Hollow fiber membrane bioreactor

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-... 

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. 

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. 

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 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... 

It is significant that the reaction mixture was worked up by removal of the unreacted ester by hexane extraction and concentration of the aqueous layer to obtain the desired (i )-amino acid. The process has a high throughput and was easy to handle on a large scale. However, because of the nature of a batch process, the enzyme catalyst could not be effectively recovered, adding significantly to the cost of the product. In the further scale up to 100-kg quantity productions, the resolution process was performed using Sepracor s membrane bioreactor module. The enzyme was immobilized by entrapment into the interlayer of the hollow-fiber membrane. Water and the substrate amino ester as a neat oil or hexane solution were circulated on each side of the membrane. The ester was hydrolyzed enantioselectively by the enzyme at the membrane interface, and the chiral acid product... 

The core part of a hollow-fiber bioreactor is the hollow-fiber membrane module, also simply known as the cartridge. It consists of a plastic cylinder containing hundreds of semi-permeable capillary tubes, known as hollow fibers. The cells are inoculated in the extracapillary space (ECS). The cells colonize the external surface of the fibers and grow in this region. The culture medium is pumped through the lumen of the fibers, known as the intracapillary space (ICS), as shown in Figure 9.11. 

Kelsey LJ, Pillarella MR, Zydney AL (1990) Theoretical analysis of convective flow profiles in a hollow-fiber membrane bioreactor. Chem Eng Sci 45 3211-3220... 

There have been numerous studies exploring the concept of membrane reactors. Many of them, however, are related to biotechnological applications where enzymes are used as catalysts in such reactions as saccharification of celluloses and hydrolysis of proteins at relatively low temperatures. Some applications such as production of monoclonal antibodies in a hollow fiber membrane bioreactor have just begun to be commercialized. 

An early example of a patent on membrane contactor for gas transfer is in Ref. [12]. Harvesting of oxygen dissolved in water and discharging of CO2 to the water is presented in Ref. [13]. A membrane device to separate gas bubbles from infusion fluids such as human-body fluids is claimed in Ref. [14]. A hollow fiber membrane device for removal of gas bubbles that dissolve gasses from fluids delivered into a patient during medical procedures is disclosed in Ref. [15]. Membrane contactors have also found application in dissolved gas control in bioreactors discussed in Refs. [16-17]. 

Aziz CE, Fitch MW, Linquist LK, Pressman JG, Georgiou G, and Speitel GE, Methanotropic biodegradation of trichloroethylene in a hollow fiber membrane bioreactor. Environmental Science and Technology 1995, 29(10), 2574-2583. 

Sun X, Shi Y, Yu H, and Shen Z. Bioconversion of acrylnitrile to acrylamide using hollow-fiber membrane bioreactor system. Biochem Eng J, 2004 18(3) 239-243. 

Membrane bioreactors have been tested for the treatment of foul condensates at various temperatures. The temperature of the foul condensates originating from kraft evaporators and digesters is around 50°C-70°C and an interesting option is to treat this stream using MBRs at thermophilic conditions without cooling the stream [98]. Dias et al. [99] used an MBR technique (0.03 pm hollow fiber membrane) to purify foul condensates from a Brazilian kraft mill (Eucalyptus) at different temperatures. They achieved a very high COD removal as shown in Table 35.3. 

Fig. 7 (A) Overview of the module (B) close-up of the module and (C) close-up of the hollow fiber membrane used in a membrane bioreactor for wastewater treatment. (Courtesy of CH2M Hill.)...

An example of aldehyde formation is the production of isovaleraldehyde by Gluconobacter oxydans R (Fig. 16.2-45) 202, 206. Glycerol-grown Gluconobacter oxydans slowly oxidizes 3-methyl-l-butanol to isovaleraldehyde, with yields of over 90%. The product was recovered by bisulphite trapping or cold traps 202. Extractive bioconversion in a hollow-fiber membrane bioreactor allowed continuous produc-... 

Robertson and his colleagues at Stanford University have examined hollow-fiber membrane bioreactors as a means for continuous... 

Some of the efforts, so far, to model such membrane bioreactors seem to not have considered the complications that may result from the presence of the biomass. Tharakan and Chau [5.101], for example, developed a model and carried out numerical simulations to describe a radial flow, hollow fiber membrane bioreactor, in which the biocatalyst consisted of a mammalian cell culture placed in the annular volume between the reactor cell and the hollow fibers. Their model utilizes the appropriate non-linear kinetics to describe the substrate consumption however, the flow patterns assumed for the model were based on those obtained with an empty reactor, and would probably be inappropriate, when the annular volume is substantially filled with microorganisms. A model to describe a hollow-fiber perfusion system utilizing mouse adrenal tumor cells as biocatalysts was developed by Cima et al [5.102]. In contrast, to the model of Tharakan and Chau [5.101], this model took into account the effect of the biomass, and the flow pattern distribution in the annular volume. These effects are of key importance for conditions encountered in long-term cell cultures, when the cell mass is very dense and small voids can completely distort the flow patterns. However, the model calculations of Cima et al. [5.102] did not take into account the dynamic evolution of the cell culture due to growth, and its influence on the permeate flow rate. Their model is appropriate for constant biocatalyst concentration. 

Steady state models of membrane bioreactors utilizing a multi-enzyme system, which in addition to the main reaction promotes the simultaneous regeneration of the co-factor (for further discussion see Chapter 4) have been developed by different groups in Japan [5.109, 5.110]. Several of these studies have also considered the effect of backmixing [5.111, 5.112]. A model of an enzymatic hollow fiber membrane bioreactor with a single enzyme, which utilizes two different substrates (reaction 5.42) has been developed recently by Salzman et al [5.113]. 

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