems.
Biomedical sciences instrumentation, 2020Co-Authors: Nils R. Frühauf, Nosser Sa, Gernot M. Kaiser, Augustinus Bader, Karl J. OldhaferAbstract:After development of a Flat Membrane bioreactor using primary hepatocytes (FMB) further preclinical investigations were necessary. To study safety and efficiency of liver support systems there is a need for a well-defined large animal model.
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Biotransformation of diazepam in a clinically relevant Flat Membrane bioreactor model using primary porcine hepatocytes.
Fundamental & Clinical Pharmacology, 2011Co-Authors: Michael Maringka, Shibashish Giri, Karen Nieber, Ali Acikgöz, Augustinus BaderAbstract:: In vitro biotransformation of drug using commercial culture medium with serum may not be the ideal culture medium for clinical application in extracorporeal bioartificial liver support (BAL) systems. In these systems, patient's blood or plasma is plumbed to primary hepatocytes within a seeded bioreactor, creating interaction between plasma and seeded hepatocytes. To address this situation, we investigated the biotransformation potential of diazepam in primary porcine hepatocytes with a Flat Membrane bioreactor (FMB); we used human plasma exposure and serum-free media in organotypical double gel culture model for long-term culture. We investigated diazepam clearance and all major metabolites of diazepam, such as oxazepam, temazepam, and desmethyldiazepam, in conventional single gel and organotypical sandwich models and compared them to the FMB model. Diazepam elimination was higher in double gel cultures with exposure to both SF 3 medium conditions and plasma, when compared to the single gel model in a Petri dish. It was observed that in the FMB, diazepam elimination was stable at about 3 pg/h/cell in plasma and SF 3 exposure. Oxazepam synthesis in the bioreactor was approximately one quarter less than in the Petri dish, but there were no differences between N-desmethyldiazepam and temazepam synthesis in double gel culture. In the Flat Membrane bioreactor, there was no decrease in the biotransformation of diazepam in plasma exposure compared with the control group. Our results suggest that this plasma exposure bioreactor may offer a useful approach in clinical use of extracorporeal BAL, as well as for drug metabolite investigation into toxicological research.
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Cryopreservation of primary porcine liver cells in an organotypical sandwich model in a clinically relevant Flat Membrane bioreactor
Biotechnology Letters, 2010Co-Authors: Shibashish Giri, Karen Nieber, Ali Acikgöz, Ute Weingartz, Augustinus BaderAbstract:To overcome the logistical difficulties of continuously supplying freshly-isolated, primary porcine liver cells to bioartificial liver support bioreactors, we developed a cryopreservation method using an organotypical sandwich model in a Flat Membrane bioreactor (FMB). We measured albumin secretion rate, urea synthesis rate and 7-ethoxy coumarin (ECOD) in long-term cultures of cryopreserved cells (up to 14 days). The albumin secretion rate was 62% that of non-cryopreserved cells at days 11 and 14. The ECOD activity was 54% that of fresh, control cells initially and increased up to 79% by the 14th day. The urea synthesis rate was stable at 60% that of the control. This study showed that cryopreserved cells can recover liver-specific functions. This result has the potential to dramatically expand the clinical application of bioartificial liver supports.
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Preclinical characterization of primary porcine hepatocytes in a clinically relevant Flat Membrane bioreactor.
Biomaterials, 2009Co-Authors: Michael Maringka, Shibashish Giri, Augustinus BaderAbstract:Using primary porcine hepatocytes, artificial extracorporeal liver support (AEL) is a therapy that carries out the liver functions of liver failure patients until their own organs have been regenerated or until whole organ transplantation. Significant variation exists with regard to current bioreactor designs for AEL, and they may not reflect the in vivo architecture of the liver since each individual hepatocyte has its own direct contact with blood plasma for oxygen and nutrient supply and detoxification. The present study, based on our Flat Membrane bioreactor (FMB), aimed at in vivo liver architecture and to meet authentic clinical levels of human plasma exposure. Since many existing preclinical AELs are based on commercial culture medium with or without nonhuman serum, they may not authentically reflect the clinical situation in human patients, and little research has been done on human plasma exposure in in vitro culture-based bioreactors. To address this situation, herein we examined liver-specific functions such as albumin secretion, urea synthesis, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), cell Membrane stability by lactate dehydrogenase (LDH) test and ammonia clearance by using human plasma and serum-free medium in long-term culture of primary porcine hepatocytes to show the potential of our clinically relevant FMB. We observed that the organotypical double-gel (DG) culture is superior to conventional collagen-coated single-gel (SG) cultures. The performance of liver-specific functions by the FMB has long-term stability with intact cell morphology for up to 20 days under both plasma exposure and serum-free media. Our three focus points (long-term culture that correlates with the generation time of spontaneous regeneration, high-density culture, organotypical culture model using human plasma) may provide valuable clinical clues for AEL.
