See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/287302702 Application of different types of bioreactors in bioprocesses Article · January 2011 CITATIONS READS 0 1,273 4 authors: Michele Rigon Spier Luciana Vandenberghe Federal University of Paraná, UFPR Universidade Federal do Paraná 60 PUBLICATIONS 245 CITATIONS 99 PUBLICATIONS 1,484 CITATIONS SEE PROFILE SEE PROFILE Adriane Medeiros Carlos Soccol Universidade Federal do Paraná Universidade Federal do Paraná 42 PUBLICATIONS 585 CITATIONS 455 PUBLICATIONS 10,032 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Bioprocess in Food Engineering; Enzymes in Food Processing; Food and Beverages Biotechnology View project All in-text references underlined in blue are linked to publications on ResearchGate, Available from: Michele Rigon Spier letting you access and read them immediately. Retrieved on: 24 October 2016 In: Bioreactors: Design, Properties and Applications ISBN: 978-1-62100-164-5 Editors: P.G. Antolli and Z. Liu, pp. 55-90 © 2011 Nova Science Publishers, Inc. Chapter 2 APPLICATION OF DIFFERENT TYPES OF BIOREACTORS IN BIOPROCESSES Michele Rigon Spier*, Luciana Porto de Souza Vandenberghe, Adriane Bianchi Pedroni Medeiros and Carlos Ricardo Soccol Federal University of Parana, Bioprocess Engineering and Biotechnology Department, Paraná, Brazil Abstract This chapter presents bioreactors models applied to bioprocesses including submerged (stirred tank reactor, bubble column, air-lift, membrane, packed bed and fluidized bed bioreactors) and solid-state fermentation processes (horizontal drum, tray-type, packed bed bioreactor and bench scale bioreactors) for the production of important biomolecules for industrial applications. Some recent applications of bioreactors are mammalian cell culture, vegetable cell culture and photobioreactors for algae culture, which are also presented. An overview of bioreactors types, their design and properties will be considered for biomolecules production such as biomass, enzymes, organic acids, aroma compounds, spores, mushroom production, pigments, antibiotics and others. In this chapter some attention was given to bioreactors applied to animal cell culture and algae production that require some special specifications due to some factors that affect these biomolecules production. Some important details of mass transfer and scale-up of bioprocesses will also be described. Introduction The bioreactors are the main unit operations for industrial biochemical transformation in which the treated materials promote the biotransformation by the action of the living cells or by the cellular components such as enzymes (Pandey et al, 2008). Bioreactors are tanks or vessels in which cells or cell-free enzymes transform raw materials into biochemical products and or less undesirable byproducts. These reactors are commonly cylindrical, ranging in size from a liter to some cube meters, but differs depending on the design and the operation mode * E-mail address:
[email protected]. (Corresponding Author) 56 M.R. Spier, L.P. de Souza Vandenberghe, A.B. Pedroni Medeiros et al. in industrial bioprocesses. Although the bioreactor may be simple or highly instrumental, its ability to produce the desired product or results is important to consider. The bioreactor is designed and operated to provide the environment for product formation selected by scientists, bakers, or winemakers. It is the heart of many biotechnological systems that are used for agricultural, environmental, industrial and medical applications (Schaechter & Lederberg, 2004). All the bioreactors present great importance due the generation of products in these equipments, which are the heart of the bioprocesses (Cinar et al, 2003). In some cases, the bioreactor may be applied for biomass production (e.g. single cell protein, Baker´s yeast, animal cells, microalgae); for metabolite formation (e.g. organic acids, ethanol, antibiotic, aromatic compounds, pigments); to transform substrates (e.g. steroids) or even for production of an active cell molecule (e.g. enzymes). The systems based on the mammalian or plant cells culture are usually referred as tissue cultures, while those based on the dispersed non-tissue-culture-forming culture of the microorganisms (bacteria, yeast, fungi) are loosely referred to as “microbial” reactors (bioreactor, fermenter). In the enzyme reactors, no live- cells are used for the transformation of the substrate. Frequently, these reactors employ immobilized enzymes where the solid supports are used to entrap (internally) or attach (externally) the enzyme (biocatalyst) so that it can be repeatedly used to economize the enzyme consumption (Bhattacharyya et al., 2008). A bioreactor consists of a complex system of pipes, fittings, wires, and sensors; it is exposed to operational problems. With the aid of on-line monitoring and diagnosis tools, it is now possible to detect many things that can go wrong during the process (Cinar et al., 2003). The bioreactor has origin in early history and some important marks are shown in Table 1. Before 500 B.C. the Babylonians still produce beer in tanks which had the function of a bioreactor. Wine was produced in wineskins, which were carefully selected for their ability to produce a beverage that met the approval of the king and other members of his sensory analysis. Early recorded history shows that some understood the importance of the components and the environmental or operating conditions of the reactor. This allowed leavened bread and cheese to be produced n Egypt more than 3000 years ago (Schaechter & Lederberg, 2004). Bioreactor operation mode is classified in: batch processes, bed-batch and continuous processes. Normally these operations mode are used in submerged or liquid fermentations or during cell culture such as tissue culture or algae growth. Batch processes has increased significantly nowadays and are extensively used to produce specialty biomolecules for uses in chemical, biotechnological, pharmaceutical industries. The production of these high value- added bioproducts contributes to a significant and growing portion of the revenue and earnings of bioprocess industries (Cinar et al, 2003). Batch processes refer to a partially closed system in which most of the materials required are loaded onto the bioreactor aseptically and are removed at the end of the operation. In a batch bioprocess, the only material added and removed during the course of operation is air/gas exchange, antifoam and pH controlling agents. Most modern bioprocesses incorporate adjustments to the medium to control conditions and to supply nutrients and compounds that promote biosynthesis of the desired product (Cinar et al, 2003). Bioreactors for fed-batch processes represent an important class of bioprocesses, mainly in the food industry and in the pharmaceutical industry but also e.g. for biopolymer applications (PHB). One of the key issues in the operation of fed-batch reactors is to optimize the production of a synthesis product such as enzymes and penicillin or even biomass Commonly used SSF bioreactors can be divided into four types based on type of aeration or the mixed system employed. 