Oxygen Transfer in a Diffusion‐Limited Hollow Fiber Bioartificial Liver

Hay, P.D.; Veitch, A.R.; Smith, Mark D.; Cousins, Roderick; Gaylor, J.D.S.

doi:10.1046/j.1525-1594.2000.06499.x

Cited by 88 publications

(73 citation statements)

References 23 publications

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“…Xu et al pointed out that four bioreactor compartments are necessary to enable oxygenation and distributed mass exchange with low gradients 27 . Integral oxygenation allows mass exchange limitations to be addressed using separate oxygenators in a circuit 28 , but most of these models were used only for clinical applications and are not available or cost effective for laboratory scale research applications. In this study, we show the feasibility of scaling down a 3D multicompartment bioreactor perfusion technology previously used for extracorporeal liver support from a cell compartment volume of 600-to 800-mL scale to a miniaturized laboratory scale with cell compartment volumes of 2 and 8 mL for in vitro studies on CD34 + HSC differentiation towards RBC.…”

Section: Discussionmentioning

confidence: 99%

Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells

Housler

Miki

Schmelzer

et al. 2012

Tissue Engineering Part C: Methods

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Continuous production of red blood cells (RBCs) in an automated closed culture system using hematopoietic stem cell (HSC) progenitor cell populations is of interest for clinical application because of the high demand for blood transfusions. Previously, we introduced a four-compartment bioreactor that consisted of two bundles of hollow fiber microfiltration membranes for transport of culture medium (forming two medium compartments), interwoven with one bundle of hollow fiber membranes for transport of oxygen (O 2 ), carbon dioxide (CO 2 ), and other gases (forming one gas compartment). Small-scale prototypes were developed of the three-dimensional (3D) perfusion cell culture systems, which enable convection-based mass transfer and integral oxygenation in the cell compartment. CD34+ HSC were isolated from human cord blood units using a magnetic separation procedure. Cells were inoculated into 2-or 8-mL scaled-down versions of the previously designed 800-mL cell compartment devices and perfused with erythrocyte proliferation and differentiation medium. First, using the small-scale 2-mL analytical scale bioreactor, with an initial seeding density of 800,000 cells/mL, we demonstrated approximately 100-fold cell expansion and differentiation after 7 days of culture. An 8-mL laboratoryscale bioreactor was then used to show pseudocontinuous production by intermediately harvesting cells. Subsequently, we were able to use a model to demonstrate semicontinuous production with up to 14,288-fold expansion using seeding densities of 800,000 cells/mL. The down-scaled culture technology allows for expansion of CD34 + cells and stimulating these progenitors towards RBC lineage, expressing approximately 40% CD235 + and enucleation. The 3D perfusion technology provides an innovative tool for studies on RBC production, which is scalable.

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Section: Discussionmentioning

confidence: 99%

Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells

Housler

Miki

Schmelzer

et al. 2012

Tissue Engineering Part C: Methods

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“…In vivo, oxygen supply to the hepatocytes is provided by both the oxygen rich arterial circulation and portal circulation Balis et al (1999), resulting in a microenvironment with an oxygen concentration ranging between of 2 and 7 mol/m 3 Nahmias et al (2006). In vitro, oxygen concentration becomes the limiting factor for cellular viability and many hepatic functions due to low oxygen diffusivity (2.88 Â 10 À9 m 2 /s) and solubility (1.19 nmol/cm mmHg) within the culture medium (Consolo et al, 2009;Hay et al, 2001). This limitation is further compounded by the increased of oxygen uptake rate ($300%) during the beginning of cell culturing, which corresponds to the initial phase of the cells' attachment and spreading on the substrate as they interact with the extracellular matrix Yanagi and Ohshima, 2001).…”

Section: The Importance Of Direct Oxygenationmentioning

confidence: 99%

A thin‐walled polydimethylsiloxane bioreactor for high‐density hepatocyte sandwich culture

