Hollow fiber devices

The success of Matsushita s method and the encouraging developments in our laborabory set the stage for a decade of independent research into what we see as the best technology for the development of a liver-assist device. In a sense, Matsushita s work confirmed the structure of the device and our work confirmed the chemistry of the surface. Matsushita continued his work without the benefit of our technology and has successfully demonstrated the use of his device in a dog model. In a 1999 report, an artificial liver was reported to be equal, and probably superior to the most successful hollow-fiber device. 

Extracorporeal devices to support a compromised liver were reviewed by Allen et al. and Strain and Neubcrgcr.Various nonbiological approaches such as hemodialysis or hemoperfusion over charcoal have met with limited success, presumably because these systems inadequately replaced the synthetic and metabolic functions of the liver. Conversely, biological approaches such as hollow fiber devices, flat plate systems, perfusion beds, and suspension reactors have shown encouraging results but are difficult to implement in a clinical setting. 

The last topic in evaluating the suitability of reticulated foam as the scaffold of a composite is somewhat qualitative. It is known that hepatic cells do not function when cultured on a flat plate. At least part of the reason for this is the deformation of the cells developed during the spreading process. It seems likely that if a cell is sufficiently deactivated by a flat surface, the effect will be as severe as when culturing on a convex surface such as the outside shape of a hollow fiber. A reticulated foam, however, presents a cell with several opportunities for a more natural attachment. The dodecahedron structure of each foam cell would appear to be a more natural scaffold for attachment. This perhaps explains the claimed superiority of a scaffold based on a reticulated foam of Gion et al. - over the HepatAssist hollow fiber device. Part of the research program that we will propose is that the effects of conformational aspects of an efficient scaffold will be quantified. 

Kolf s first tubular dialyzer, shown in Figure 12.2, required several liters of blood to prime the system, a major operational problem. In the 1950s, tubular dialyzers were replaced with coil (spiral) devices, also developed by Kolf and coworkers. This coil system was the basis for the first disposable dialyzer produced commercially in the early 1960s. The blood volume required to prime the device was still excessive, however, and during the 1960s the plate-and-frame and hollow fiber devices shown in Figure 12.3 were developed. In the US in 1975, about 65 % of all dialyzers were coil, 20 % hollow fiber systems and 15 % plate-and-frame. Within 10 years the coil dialyzer had essentially disappeared, and the market was divided two-thirds hollow fibers and one-third plate-and-frame. By 1996, hollow fiber dialyzers had more than 95 % of the market. 

Figure 9.19 shows typical cell concentrations reached in the main industrial bioreactors and a comparison of these values with those found in microbial fermentations. As can be observed, batch and fed-batch cultivations attain dry biomass values comparable to those of continuous cultures of microorganisms, so that mass and heat transfer capacities are not limited for these operation modes. However, high cell density cultivation in heterogeneous bioreactors, such as hollow-fiber devices, reaches dry biomass values similar to the maxima observed in microbial cultures. 

As mentioned earlier, membrane blood oxygenators probably would qualify as the earliest form of membrane contactors. Reference [11] is a good illustration of a hollow fiber device. However, most work on liquid-gas membrane contactor over the years has focused mainly on two categories (1) separation, purification, and treatment of water or aqueous media and (2) absorption of gaseous species from air either for purification or for recovery, which will be discussed separately. Applications in multiple markets and industries have been investigated in each category. 

Cooney DO and Jackson CC, Gas absorption in a hollow fiber device. Chemical Engineering Communications 1989, 79, 153-163. 

FIGURE 12.2 Hollow-fiber devices for membrane extraction, (a) Hollow-fiber loops for equilibrium extraction redrawn after Liu et al. (From Liu, J.-F., Jbnsson, J.A., and Mayer, P., Anal. Chem., 77, 4800, 2005.) (b) Liquid-phase microextraction after Pedersen-Bjergaard and Rasmussen. (From Grpuhaug Halvorsen, T., Pedersen-Bjergaard, S., Reubsaet, J.L.E., and Rasmussen, K.E., J. Sep. ScL, 24, 615, 2001. With permission.) (c) Syringe-based hollow fiber LPME. (Erom Zhao, L. and Lee, H.K., Anal. Chem., 74, 2486, 2002. Copyright 2002 American Chemical Society. With permission.)... 

Hollow fiber devices working in flow systems are also known [34]. In those cases, either single fibers or bundles of fibers, perhaps in commercial cartridges, are employed and used in flow system configurations. 

Bhaumik et al. [4] demonstrated the efficiency of transverse flow hollow fiber devices equipped with fibers in a mat wrapped around a central tube (distributor of the liquid) for the absorption of CO2 in water. 