2003) and may be used different types of bioreactors for lead the solid state fermentation. 2008). These are tray. compared to the batch systems. with little fluctuation of the nutrients. however. However. cell numbers or biomass (Binod et al. Besides substrate. pigments. The continuous cultivation gives a near-balanced growth. 2003). linear growth. and to avoid mutation and plasmid instability found in continuous culture (Nag. In fed-batch or also called semi-continuous bioreactor characterize by the feeding of sterile substrate. 2008). organic acids. fresh medium is added into the batch system at the exponential phase of the microbial growth with a corresponding withdrawal of the medium containing the product. horizontal drums and fluidized bead having their own advantages and disadvantages. This process recycles agro-industrial residues without economic fate for many different applications in bioprocesses such as enrichment. vegetable hormones (Soccol & Vandenberghe.C. In continuous culture. food aroma compounds. Baking. Dochain (2008) . to demand less initial biomass. biopesticides. Table 1. Main events using bioreactors in the history Year Event 4000-3000 B. packed- bed. the absence of outflow from the fermenter and the increase in volume (accumulation of total mass) in the bioreactor. fed-batch and continuous operation systems must be analysed according to the different models of bioreactors and the process itself. which promoted the necessity to develop novel bioreactors with better design (Singhania et al. USA) 1940s Production of penicillin by fermentation (USA) 1950s Design and scale-up pf large aerated fermenters 1970s More than 100 new drugs and vaccines produced by bioprocesses 1980s Control of fed-batch bioreactors Source: Based on Heinzle et al (2006). The operation mode of solid state fermentation most used industrially is the batch system. Differ from submerged fermentation. brewer 2000 B. the substrate must possess enough moisture to support growth and metabolism of the microorganism. Fed-batch processes have been utilized to avoid utilizing substrates that inhibit growth rate if present at high concentration. Ethanol production and distillation (China) 1923 Commercial production of acid citric (Pfizer. and use of alternative feed strategies (Dunn.C. mushrooms. to overcome the problem of contamination. xanthan gum. These operations present some advantages. although they need some investments and rigorous instrumentation and control. solid-state fermentation (SSF) has been defined as the fermentation process which involves solid matrix and is carried out in absence or near absence of freewater. It can be used to demonstrate the important characteristics of quasi-ready state. production of biomolecules such as enzyme. 2008). metabolites. Application of Different Types of Bioreactors in Bioprocesses 57 (Dochain. biological detoxification. 2009). Batch operation systems can be applied for all types of bioreactors. to overcome catabolic repression. required nutrients also are added continuously or intermittently to the initial medium after the start of cultivation or from the point halfway through the batch process. they are generally made of staining steel. there are several factors that must be considered in the construction of bioreactor.P. Current reactor technologies. temperature and pH control. In this case. 2008). Generally. The main hole of the bioreactor is to provide an adequate and controlled environment for cell growth and product synthesis. In the bioreactor. Because of its versatility and flexibility the mechanically stirred tank reactors (STR) remains the mainstay for industry. aeration and mixing systems (when necessary). which can be controlled by a foam breaker. when the aeration is required. The most important bioreactor for industrial applications is the conventional STR due to its low operation costs. Pedroni Medeiros et al. Among them sterility. beer and cheese. 1995). the homogeneity and bubble dispersion is achieved by mechanical agitation. There is a great variety of impellers that are described.Non-mixed and non-aerated systems: approximately 70% 2. 70-80% of the total volume of the STR is filled with liquid. Different materials and their combinations can be used for their manufacture. A. (Engasser. 1995).Non-mixed and aerated systems: approximately 10% 3. there is a headspace for gas exhaustion and foam formation. the aeration rate must be higher to promote a higher contact between the air bubbles and the liquid. In a closely controlled environment they have to provide efficient means of mixing. Submerged Bioreactors Stirred Tank Reactors . 1988). low energy consumption and adequate size and material (Stanbury. According to Najafpour (2008). For higher volumes. depending on the heat to be removed (Najafpour. The ration 1:1 is probably the most economic because it presents a lower superficial area and. de Souza Vandenberghe. which requires relatively high energy consumption per unit of volume (Doran. The relation between high and diameter may vary between 2:1 till 6:1. mass and heat transfer between the different phases.58 M. consequently. However. 1995). it needs less material. Non-aerated and non-mixed tanks are used in the production of traditional products such as wine. new types of bioreactors are constantly being developed in order to optimize and improve productivities. geometry. 2008). which produce different flow patterns in the tank. which is carried out in mixed and aerated tanks (Najafpour. L. .STR Bioreactors designed for the most efficient expression of the biological properties of the living cells must achieve optimal interactions between the cells and the culture media. there are three main types of fermenters that are used in industrial scale: 1. Laboratory-scale tanks with a volume of maximum 20 liters are made of glass. In this way. but also a higher hydrostatic pressure on the top of fermenter (Doran.Mixed and aerated systems: approximately 20%. Spier. The size of the tanks may vary between some dm3 till hundreds of m3.B.R. The major part of the new products are obtained from the cultivation of microorganisms. it is difficult to choose the right one for a certain application (Mirro & Voll. The use of different types of impellers is defined according to the different scales of viscosity. Continuous Stirred Tank Reactors . concentration. the development of new models of impellers. The sensibility of the biocatalyzers must be studied and analyzed in each case (Doran. Some cells can suffer strongly with the shear stress generated by the mixing that causes their inactivation or a negative influence on them. very sensitive and need a special attention and of course. Application of Different Types of Bioreactors in Bioprocesses 59 STRs are used for free and immobilized cells and enzymes. An ideal CSTR can be modeled considering a perfect mixing. There are two types of CSTR operation strategies. density and viscosity of the fluid to be mixed. Actually. 