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Flat Membrane bioreactor for the replacement of liver functions.
Ernst Schering Research Foundation workshop, 2002Co-Authors: L. De Bartolo, Augustinus BaderAbstract:Each year in the U.S., approximately 150,000 people are hospitalised with liver disease and over 43,000 people die from it (Langer and Vacanti 1993). These numbers are expected to increase as the 4 million people currently infected with Hepatitis C advance to liver failure. Transplantation, the only effective means of treating liver failure, is not an option for many patients. Some are simply not sick enough to justify the massive cost, invasiveness and risk of a transplant, leaving them unaided today. Other patients are too sick to qualify, while others die awaiting a transplant.
B. Wagner - One of the best experts on this subject based on the ideXlab platform.
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Surface micromachined piezoresistive pressure sensors with step-type bent and Flat Membrane structures
IEEE Transactions on Electron Devices, 1996Co-Authors: T. Lisec, M. Kreutzer, B. WagnerAbstract:Surface micromachined pressure sensors with step-type bent and nearly Flat Membranes are compared. The influence of the Membrane structure on the sensor characteristics is investigated. The sensors contain four polysilicon piezoresistors arranged at the underside of a polysilicon Membrane. For the step-type bent version of the sensor polysilicon is used as sacrificial layer and aqueous TMAH solution for underetching. Devices with a nearly Flat structure are fabricated by applying a combined TMAH and HF sacrificial layer etching technique of a polysilicon/oxide sandwich. Compared to step-type bent, nearly Flat structures provide decisive advantages for fabrication and show improved performance. Pressure response, noise behavior as well as the thermal drift of both types of sensors is presented.
Charles N. Baroud - One of the best experts on this subject based on the ideXlab platform.
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Capillary origami: Spontaneous wrapping of a droplet with an elastic sheet
Physical Review Letters, 2007Co-Authors: Charlotte Py, Benoit Roman, José Bico, Lionel Doppler, Paul Reverdy, Charles N. BaroudAbstract:The interaction between elasticity and capillarity is used to produce three dimensional structures, through the wrapping of a liquid droplet by a planar sheet. The final encapsulated 3D shape is controlled by tayloring the initial geometry of the Flat Membrane. A 2D model shows the evolution of open sheets to closed structures and predicts a critical length scale below which encapsulation cannot occur, which is verified experimentally. This {\it elastocapillary length} is found to depend on the thickness as $h^{3/2}$, a scaling favorable to miniaturization which suggests a new way of mass production of 3D micro- or nano-scale objects.
L. De Bartolo - One of the best experts on this subject based on the ideXlab platform.
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Flat Membrane bioreactor for the replacement of liver functions.
Ernst Schering Research Foundation workshop, 2002Co-Authors: L. De Bartolo, Augustinus BaderAbstract:Each year in the U.S., approximately 150,000 people are hospitalised with liver disease and over 43,000 people die from it (Langer and Vacanti 1993). These numbers are expected to increase as the 4 million people currently infected with Hepatitis C advance to liver failure. Transplantation, the only effective means of treating liver failure, is not an option for many patients. Some are simply not sick enough to justify the massive cost, invasiveness and risk of a transplant, leaving them unaided today. Other patients are too sick to qualify, while others die awaiting a transplant.
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Reviewof a Flat Membrane Bioreactor as a Bioartificial Liver
Annals of Transplantation, 2001Co-Authors: L. De Bartolo, Augustinus BaderAbstract:: Recent developments in tissue engineering permit to use isolated hepatocytes in a bioreactor for the creation of a bioartificial liver which supports patients suffering from acute liver failure. In this study, the authors discuss the development of a Flat Membrane bioreactor using pig hepatocytes for the replacement of liver functions. The Flat Membrane bioreactor permits a high-density hepatocyte culture under sufficient oxygenation conditions, comparable to an in vivo microenvironment. In this bioreactor, built according to the in vivo organisation of the liver, pig hepatocytes are cultured with non-parenchymal cells within an extracellular matrix between oxygen-permeable Flat-sheet Membranes as individual plates. The performance of the "scale-up bioreactor" was tested in vitro for 18 days in static and flux conditions. Pig hepatocytes in the bioreactor were maintained in three-dimensional co-culture with non-parenchymal cells and are reorganised in a way similar to the liver cell plates in vivo: cells remained polarised in vitro clearly demonstrating biliary zones surrounding individual hepatocytes. The biochemical performance of the bioreactor was assessed by estimating its ability to remove two of the major toxins associated with hepatic encephalopathy: benzodiazepines and ammonia. The rates of ammonia elimination and drug biotransformation were maintained at constant high levels for almost two weeks. This "scaled-up bioreactor" provides conditions favourable for the formation of contiguous cell sheets, which allow to maintain constant liver specific functions.