Perfusion systems have also been used for successful scale-up of MoAb production. During the culture period, cell growth occurs exponentially until the cell density reaches a maximum. At that point, the medium needs a continuous supplementation of fresh nutrients and elimination of waste. In perfusion systems, fresh nutrients are supplied and wastes are removed continuously so that the medium meets the physiological needs of the cells. At steady state, the cell concentration is determined by space and other limitations. High cell densities have been achieved by immobilizing the cells in porous ceramic matrices or hollow fiber devices. Intermediate cell densities have been achieved by perfusion reactors with a spin filter, or in a fluidized bed reactor in which the cells are embedded in sponge-like... 

Ethylene oxide (ETO) Is the predominantly used sterilant In the United States for membrane devices destined for medical use. Conditions for Its use have been well established to assure sterility (51), although some problems arise from the slow diffusion of the gas from thick sections of thermoplastics, such as the headers In hollow fiber devices. The majority of hemodlalyzers are prepared with cellulosic membranes, which are partially... 

After the experiment the reactor was dismantled and each of ten dual hollow-fiber units was visually examined. Only in 4 out of the ten fibers cells were densely packed, which suggests that the medium was not adequately supplied to many of these fibers. Probably the medium was not equally distributed among the fibers. In other words, in some of fibers the medium flow was not adequate to support the cell growth in the fiber. The nonuniform flow distribution among the fibers of a hollow fiber device is an intrinsic problem, which was studied in depth in the authors laboratory (16). The work of JL coli immobilization in the dual hollow fiber reactor was reported previously from the authors laboratory (17). 

Hallow Fiber. All commercial designs to dele use shell-side pressurization and tube-side permeate collection. The dominant design has vety fine fibers, but larger fiber deviees also are fband. Fine hollow fiber devices are intolerant of colloidal metier in the feed and require care in feed pretreat-ment. 

The disadvantages of primary hepatocytes are mainly related to their inability to multiply in culture. Human liver cell lines (such as the ACTIVTox system) that retain all of the major liver metabolic pathways have been developed ACTIVTox cells are reported to be a highly selected subclone of HepG2 that has retained many of the properties of normal adult hepatocytes, including metabolic activity. If cultured in small hollow fiber devices, they offer potential for long-term interaction and secondary metabolite studies [53]. 

Porous membranes can be incorporated into compact modules with several shapes [167]. Hollow-fiber devices are, by far, the most widespread modules, mainly due to the high packing density (500-9 x 10 m m ) and low cost. They are, however, prone to fouling and are difficult to clean relative to other modules [167]. Plate and frame and tubular modules are also used [103]. 

In terms of membrane area used and dollar value of the membrane produced, artificial kidneys are the single largest application of membranes. Similar hollow-fiber devices are being explored for other medical uses, including an artificial pancreas, in which islets of Langerhans supply insulin to diabetic patients, or an artificial liver, in which adsorbent materials remove bilirubin and other toxins. 

One example is the blood oxygenator used during surgery when the patient s lungs cannot fimction normally. A flow schematic of one of these hollow-fiber devices is shown in Figure 48. More than 1 million procedures per year use blood... 

D. O. Cooney and M. S. Poufos, Liquid-liquid extraction in a hollow-fiber device, Chem. Eng. Commun., 61, 159-167 (1987). 

Roy et fl/.[62] carried out a copolymerization of MMA and nBA in microemulsion through semicontinuous addition of a monomer to the emulsion to obtain a 40 wt% solid content of latex of about 30 nm particle size using 4 wt% Dowfax 2A-1 as surfactant and 0.4 wt% acrylamide as cosurfactant. Xu et monomer continuously into... 

Other bioreactor configurations have been developed specifically for immobilized enzymes and cells. Enzymes immobilized within polymeric membranes are used in hollow fiber (Fig. 16) and spiral membrane bioreactors (Fig. 17). In the hollow fiber device, many fibers are held in a shell-and-tube configuration (Fig. 16) and the reactant solution (or feed) flows inside the hollow fibers. The permeate that has passed through the porous walls of the fibers is collected on the shell side and contains the product of the enzymatic reaction. Also, instead of being immobilized in the fiber wall, enzymes bound to a soluble inert polymer may be held in solution that flows inside the hollow fiber. The soluble product of the reaction then passes through the fiber wall and is collected on the shell side the enzyme molecule, sometimes linked to a soluble polymer, is too large to pass through the fiber wall. 

There are many studies on how to determine fiber dimensions, spacing, and reactor length however, commercially available units come in a relatively limited number of sizes, usually with inner liber diameters of 500 /rm or more. Several reports in the literature describe the use of hollow-flber systems in the development of a bioartiflcial pancreas, which place the islets on the shell side, while perfusing the fibers with the animal s plasma or blood. The fibers can be made relatively non-thrombogenic and of porosity sufficiently small as to avoid immune attack of the cells inside the shell. One difficulty with this configuration is that interfiber distances in the hollow-fiber device are not well controlled, so that regions within the shell space receive too little nutrients. 

For a hollow fiber device with a symmetrical hollow fiber membrane of diameters di and d and total number of fibers being n,... 

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