1999). They are normally in the center and suspended in the superior part of the tank. Mirro & Voll (2009) listed several impellers commonly used in fermentation showing the best suited for each type of cell culture processes. The second one is the Turbidostat where the cell concentration is maintained constant by the monitoring of the culture optical density and the liquid volume is kept constant by setting the outlet flow rate equal to the inlet flow rate (Laska & Cooney. if possible. which is positive to mass and heat transfer contributing for an efficient reaction. In this case. The propeller type is recommended for the range of 1 to 104 centipoises. So. Mammalian and plant cells are. fluid properties and reaction rate variations. 2009). 1995). Depending on the impeller used. They are divided into two main groups: turbine impeller and paddle impeller. 1999). media and total volume. It means that inlet and outlet streams have the same properties of the bioreactor medium.CSTR The CSTR are defined as STR that works in a continuous operation including feeding and remove of mass and energy. Some Dispositive of STRs Impellers The mixing in bioreactors is done mechanically using impellers. there are three flux profiles: radial. there is a great variety of impellers. The correct choice of impellers is based on the bioreactor dimensions. Impeller designs are almost as varied as the types of cell lines they are designed to help grow. the instrumentation and control systems are different and more sophisticated (Laska & Cooney. for example. it is critical to choose the impeller type that is best suited for the each process. axial and tangential. All properties of the CSTR are determined exactly as for the batch bioreactor. However. . specific for each kind of process. there is a high degree of interaction between the substrate and biocatalyzers (microorganisms and enzymes). Even so. CSTRs can be used in series with more than one bioreactor with different conditions in each one. without temperature. with a wide range of impeller designs. One of them is the Chemostat that is used for cell culture in which all nutrients are added in excess and the liquid volume is kept constant by setting the inlet and outlet flow rates equal. When there is a satisfactory mixing. the intensity of mixing depends on the type of process. In these correlations. A. there are also magnetic impellers for industrial applications. Nevertheless. which can be described by the power-law model. For low-viscosity liquids. affecting mixing pattern. It assures a very efficient mixing independently of the volume of the fluid. 1993).B. These arrangements prevent sedimentation and development of stagnant zones at the inner edge of the baffle during mixing of viscous cell suspensions (Doran. Mass and Heat Transfer in STRs Fermentation broths containing mycelial cells frequently exhibit a pseudoplastic non- Newtonian rheological behavior. Alternatively. The magnetic agitator is directly connected to the bottom of the tank. Two types of correlations have been proposed for the volumetric oxygen transfer coefficient (kLa). in order to maintain adequate kLa values. or set at an angle. Various investigators have correlated kLa values to power density (Pg/V) and superficial gas velocity (vs) over one or two similar vessel sizes. The first does not make use of any dimensional criterion. Pedroni Medeiros et al. Magnetic Mixing Besides the mechanical impellers. with consequent physical damage to the cells and a reduction in the process productivity (Smith at al. Baffles are attached to the tank by means of welded brackets. L. This fact eliminates the need of sealing that can provoke contamination or fluid losses. de Souza Vandenberghe. but the prediction of kLa is extremely difficult because of the complexity of the gas–liquid hydrodynamics. This behavior exerts a profound effect on the bioreactor performance. baffles are usually attached perpendicular to the wall. baffles can be mounted away from the wall with a clearance of about 1/50 the tank diameter. power requirement. Moreover.(vs ) 1 b . when compared to the ones with mechanical impellers. four equally-spaced baffles are usually sufficient to prevent vortex formation. high impeller speeds (N) lead to the formation of high shear zones close to the impellers. heat and mass transfer processes (Gavrilescu et al. 1995). Spier.R. 1944): a1 Pg kL a α V .P. Baffles Baffles are vertical strips of metal mounted against the wall of the tank. STRs are used in a variety of process industries. They are installed to reduce vortexing and swirling of the liquid. and facilitate the cleaning of the bioreactor. 1990). The increase in the broth apparent viscosity (µap) during aerobic fermentations can be partially compensated by increments in the operating conditions (N and Q).60 M. (Cooper et al. the use of magnetic agitators requires smaller engines. kLa is related to the gassed power consumption per unit volume of broth (Pg/V) and the superficial gas velocity (vs). The optimum baffle width depends on the impeller design and fluid viscosity but is of the order 1/10-1/12 the tank diameter. as originally proposed by Cooper et al. volumetric gas flow rate per unit volume of liquid (Q/V or VVM). 2001). Some examples of this strategy were presented by Ju & Chase (1992). specific power input. The number of realizable factors. the range of variables covered and the experimental methodology used (Bandino et al. and constant Q/V with D t/D T adjusted within the limits suggested by Oldshue (1966). Scale-Up of STRs Scale-up means reproducing in plant-scale equipment the results from a successful fermentation made in laboratory. maximum shear. design. 3) Constant kL a. constant impeller tip speed NDi. superficial air velocity) on kLa for submerged and surface aeration. and constant maximum shear (or constant impeller tip speed NDi) with Q calculated from the kLa correlation. Accordingly. type. the experiments were carried out for non-respiring biomass suspensions of Propionibacterium shermanii. 