Liu ZhaohuiZhang Kuishan, Xin Feng
(School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China)
Received Nov. 14, 2003.
Abstract Membrane bioreactors (MBRs), which integrate membrane with bioreactor, simultaneously hold two functions: biocatalysis and membrane separation. Firstly, their advantages and classifications are involved in this paper. Then various applications of MBR in the food industry, fine chemical, pharmaceutical, biomedical productions and environmental treatment are enumerated respectively. These applications obviously denote the potential advantages of MBRs over those in conventional bioreactors (e.g. batch reactor). Finally, current technical challenges facing with in commercial applications of MBRs are described and a perspective is given.
Nowadays, MBRs, as the most promising reactive separation bioprocess, have been attracting more and more study and industry interests. In document , Blatt et al. initially defined a membrane bioreactor in the late 1960’s. Though it is only composed of two functional units- bioreactor and membrane separation, the MBR may theoretically obtain relatively higher yield and conversion than the conventional bioreactors. Since then, a lot of newly-developed MBRs have been reviewed in the literature [1, 2]. In addition to the compact reactor configuration, MBRs can be operated easily and reduced energy consumption. The common advantages of MBRs over conventional bioprocesses have been involved in this article. Moreover, many of them had been successfully used in the food, chemical, medicinal and biological industry, as well as in the environmental treatment . With the progress of related technologies and research fields (e.g. novel membrane material, high-active biocatalysts, biocatalyst immobilization approaches and process design optimization and so on), MBRs have efficiently combined the selective permeation of membrane with a bioreactor to obtain more economic and environmental benefits.
2. ADVANTAGES OF MBRS
There are some main potential advantages  of MBRs summarized as follows:
(1) Selectivity of biocatalysts is usually much higher than that of the conventional chemical catalysts. Moreover, the bioreaction condition in MBRs is very mild, and the products can be selectively permeated through the membrane. As an environmental friendly technology, byproducts can be suppressed.
(2) Biocatalysts-loaded membrane in MBR has a similar effect to a biofilm in nature.
(3) As the products are continuously extracted from the reaction zone, the bioreaction thermodynamic equilibrium limit will be breached. The bioreaction conversion and/or yield will be correspondingly increased.
(4) In MBRs, it is easy to realize that the free diffusion can be replaced by the convective mass transport, which will largely enhance both mass transport rate and reaction rate.
(5) A continuous process with automatic control can be effectively realized in the MBRs.
(6) Processes based on membrane bioreactive separation may largely predigest those downstream purification processes, save labor and energy, integration of membrane and bioreactor can also shortage operation cycle. Furthermore, either free biocatalyst with a suitable biocatalyst cut-off membrane or immobilization biocatalyst in MBRs will reduce biocatalyst loss and save dosage, which will decrease the total cost of facilities and operation.
3. CLASSIFICATIONS OF MBRS[3, 4]
On the basis of biocatalyst immobilization and membrane function, generally, the MBRs are classified into two types (Fig 1): (a) biocatalysts are suspended in solution and compartmentalized by membrane in a reaction vessel, where the membrane only serves as a separation function; (b) biocatalysts are immobilized within membrane, and the membrane acts as a support for the biocatalysts as well as a separation unit. A detailed classification (including immobilization approach) is shown in Fig 2.
Figure 1 Main configuration types of membrane reactors
Figure 2 Examples of biocatalytic membrane reactors with enzymes immobilized using different approaches
In terms of both different shapes of membrane and membrane modules, there are correspondingly various MBRs. Of them, use of hollow fiber membrane bioreactor is the widest in bioprocess . The MBRs can be also classified by the types of membrane materials (e.g. organic, polymeric, inorganic, etc). Inorganic membranes  are attracting much industrial interest to be used in MBRs because of (1) good chemical and mechanical strength; (2) well-distributed pores and (3) easy membrane fouling removal and cleaning.
Otherwise, MBRs are commonly distinguished with their operation modes, such as ultrafiltration membrane (UF) bioreactor, biphasic (organic and aqueous) membrane bioreactor and so on. In a UF membrane reactor, substrates and products are homogeneous, as shown in Fig.3a, if substrate has a higher molecular weight, it can not pass through the UF membrane; while the product easily do so and can be recovered from the other side of the membrane. If substrates and products have different solubilities (e.g. an ester and its hydrolysis products), as Fig.3b shown, a biphasic membrane reactor may be used. In such a bioreactor, the biocatalyst-loaded membrane is located between the organic and aqueous phases.
Figure 3 Examples of biocatalytic membrane reactors with two different operation approaches
4. APPLICATIONS OF MBRS
4.1 MBRs in food industry
MBRs have been widely used in alcohol fermentation , starch hydrolysis [8, 9], juice clarification  and so on. Zhang  invented a novel MBR where membrane is coated with active materials (e.g. diatomite, active carbon, hemp powder) for beer and alcohol production. This MBR easily equipped in primary fermentation process and condition may shortage 20% of production cycle and increase by 30-40% beer yield as well as save energy. Rios et al. applied a continuous recycle MBR for one–step starch hydrolysis to produce high dextrose equivalent sugar syrups and examined the effect of enzyme concentration and space time on the performance of the reactor. The experimental results show that as the two parameters increase, the conversion is enhanced, but capacity and productivity are decreased. Accordingly, optimization of these two parameters depends on the economic rules. Li et al. employed a hollow-fiber membrane bioreactor for a continuous production of isomaltooligosaccharide following a two-step procedure. During the first step, starch is solubilized in water with pH5.3-5.8 and partially hydrolyzed with an-amylase and isoamylase. In the second step, saccharifying enzymes (e.g.-glucosidase, epiphyte amylase) convert liquefied starch into final product—isomaltooligosaccharide. The new-developed process may save enzyme dosage and production period besides obtaining a stable high quality product. To clarify apple juice, Coca et al.  turned to a new integrated MBR and compared this integrated membrane process with conventional methods, total manufacturing costs decrease by 8% when operated with immobilized enzyme, and using an initial enzyme percentage of 0.5% (v/v), as an optimal enzyme concentration, may give a better permeation flux. Clearly, MBRs certainly accelerate the development of food industry.
