Hollow fibers bioreactors

Stirred-tank bioreactors Air-lift bioreactors Wave bioreactors Microcarrier-based systems Packed-bed bioreactors Fluidized-bed bioreactors Hollow-fiber bioreactors Bioreactors providing surfaces for attached cell growth (roller bottles, CellCube , Cell Factory)... 

Pharmaceuticals. Hundreds of pharmaceuticals are proteins made by genetically engineered organisms. Because these reagents are intended for clinical use, they must be produced under completely sterile conditions and are usually grown in disposable (plastic), prepackaged, sterile bioreactor systems. A variety of wave bioreactors, hollow-fiber membrane bioreactors, and variations on these devices help grow the cells that make these products. 

An example of an industrial membrane bioreactor is the hollow-fiber membrane system for the production of (-)-MPGM (3-(4-methoxyphenyl)glycidic acid methyl ester), which is an important intermediate for the production of diltiazem hydrochloride [81, 82]. For the enantiospecific hydrolysis of MPGM a hollow-fiber ultrafiltration membrane with immobilized lipase from Serratia marcescens is used. (-f)-MPGM is selectively converted into (2S,3J )-(-F)-3-(4-methoxyphenyl)glyci-dic acid and methanol. The reactant is dissolved in toluene, whereas the hydrophilic product is removed via the aqueous phase at the permeate side of the membrane, see Fig. 13.9. EnantiomericaUy pure (-)-MPGM is obtained from the to-... 

Keywords. Bioartificial liver, cell culture, hollow fiber bioreactor, flat membrane bioreactor, spheroids... 

Naruse et al. proposed another bioreactor design [22,23], in which porcine hepatocyte spheroids are immobilized on non-woven polyester fabric. This device allows more direct contact between hepatocytes and perfused medium and improves, therefore, the mass transfer capacity. The non-woven fabric module expressed better metabohc and synthetic functions at 24 hours than a hollow fiber module containing spheroids in suspension culture. Longer term results are not yet available and the immunoexclusion properties of this fabric have not been addressed. 

Demetriou et al. [25] described a capillary hollow fiber membrane based bioreactor in which microcarrier-attached hepatocytes are placed in the extracapillary space on the exterior surface of the capillary hollow fiber membranes as shown in Fig. 1. Recent experimental studies with this device have demonstrated its efficacy in animal models. By using cryopreserved microcarrier-attached hepatocytes this system offers the convenience of being readily available when needed. 

Several innovative membrane-based bioreactor designs have recently been proposed, including that by Sussman et al. [10], which involves the cultivation of hepatoma cells on the exterior surfaces of semipermeable capillary hollow fiber membranes which are bundled together with an enclosing plastic shell (Fig. 2). Required nutrient medium is circulated within the capillaries. After the hepa-tocytes have attached and formed a mass of liver tissue, the capillary membranes are perfused with the media. 

Although several hepatocyte-based Ever support systems have been proposed, there is no current consensus on its eventual design configuration. The most devices used currently are based on conventional hollow fiber membranes, and there are many opportunities for bioengineers to design new bioreactors that will optimize device function, particularly with regard to oxygen and nutrient provision. 

Commercial scale cultivation of mammalian cells is accompHshed using different technologies roller bottles, microcarriers, suspension (batch, fed-batch or perfusion mode) and hollow fiber bioreactors (Table 2). However, especially for products needed in large amounts, suspension cultivation seems to be the most effective system [4, 5]. Suspension-based systems are characterized by a homogeneous concentration of cells, nutrients, metabolites and product, thereby facilitating scale-up [6] and enabling an accurate monitoring and control of the culture [7]. 

The core of double membrane stirrer perfusion bioreactors is a stirrer on which two microporous hollow fiber membranes are mounted, one of them being hydrophobic and used for bubble-free aeration, the second of them being hydrophilic and used for cell-free medium exchange [15]. This system has been reported to provide viable cell densities of 20 million cells per miUiliter for more than two months [106]. Although Lehmann et al. [15] have described the scale-up of this system to the 20-L and 150-L scale, it has been most commonly employed at the bench-scale. 

Immobilization of lipases on membranes have also been described and several bioreactors were developed (see review, Balcao, Paiva Malcata, 1996). The immobilization can be done by simple physical adsorption of the lipase on hydrophobic hollow fibers or flat sheets where polypropylene types are the preferred e.g. Accnrel or Celgard) (Bouwer, Cupenus Derksen, 1997). 

Batch cultivation is perhaps the simplest way to operate a fermentor or bioreactor. It is easy to scale up, easy to operate, quick to turn around, and reliable for scale-up. Batch sizes of 15,000 L have been reported for animal cell cultivation [2], and vessels of over 100,000 L for fermentation are also available. Continuous processes can be classified into cell retention and non-cell retention. The devices typically used for cell retention are spin filters, hollow fibers, and decanters. Large-scale operation of continuous processes can reach up to 2,000 L of bioreactor volume. Typically, the process is operated at 1-2 bioreactor volumes... 

A Simple Hollow-Fiber Bioreactor for the In-House Production of Monoclonal Antibodies... 

The hollow-fiber bioreactor is a stenle renal dialysis cartridge, and may be obtained from distributors or hospital supplies departments There are various sizes, but we find the most useful to have an internal volume of 50 or 150 mL. Not all dialysis cartridges are suitable for growing cells The fibers should be of regenerated cellulose, about 10,000 in number, and approx 200-jum diameter and 8-10-pm wall thickness. 

Another type of microbiological reactor is the hollow fiber membrane bioreactor shown in Figure 13.19. In this device, the microbial cells are trapped on... 

The performance of a hollow-fiber or sheet bioreactor is primarily determined by the momentum and mass -transport rate [15,16] ofthe key nutrients through the biocatalytic membrane layer. Thus, the operating conditions (transmembrane pressure, feed velocity), the physical properties of membrane (porosity, wall thickness, lumen radius, matrix structure, etc.) can considerably influence the performance of a bioreactor, the... 

The value AP can change in the axial direction in the hollow fiber (AP is the pressure drop in the membrane matrix due to the momentum transfer, the velocity through the membrane is u0 , where e is the membrane porosity). Kelsey etal. [11] have solved the equation system in all three cases, namely for closed-shell operation, partial ultrafiltration and complete ultrafiltration and have plotted the dimensionless axial and radial velocities as well as the flow streamlines. Typical axial and radial velocity profiles are shown in the hollow-fiber membrane bioreactor at several axial positions in Figure 14.8 plotted by Kelsey etal. [ 11]. This figure illustrates clearly the change of the relative values of both the axial and the radial velocity [V=vL/(u0Ro), U=u/u0 where uc is the inlet centerline axial velocity]. 

Figure 14.8 Axial (top panel and radial (bottom panel) velocity profiles in the hollow-fiber membrane bioreactor at several axial position for a= 1 +8/R0 = 1.7 p/Ot = 1.4 (where (5 = Rs/...

Mass Transport in the Feed Side of the Hollow-Fiber Membrane Bioreactor... 

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