2) Geometric similarity. using a large domain of operating variables. superficial gas velocity (vs). Theoretical predictions of both the volumetric mass transfer coefficient and the enhancement factor that have been recently proposed are described. however is limited by the degrees of freedom available in process. In this way. 1992). then the main empirical equations. are considered. . For quantifying the effects of the considered factors (concentration and morphology of biomass. Galaction et al. including those using dimensionless numbers. the following combinations of scale-up criteria have been suggested: 1) Geometric similarity (or constant DI/DT) . mixing time. (2005) studied the oxygen mass transfer rate through the mass transfer coefficient. a current scale-up strategy is to maintain one or two of the in the order of criticality to the performance of the bioprocess. scale-up and development of bioreactors. the maximum number of criteria that can be maintained constant in a conventional scale-up strategy is three. and constant Q/V (or VVM) with N determined by the k L a correlation. impeller Reynolds number (Re) and momentum factor (Ju & Chase. depending on the system geometry.or pilot-scale equipment (Hubbard. Saccharomyces cerevisiae and Penicillium chrysogenum. different criteria for bioreactor scale-up are considered in the light of the influence of OTR and OUR affecting the dissolved oxygen concentration in real bioprocess. The possible increasing on OTR due to the oxygen consumption by the cells is taken into account through the use of the biological enhancement factor. some parameters of the process must be maintained constant during the scale-up: reactor geometry. constant ICE a. media composition. concentration and microorganisms morphology. 1997). Application of Different Types of Bioreactors in Bioprocesses 61 where the values of the constants a1 and b1 may vary considerably. The scale-up process thus directly influences the production capacity and efficiency of a bioprocess. the most used measuring methods are revised. finally. constant k L a. Garcia-Ochoa & Gomez (2009) reported a very important review of the oxygen transfer rate (OTR) in bioprocesses to provide a better knowledge about the selection. mycelial aggregates (pellets) and free mycelia morphological structures. operational characteristics of the vessels. power input per unit volume of liquid (Pg/V). First. for a STR and different fermentation broths. volumetric oxygen transfer coefficient KLa. For example. Normally. B. The term Airlift is linked to the characteristics of pneumatic contact of the gas-liquid or gas-liquid-solid defined by the circulation of the fluids in a cyclic pattern (Flickinger & Drew. A. mammalian and plant cells. Kantarcia et al. 2001. Hold up is the proportion of liquid that is occupied by the gas or the bubble volume in relation to the liquid. Some important applications of bubble columns are the production of industrially valuable products such as enzymes. Spier. Bubble Column Bioreactors Bubble column reactors (BCRs) are pneumatic mixed reactors. de Souza Vandenberghe. Bubble columns are intensively utilized as multiphase contactors and reactors in chemical. . Several recent biochemical studies utilizing bubble columns as bioreactors will be presented in Table 2. 2005). biochemical and metallurgical industries (Degaleesan. The gas is sparged in the form of bubbles into either a liquid phase or a liquid– solid suspension. petrochemical. the residence time. BCRs usually consist of a cylinder with a ratio high:diameter of 2:1 or even 3:1. ring type distributors and arm spargers. On the top of the BCRs the diameter of the cylinder is larger to facilitate the liberation of bubbles and foam break. 1999). Gas holdup is a dimensionless key parameter for design purposes that characterizes transport phenomena of bubble column systems (Luo et al. accurate and successful design and scale-up require an improved understanding of multiphase fluid dynamics and its influences (Kantarci et al.R. porous plate. The sparger used definitely determines the bubble sizes observed in the column. the interfacial area and the mass transfer. L. and equalize the shear stress that is provoked by the mixing. This fact reduces the coalescence of bubbles. Gas sparger type is an important parameter that can alter bubble characteristics which in turn affects gas holdup values and thus many other parameters characterizing bubble columns. 2005). differently to STRs. in order to allow a better time of contact of the air and the liquid. The most important parameters in this type of bioreactor are the bubble ascending speed. proteins. The main difference is a central tube or other components (channels) that are responsible for an efficient mixing and re- circulation of the fluid. The aeration is promoted with compressed air through some spargers that are installed in the bottom of the tank. membrane. etc. Pedroni Medeiros et al. 1999). It is basically defined as the volume fraction of gas phase occupied by the gas bubbles.P. antibiotics. A bubble column reactor (BCR) is basically a cylindrical vessel with a gas distributor at the bottom. Some common gas sparger types that are used in literature studies are perforated plate. the “hold up”. For some applications it is possible to find the ratio high:diameter of 6:1. Air Lift Bioreactors Airlift bioreactors (ARL) are a variation of the BCRs. which were developed for sensitive cells culture such as filamentous fungus cells. All studies examine gas holdup because it plays an important role in design and analysis of bubble columns (Kantarci et al. Although the construction of bubble columns is simple. which circulate through the reactor. 2005). There are not other internal components.62 M. Small orifice diameter plates enable the formation of smaller sized bubbles. These reactors are generally referred to as slurry bubble column reactors when a solid phase exists. the circulation of the fluids follow distintc channels. glass fibers (Perry & Wang. There are some different structures of external loop reactors and internal loop reactors. where the ratio of height to diameter (aspect ratio) is typically greater than 10:1. medium perfusion rate.b). the reservoir of the medium (Wang et al. A frequent approach in developing PBRs is to first use a small-scale model bed to identify the optimal packing matrix for the cell line of interest. These configurations can be re-worked with the development of new possibilities for tha amelioration of the fluid dynamic and a better liberation of the gas in the liquid according to the different processes. Packed Bed Bioreactors The Packed Bed Bioreactors (PBRs) typically consist of a packed-bed that supports the cells on or within carriers and a reservoir that is used to re-circulate the oxygenated nutrient medium through the bed. Application of Different Types of Bioreactors in Bioprocesses 63 There are two main basic configurations of the ALRs: External loop reactors and internal loop reactors. which crieates some channels for the circulation or concetric tubes that creates a central and a periferic channel (Flickinger & Drew. 1992a. An optimal matrix is one that provides the requisite combination of cell attachment. 