4.2 MBRs in production of pharmaceuticals and biomedicals
In pharmacy, applications of MBRs have a unique potential that conventional processes never attain. Highly effective production of penicillin, a very valuable antibiotic, will benefit us a lot. Many studies [11, 12] have already employed MBRs technologies for the production of penicillin and its stuff. Yuan et al.  designed a novel MBR with immobilized cell to produce 6-amino-pencillanic acid (6-APA). This MBR uses polysulfone hollow-fiber membrane or flat membrane, which always has a large surface area-volume ratio, the whole penicillin acylase cell is entrapped in the microfiltration or ultrafiltration membrane with the capacity to cut off a suitable molecular weight. This may lead to higher yield and purity than conventional processes. Moreover, MBR mode has few scale-up problems under backflushing mode. Giordano et al. had recently simulated a ceramic MBR for the cultivation of penicillin chrysogenum, immobilized in the upper surface of a porous membrane. To increase the penicillin productivity, the culture medium is diluted at the end of the trophophase , a consistent set of initial conditions has to be selected in order that the numerical solvers can converge. This means the importance of consistent initialization for solving differential-algebraic equations systems, which is useful to evaluate the performance of the bioreactor, to predict its behavior on a large scale and to guide new bioreactor design.
Lactic acid, an important chemical and pharmaceutical additive and preservative agent, is attracting one’s interest [13, 14]. Olmos-Dichara and coworkers  compared the performance of a batch reactor with a MBR for production of lactic acid from lactose over L.cassei sp. Rhamnosus biocatalyst. The MBR consists of a batch bioreactor coupled with a cross-flow mineral membrane filtration unit. The results showed that the productivity of MBR was eight times as high as that of the batch reactor, while the biomass concentration (77g L-1) in the MBR was nineteen times that found in the batch culture. Boyaval et al.  developed a bioreactor coupled with nanofiltration membranes for semicontinuous production of lactic acid from whey permeate. They achieved the highest volumetric productivity 7.5 g L-1 h-1 and the specific productivity 3.54 h-1. After 44h of fermentation more than 99% of the membrane fouling was reversible.
There are some successful applications of MBRs in production of other medicines (e.g. cyclodextrins, microbial alginate, glycerol, monoglyceride, formaldehyde, amino acids and so on). In addition, many fine-chemicals and pharmaceuticals may be produced by resolution method in MBRs . Consequently, we can easily realize that MBRs have played a constructive role in medicine production.
MBRs also have important applications in biomedical area. A valuable application, for instance, is involved in that Yazaki and coworker  produced recombinant anti-carcinoembryonic antigen (anti-CEA) diabody and minibody for clinical applications using a hollow-fiber bioreactor. They firstly gained 137-307 mg of crude antibody in the small-scale hollow-fiber bioreactor, a high-level mammalian expression system. Then their scale-up for clinical studies produced 3.4g minibody with the help of a bigger hollow-fiber bioreactor. In a word, the use of MBRs really facilitates biomedical industry.
4.3 MBRs in environment
MBR was early used in the treatment of sewage water . Since then MBRs have been used in a variety of other applications including purification of underground, surface water and treatment of domestic and industrial wastewater. Lu et al. used a rotary disk UF module coupled with an aerated bioreactor to treat high-strength fermentation wastewater. The MBR can work continuously during 130 days and be demonstrated to be amenable for the treatment of fermentation wastewater. In a recent patent, Peretti et al.  reported treatment of waste gas streams containing VOC using a modular MBR system, which is able to withstand fluctuations in pollutant concentrations. The VOC in the waste gas stream are perstracted with an oleic solvent phase using a bundle of hollow fiber hydrophobic porous membranes serving as a contactor between the gas and the oil phases. The pollutants are biodegraded in a MBR, which contains a second bundle of porous hydrophobic membranes separating the oleic and aqueous phases, and serves as a support for the biofilm. In short, MBRs have been successfully used for wastewater and waste gas treatments.
5. CHALLENGES AND PROSPECTIVES
Though many MBRs have been to some extent used in industrial processes, much broader applications of MBRs are limited by some technical challenges [2, 3], such as (1) biocatalyst deactivation when the biocatalyst is immobilized within the membrane or high mechanical stress to maintain a good transmembrane flux; (2) biofouling and cleaning in MBR; (3) bioprocess design for large-scale production; (4) control of reaction and kinetic mechanisms; (5) computer simulation and optimization of MBRs and so on. Therefore, in order to fully establish the industrial use of MBRs in fine chemical, pharmaceutical, and food industries, some indispensable studies on these challenges need to be continued in the coming years.