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High level benzodiazepine and ammonia clearance by Flat Membrane bioreactors with porcine liver cells.
Journal of biotechnology, 2000Co-Authors: A Bader, L. De Bartolo, A HaverichAbstract:The onset of hepatic encephalopathy is a multifactorial process in which endogenous benzodiazepines and hyperammonemia play a pivotal role. The treatment of comatose states in liver failure is one of the major functions of a bioartificial liver. A controlled study demonstrating the capacity of a large scale bioartificial liver to detoxify benzodiazepines could be a crucial prerequisite to break this circle of events leading to coma. The aim of this study was therefore to expose the bioreactor to high levels of benzodiazepines and ammonia for evaluation of its detoxifying capacity. We have developed a novel and unique device reconstructing the plate architecture of the liver. Porcine hepatocytes were co-cultured with non-parenchymal cells. We investigated benzodiazepine metabolism using diazepam as model drug. The bioreactor was also loaded with high levels of ammonia and ammonia clearance as well as urea secretion with ammonia challenge were investigated. Albumin secretion was analysed in parallel as a control viability and tissue specific secretory parameter. The results clearly show that the velocity of diazepam turnover increases between day 1 and 2 and stabilises at high levels. Typical diazepam metabolites including temazepam, N-desmethyl-diazepam and oxazepam were generated. Cell specific functions, including albumin secretion, were comparable to an in vivo liver. We conclude that the Flat Membrane bioreactor used as bioartificial liver has the potential to detoxify diazepam and ammonia at significant amounts. Maintenance of monoxygenase activities in vitro is one of the strongholds of the bioreactor concept presented in this study.
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a novel full scale Flat Membrane bioreactor utilizing porcine hepatocytes cell viability and tissue specific functions
Biotechnology Progress, 2000Co-Authors: L. De Bartolo, Jaroschvon G Schweder, Axel Haverich, Augustinus BaderAbstract:: When designing an extracorporeal hybrid liver support device, special attention should be paid to providing the architectural basis for reconstructing a proper cellular microenvironment that ensures highest and prolonged functional activity of the liver cells. The common goal is to achieve high cell density culture and to design the bioreactor for full-scale primary liver cell cultures under adequate mass transfer conditions. An important aim of this study was to evaluate the biochemical performance of a Flat Membrane bioreactor that permits high-density hepatocyte culture and simultaneously to culture cells under sufficient oxygenation availability conditions comparable to the in vivo-like microenvironment. In such a bioreactor pig liver cells were cultured within an extracellular matrix between oxygen-permeable Flat-sheet Membranes. In this investigation we used a novel scaled-up prototype consisting of up to 20 modules in a parallel mode. Each module was seeded with 2 x 10(8) cells. Microscopic examination of the hepatocytes revealed morphological characteristics as found in vivo. Cell concentration increased in the first days of culture, as indicated by DNA measurements. The performance of the bioreactor was monitored for 18 days in terms of albumin synthesis, urea synthesis, ammonia elimination, and diazepam metabolism. The ability of the hepatocytes to synthesize albumin and urea increased during the first days of culture. Higher rates of albumin synthesis were obtained at day 9 and remained at a value of 1.41 pg/h/cell until day 18 of culture. The rate of urea synthesis increased from 23 ng/h/cell to 28 ng/h/cell and then remained constant. Cells eliminated ammonia at a rate of about 56 pg/h/cell, which was constant over the experimental period. Hepatocytes in the bioreactor metabolized diazepam and generated three different metabolites: nordiazepam, temazepam, and oxazepam. The production of such metabolites was sustained until 18 days of culture. These results demonstrated that the scale-up of the bioreactor was assessed, and it could be demonstrated that the device design aimed at the reconstruction of the liver-specific tissue architecture supported the expression of liver-specific functions of primary pig liver cells.
T. Lisec - One of the best experts on this subject based on the ideXlab platform.
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Surface micromachined piezoresistive pressure sensors with step-type bent and Flat Membrane structures
IEEE Transactions on Electron Devices, 1996Co-Authors: T. Lisec, M. Kreutzer, B. WagnerAbstract:Surface micromachined pressure sensors with step-type bent and nearly Flat Membranes are compared. The influence of the Membrane structure on the sensor characteristics is investigated. The sensors contain four polysilicon piezoresistors arranged at the underside of a polysilicon Membrane. For the step-type bent version of the sensor polysilicon is used as sacrificial layer and aqueous TMAH solution for underetching. Devices with a nearly Flat structure are fabricated by applying a combined TMAH and HF sacrificial layer etching technique of a polysilicon/oxide sandwich. Compared to step-type bent, nearly Flat structures provide decisive advantages for fabrication and show improved performance. Pressure response, noise behavior as well as the thermal drift of both types of sensors is presented.