1989. A relatively well-known example of such application is the bioartificial liver device (BAL) (Allen & Bhatia.80 to 0. or within.95 were reached with the next generation of packing materials such as disks made of non-woven polyester and polypropylene screen. ceramic spheres and other shapes. 1999). polyurethane and polyvinyl foams or resins (Meuwly et al. proliferation and productivity. PBRs can provide extremely high productivity within a compact size is the. There has been an increasing trend in identifying support materials that were compatible with different types of cells (microorganisms cells and mammalian cells). The column diameter should ideally be at least 50-times the particle diameter. Many authors presented the potential of the use of PBRs as “artificial organs” (Allen et al. Fluidized Bed Reactors Fermenters for fluidized bed (FB) operation are tall columns. For example. Chiou et al. This matrix is then used to optimize the operational parameters (e. etc. Higher internal porosities ranging from 0. but in the . depending on the number and position of spargers. with the packed-bed compartment located either external to. in the internal loop with concentric tubes.g. 1991). Two major configurations are possible. Dempsey [1994] reported that fermenters with an aspect ratio of either 20:1 or 40:1 have been designed and operated. in the second one there is only a barrier strategically positioned in a unic vessel. holdup and dynamic of the fluids must be analysed. 2007). 2002). the ascendent gas flux can be produced at both the central or periferic part of the bioreactor. PBRs have been used widely for perfusion culture of immobilized mammalian cells. 2007). where the superficial gas velocity. 2001) in biomedical applications. packed-bed height and volume.) of the PBR through perfusion experiments that are generally performed at laboratory-scale (Meuwly et al. Scale-up studies of ARLs pass through the same analysis made for BCRs. In the first one. as it was presented bellow. In addition. Membrane bioreactor (MBR) technology is advancing rapidly around the world both in research and commercial applications. in doing so. MBR applications in many areas extended widely (Meng et al. the wastewater. the fluidizing medium is usually the broth. Additionally. large-scale use of MBRs in wastewater treatment will require a significant decrease in price of the membranes (Meng et al. Yang et al. Meng et al. Applications of Submerged Bioreactors For many reasons STRs are the most widely used bioreactors in the biotechnological industrial applications. with the development of submerged MBRsystem. where a small footprint. Since the effective pore size is generally below 0. 2009). Spier. with the liquid flowing up through the bed. Pedroni Medeiros et al. Several generations of MBR systems have evolved. with the flow being upwards for fluidization of particles more dense than the fluid. In the water and effluent treatment context. an MBR comprises a conventional activated sludge process coupled with membrane separation to retain the biomass. water reuse. 2011). there are some variations and more recent developed models of bioreactors such as the bubble columns and . Visvanathan et al. 2000. or downwards for particles of lower density. membrane bioreactors (MBR) are been used. reduces the necessary tank size and also increases the efficiency of the biotreatment process (Santos et al.P. MBRs allow high concentrations of mixed liquor suspended solids (MLSS) and low production of excess sludge. After the mid 1990s. As well as applications in wastewater treatment. it concentrates up the biomass and. de Souza Vandenberghe. membrane fouling is a major obstacle to the wide application of MBRs. L. STRs offer unmatched flexibility and control over transport processes occurring within the reactor.R. or stringent discharge standards were required. 2006. MBR systems have mostly been used to treat industrial wastewater. enable high removal efficiency of biological oxygen demand (BOD) and chemical oxygen demand (COD). or a mixture of the two. Up to this date. 2009). A. They have one or more impellers that are used to generate flow and mixing within the reactor. more stringent regulations and water reuse initiatives (Cicek 2003. laboratory it is often necessary to compromise between this ideal ratio and the need to minimize the volume of the fermenter. however. The fluidizing medium can be gas. liquid. 2009).B. in the case of the fluidized bed fermentation (FBF)s. Membrane Bioreactors Since 1990. the MBR effectively produces a clarified and substantially disinfected effluent. It is expected. and water reclamation. FB technology can also be applied to pure culture fermentations for the production of microbial metabolites or biomass. domestic wastewater and specific municipal wastewater.1 µm. lab-scale fermenters have a ratio between 25:1 and 40:1. that MBRsystems will increase in capacity and broaden in application area due to future. However. and for biological fluidized bed (BFBs). in which case the membrane modules are outside the bioreactor and biomass is re-circulated through a filtration loop. They are maily composed by installations that are constructed in external configuration. Typically. However.64 M. Ryan et al. Mohorčič et al. Tavares et al. Ahamed & Vermette 2008a.. Other models of bioreactors are also being exploited such as the packed bed and membrane bioreactors for immobilized cells and/or enzymes. 1997. Application of Different Types of Bioreactors in Bioprocesses 65 airlift bioreactors. 1998 Exopolysaccharides Xu et al. 2006 Tissue mass culture Martin & Vermette.. (2002). (2003).. Wu & Merchuk. Szijarto et al.. 2009 Water treatment Williams & Pirbazari. 2005. 2002 Hydrogen production Lee et al. 2006 Cellulase Szabo et al. 2000. (2002). 2010 Chitinolytic enzymes Chen et al. Table 2. Rodríguez Couto et al. Hess et al. Some of the important applications of submerged bioreactors are presented in Table 2. Hreggvidsson et al.. Jang & Chang. (2004). 2010 Air Lift Antibiotic Ohta et al. Kasinath et al. 2004. 2005. 2006 Cellulase Ahamed & Vermette 2010 Lactic acid Yin et al.. 2008 Mammalian cells Meuwly et al. Sedarati et al. 2009 Tissue mass culture Martin & Vermette. 