Tan

Toh

Birgersson

et al. 2013

Biotech & Bioengineering

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In vitro drug testing requires long-term maintenance of hepatocyte liver specific functions. Hepatocytes cultured at a higher seeding density in a sandwich configuration exhibit an increased level of liver specific functions when compared to low density cultures due to the better cell to cell contacts that promote long term maintenance of polarity and liver specific functions. However, culturing hepatocytes at high seeding densities in a standard 24-well plate poses problems in terms of the mass transport of nutrients and oxygen to the cells. In view of this drawback, we have developed a polydimethylsiloxane (PDMS) bioreactor that was able to maintain the long-term liver specific functions of a hepatocyte sandwich culture at a high seeding density. The bioreactor was fabricated with PDMS, an oxygen permeable material, which allowed direct oxygenation and perfusion to take place simultaneously. The mass transport of oxygen and the level of shear stress acting on the cells were analyzed by computational fluid dynamics (CFD). The combination of both direct oxygenation and perfusion has a synergistic effect on the liver specific function of a high density hepatocyte sandwich culture over a period of 9 days.

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“…[9][10][11] In particular, hepatic hollow fiber (HF) bioreactors that constitute one type of bioartificial liver assist device (BLAD) suffer from O 2 limited transport mainly due to the low solubility of O 2 in the cell culture medium, long diffusion pathlengths, and high demand for O 2 by the hepatocytes cultured in the extracapillary space (ECS). [12][13][14] These devices are expected to bridge patients suffering from acute liver failure toward native liver regeneration or orthotopic liver transplantation by providing sufficient global liver functions. 15,16 In vivo, blood enters the periportal region of liver sinusoid via the hepatic artery and portal vein at a mean pO 2 of *65 mm Hg and then leaves the sinusoid in the perivenous region via the central vein at a pO 2 of *25-35 mm Hg, forming an O 2 gradient along the length of the liver sinusoid.…”

Section: Introductionmentioning

confidence: 99%

Hemoglobin Regulates the Metabolic, Synthetic, Detoxification, and Biotransformation Functions of Hepatoma Cells Cultured in a Hollow Fiber Bioreactor

Chen

Palmer

2010

Tissue Engineering Part A

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Hepatic hollow fiber (HF) bioreactors constitute one type of extracorporeal bioartificial liver assist device (BLAD). Ideally, cultured hepatocytes in a BLAD should closely mimic the in vivo oxygenation environment of the liver sinusoid to yield a device with optimal performance. However, most BLADs, including hepatic HF bioreactors, suffer from O 2 limited transport toward cultured hepatocytes, which reduces their performance. We hypothesize that supplementation of hemoglobin-based O 2 carriers into the circulating cell culture medium of hepatic HF bioreactors is a feasible and effective strategy to improve bioreactor oxygenation and performance. We examined the effect of bovine hemoglobin (BvHb) supplementation (15 g/L) in the circulating cell culture medium of hepatic HF bioreactors on hepatocyte proliferation, metabolism, and varied liver functions, including biosynthesis, detoxification, and biotransformation. It was observed that BvHb supplementation supported the maintenance of a higher cell mass in the extracapillary space, improved hepatocyte metabolic efficiency (i.e., hepatocytes consumed much less glucose), improved hepatocyte capacity for drug metabolism, and conserved both albumin synthesis and ammonia detoxification functions compared to controls (no BvHb supplementation) under the same experimental conditions.

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Oxygen Transfer in a Diffusion‐Limited Hollow Fiber Bioartificial Liver

Cited by 88 publications

References 23 publications

Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells

Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells

A thin‐walled polydimethylsiloxane bioreactor for high‐density hepatocyte sandwich culture

Hemoglobin Regulates the Metabolic, Synthetic, Detoxification, and Biotransformation Functions of Hepatoma Cells Cultured in a Hollow Fiber Bioreactor

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