2005 Fluidized Bed Laccase Blánquez et al. 1995.. Some applications of submerged bioreactors Type of Process Reference Bioreactor STR Antibiotics Ohta et al.. 2010 Laccase Galhaup & Haltrich (2001). 2005. 1996. (2006). 2007 Xylanase Reddy et al. 1995 Chitinolytic enzymes Chen et al. (2002). (2003)... (2000)..... (2004). Couto & Herrera. 2002 Chitinolytic enzymes Chen et al. 2008 Organic acids Leite et al. Shen and Xia. 1996. Belghith et al. Domínguez et al. 2003.. Sigoillot et al. Olivieri et al. 2009 Pectic and pectate lyase Gummadi & Kumar. Prasad et al. Packed bed Laccase Schliephake et al.b. 1997a. Van der Merwe (2002).. 2006. 2011 Citric acid Papagianni et al... 2009 Cellulose hydrolisis Gan et al... Luti & Mavituna.. Reczey et al.. (2003). (2005) Hydrogen Leite et al.. 2002 Lipase Brozzoli et al. 2008 Polygalacturonases Fontana et al. Zhang et al... 2007 Polygalacturonases Fontana et al. 1996. 2002 bioreactor Antibiotic Schroën et al. Font et al. (2004). (2003). Park et al. 2007 Membrane Alginate Cheze-Lange et al. 2008 Laccase Kim et al. 2010 .. 1996. 2005... Rancaño et al.b. 2010 Exopolysaccharides Xu et al. Kim et al. Thiruchelvam and Ramsay (2007).. Fenice et al.. 2001. Blánquez et al. (2006). 2009 Succinic acid Isar et al. 2007 VOCs treatment Mudliar et al.... 2006 Gibberelic acid Chavez-Parga et al. Galhaup et al. 2005 Bubble Column Algal culture Mirón et al. especially if they are non septate. and bioreactors with or without forced aeration. may be without stirring. or only with continuous rotation. L. They are mostly applied in laboratory scale due some important reasons and necessities which are: • The hyphae can be damaged by mechanical agitation. • The maintenance of uniformity is difficult for large volumes of biomass. the higher the concentration of end products. Pedroni Medeiros et al. Applications of Bioreactors in SSF Table 3 below shows some types of bioreactors used in the process of solid state fermentation. emptying and cleaning of large reactors. • There are difficulties with the inoculation. which gives problems of heat transfer system. . The construction of bioreactors must take into account the peculiarities of the SSF the variety of materials that can be used as growth media.P. allowing very few drawings that meet the needs of aeration and heat removal. higher product stability. strength. porosity and water holding capacity. cultivation of microorganisms specialized for water- insoluble substrates or mixed cultivation of various fungi.66 M. Most articles emphasizing the production of bioproducts by comparing different types of bioreactors. with respect to the presence of septate hyphae or not (which gives more or less mechanical resistance to possible unrest in the middle). perforated trays).B. Thus. coupled with the fact low humidity of the substrate. the bioreactor may or may not forced aeration. control and sterilization of large volumes of medium. These can be classified as follows: static bioreactors (fixed bed. The number and types of bioreactors used in pilot and industrial scale is small compared to those used in the laboratory scale. although nowadays it is mainly used on a laboratory scale. causing many problems. The solid state fermentation is a process that occurs in the absence of free water. All items listed must be taken into consideration in the design and control strategies of a reactor that will operate on a solid state cultivation. de Souza Vandenberghe. stirring occasionally. size. 2009). The morphology of the fungus. A. and the necessity or otherwise of sterility in the process are other factors that influence the design of bioreactors for SSF. • The maintenance and procedures for filling. the sterilization of the medium is not critical and often unnecessary due to low water activity used in SSF (Singhania et al. and their characteristics such as composition. • The solid medium can become compacted during the process. so filamentous fungi are microorganisms naturally adapted and appropriate for this type of condition. May be listed higher fermentation productivity. Spier. Commonly used SSF bioreactors can be divided into four types based on type of aeration or the mixed system employed.R. stirred bioreactor (the horizontal drum or drum stirred). lower catabolic repression. Besides these. Bioreactors for SSF Solid state fermentation (SSF) has several biotechnological advantages over submerged fermentation.and its mode of operation and control. Application of Different Types of Bioreactors in Bioprocesses 67 Table 3. niger Citric pulp Citric acid Rodrigues et flasks al. niger Cassava Citric acid Soccol et al drum aeration bagasse (2007) Erlenmeyer Natural Monascus Jackfruit Pigments Babitha et al. columns aeration bran (2011) Bioreactor Type Perforated Trays The tray reactors are characterized by being simple systems in which the substrate is laid out on trays. niger Mussel Glucose Mirón et al drum aeration processing oxidase (2010) waste Raimbault Forced A. The substrate is placed in the tray in thin layers (typically 5 to 15 cm) and the trays are arranged on each other with a spacing of several inches in a chamber or room with controlled . bioreactors aeration atrophaeus bagasse + (2009) soybean molasses Polyethylene Natural Bacillus Sugarcane Spores Sella et al. flasks purpureus seeds (2008) Erlenmeyer Natural A. usually perforated to facilitate air convection. (2009) Column Forced Bacillus Sugarcane Spores Sella et al. (2000) bagasse Horizontal Forced Ceratocystis Coffee Aroma Medeiros et drum and aeration fimbriata husk compounds al. convection atrophaeus bagasse + (2009) Erlenmeyer soybean flasks molasses Rotating Forced A. Cassava Citric acid Vandenberghe fermenter aeration niger bagasse et al (2000) Erlenmeyer Natural Kluyveromyces Palm bran Aroma Medeiros et flasks marxianus Cassava compounds al. (2006) glass columns Trays Natural A. niger Citric pulp Phytase Spier et al. Examples of Bioreactors and products development in solid-state fermentation Type of Aeration Microorganism Substrate Product Reference Bioreactor system Column Forced Aspergillus. oryzae Red gram α. wooden or stainless steel. Shankar & convection plant Galactosidase Mulinami waste + (2007) wheat bran Horizontal Forced A. niger Sugarcane Xylanase Maciel et al. bags. flasks convection bagasse + (2008) soybean meal Erlenmeyer Natural A. and may lead to problems of shear and damage the structure of the . amongst those with implementing processes on solid medium. the oxygen concentration. Obviously the reaction can not proceed in areas where there is no oxygen. Column reactors. due to the convection caused by air entering the reactor directly. There are also static drum reactors. Scaling up is easy (it increases the number of trays) but requires large area of operations. 2008). de Souza Vandenberghe. The diffusion rate of O2 transport properties depend on the tray.R. A. Despite having several advantages for process control. Temperature control is done by placing the reactor in a bath or using tactical terms columns jacketed with circulating coolant. Problems can occur in the transfer of oxygen. However. when the substrate is inoculated. temperature and humidity. The geometry of the stirred bed reactor is similar to that used in fixed bed. the shrinkage of the substrate layer due to the formation of the mycelium changes the porosity and thus the effective diffusivity. are the most studied in the laboratory scale. to have an efficient process. Fixed Bed Bioreactors The fixed bed reactors differ from the tray because they are closed systems where aeration is forced. in which other systems of agitation to ensure mixing of solid medium. The column reactors are associated with low bacterial contamination because they are closed systems. Pedroni Medeiros et al.P. Therefore. it must provide the profile of O2 concentration in different layers. The release of CO2 and heat also prevents the transport of O2 to the bottom. This can provide unfavorable low water activity (aw) and humidity. Moreover. These bioreactors have been considered interesting due to process control. can be eliminated. is a problem to be overcome in this type of reactor. At the beginning. gives space to a gradient. Furthermore.B. Spier. with the progress of fermentation. labour intensive and difficult to apply for sterile processes. which was once uniform. the CO2 released during metabolic reactions. but includes a mixing system for biomass systems as bolt or other type of agitation device. In some deeper places oxygen concentration becomes small enough to reach zero.68 M. Drum Bioreactor Agitated drum reactors are those that use agitation in the process. The use of column reactors minimizes problems with temperature gradients. the same reactor can be used for both fermentation and extraction of the final product. The agitation in this type of reactor can be continuous or sporadic. unlike the reactor tray. allowing its replacement by air. L. Adopting mixing coupled with forced aeration is possible to increase the homogeneity of the cell population and the substrate concentration in SSF. the reduction in porosity of the bed. resulting in poor microbial activity. The ability of this type of bioreactor is scalable to several tons (Pandey et al. the oxygen concentration is uniform in all layers of the substrate. such as a horizontal cylindrical vessel with a worm inside. forced aeration can result in water evaporation and drying the substrate. Over time. They are traditionally built in drum-shaped and may or may not contain baffles inside. Under these circumstances. especially by removing heat (which does not happen efficiently in large-scale processes). (10) (11) gas chromatograph (12) computer. The schematic system is showed in Figure (1). . Source: Medeiros et al (2006). (6) motor. Application of Different Types of Bioreactors in Bioprocesses 69 mycelium. where they are incubated. Several types of equipment are used for SSF. small perforated trays. jars. Medeiros et al (2006) studied the production of aroma compounds in a 3kg drum bioreactor. Roux bottles and roller bottles offer the advantage of simplicity. Rotating drum bioreactors (RDB) provide relatively gentle and uniform mixing by improving baffle design. based on monitoring (most often manual) of the important variables of the process. Examples of Laboratory-Scale Bioreactors Laboratory-scale bioreactors are of simple configuration. Erlenmeyer flasks. Petri dishes. (5) stirrer. since there is no agitator within the substrate bed. Raimbault columns. they are particularly well adapted for the screening of substrates or micro-organisms in the first step of a research and development program (Durand. Horizontal stirred drum bioreactor system for solid state fermentation: (1) compressor. (9) silica gel columns. Without forced aeration and agitation. (4) horizontal drum. often to initiate studies and optimization of procedures developed in laboratory scale. They are made of glass and have limited size. The different types of bioreactors are presented below. only the temperature of the room. Its disadvantages are: inability to control parameters. inability to regulate the process. (8) air discharge. (7) speed controller. 2003). Rotating drums have been used as bioreactors for solid-state fermentation since the 1930s and are already applied to make many products. The process occurs without agitation and aeration by diffusion. 2010). The engineering principles of RDB have recently received interest for biofuels production using cellulosic materials (Wang et al. (2) Air filter. Erlenmeyer Flasks The Erlenmeyer flasks are used in laboratory scale reactors. (3) humidifier. passive aeration. Easy to use in large numbers. These bottles are closed using cotton plugs. Its advantages are: ease of handling during research. is regulated. Figure 1. allows multiple simultaneous tests. low cost. Subsequently. Aeration (saturated air is pumped through the columns) is adjusted to the desired amount of air flow and controlled with the aid of a flowmeter attached to the air outlet of the column. (8) computer with data acquisition and control software. Typical lab-scale apparatus for solid state fermentation . Spier. removing a column in every certain interval. Components are: (1) air pump. This model of bioreactors allows study of the influence of forced aeration on the process. Pedroni Medeiros et al. (5) filter. Figure (2) shows a model of columns reactors made of glass coupled with a system that analyses the oxygen and carbon dioxide composition in the exhaust airflow from the column. (7) controllers display. the number of bioreactor types used at pilot and industrial scale is less then in the laboratory scale. (4) fermentation columns immersed in a water bath with controlled temperature. 1976) are in glass columns with 4 cm in diameter and 20 cm which are filled with the solid substrate. (9) cylindrical sensor base. and the evaluation of respirometry (measurements of O2 consumed and CO2 produced) of the microorganism.70 M. and introduced into a water bath with controlled temperature. humidity and outlet temperature. Due to the use of a few grams of solid medium and the geometry of the columns. L. The disadvantage of this type of reactor is the impossibility of withdrawing the sample from the column. Over cultivation is necessary to destructive sampling. . Basically.B. Examples of Bioreactors to Pilot Scale / Industrial As it was mentioned before. A. Figure 2. the bed temperature fermentation can be maintained easily because the heat removal by the column wall seems to be efficient. Source: Spier et al (2011).R. Lab-Scale Columns The column-type bioreactors (Raimbault & Germon. reactor. the configurations of bioreactors at pilot scale have more industrial instrumentation and control devices. de Souza Vandenberghe. (2) air distribution system. the columns are connected to air bubblers.P. (6) flow sensor. this being sterilized and inoculated separately. where the following sensors are installed: CO2 andO2. (3) humidifiers. This study is of extreme importance for the understanding of the metabolism of microorganisms used in SSF process. Pre-pilot bioreactor was developed at for defining the control strategy and optimizing the air-inlet temperature. operate and scale-up SSF bioreactors. and the trays are incubated in thermostated chambers or rooms. The microbial growth under aerobic conditions in the bioreactor results in a considerable production of heat that causes fast increase in temperature. which may arise during the process. The continuous mixing is necessary to maximize the exposure of the substrate particle to the air circulating in the headspace. The system consists of a horizontal drum and some auxiliary equipment such as compressor. An alternative to maintain sterility is the use of sterilizable and microporous bags (Durand. speed controller. air temperature probe. substrate concentration. silica column. motor. the airflow rate. The tray bioreactors are applied on commercial scale especially for oriental products such as the famous Koji process. Although it has been extensively used in industry. autosampler. In packed-bed bioreactors. The scale-up of the bioreactor are difficulty mainly by intense heat generation and heterogeneity in the system. 2003). The agitation is necessary to remove the heat accumulation in the substrate bed. but also processes involving agitation of the substrate. heater. whereas in other bioprocesses there is an absence of commercial designs of bioreactors. Scale-Up Aspects Bioreactors for solid state fermentation are used in large-scale traditionally processes such as Koji and Sake. The system consists of the following elements: a controlled environment which has ejectors and air filters. 1988). heating and thermal resistance. The gradients of temperature. intensive labour and the sterilization process is difficult. humidity probe. air recirculation. biotechnological processes in which heat sensible products or enzymes produced during the fermentation can be heat-denatured at the . moisture level and temperature are important parameters in SSF which are difficult to control. spindle. Application of Different Types of Bioreactors in Bioprocesses 71 Trays are an example of SSF bioreactor without forced aeration. Factors such as oxygen content. and posses various sizes according to their design. Wood. such as those performed in rotating drums. This effect is often undesirable especially in some. metallic or plastic trays may be perforated or not. computer. valves for outlets. This type of bioreactor consists of: a basket containing the solid medium. valves for adjusting the air flow. humidifier. box. the air is introduced through a sieve which supports the substrate. such as lack of standardized processes and limited reproducibility of the experimental results. affecting not only those processes that involve static solid beds. Discontinuously rotating drum operates like a tray reactor. Rotating drum bioreactors with air circulation and continuously mixed are commonly used in pilot or lab scale process. the agitation may occur continuously or intermittently. humidifier. the addition of water and agitation during a SSF process (Durand et al. humidity. discharge air. The major problems to overcome are related to the engineering aspects. air filter. gas chromatography (respirometry). this technology requires large areas. In a horizontal drum bioreactor with forced aeration. A large numbers of patents and publications are available on how to design. The solid medium is disposed at a maximum depth of 15 cm. perforated trays and stands. inlet and outlet air. According to Durand (2003) the largest reactor cited in the literature was a 200 L stainless steel rotating drum which used 10 kg of steamed wheat bran as substrate for kinetic studies of Rhizopus. In semi-sterile processes. and an inability to maintain photoautotrophic growth are the main problems (Paek et al. In the absence of a free aqueous phase. the cooling of the process takes place through evaporation. de Souza Vandenberghe. The modifications include a variety of impellers design distinct from the blade turbines for agitation. Pedroni Medeiros et al. Those bioreactors are fundamentally classified by agitation methods and vessel construction into: . this requires very high aeration rates because the rising metabolic activity and the associated increased heat production have to be overcompensated by high aeration intensity. spin filter bioreactor) . mechanically agitated (stirred tank bioreactor. rotating drum bioreactor. genetic instability. slow growth.R. • Bioreactors for metabolites and enzymes production • Bioreactors used for biotransformation of exogenously added metabolites. Spier. several problems have limited the commercial exploitation and application of plant cell cultures. Substrate mixing may help but it should be noted that many microorganisms respond very sensitively to the shear stress caused by it. for example. and relatively low growth and oxygen uptake rate (Xu et al. The design and operation of bioreactors is critical for successfully developing large-scale production process using plant cell cultures. The water lost by evaporation has to be in many cases replenished. via the bioreactor double walls.72 M.B. flavours and fragrances and fine chemicals has been growing. this increased water activity can in turn have adverse effects by facilitating the growth of bacterial contaminants. However. Another factor that is difficult to account for is the production of metabolic water by aerobic microorganisms. it may bring about local insufficient oxygen supply to the microorganisms. The low and unstable cell productivity. Culturing plant cells in reactors has many similarities with the growth of mammalian cells. 2005). Besides. and this can lead to undesirable local increase in water activity during static processing. whereas sterile fermentations. Instead. foaming and wall growth. A. 2009). L. shear sensitivity. but with different nutritional and control requirements. The implications of these factors on bioreactor design and operation have been comprehensively reviewed (Huang & McDonald. which can cause problems especially in the formation of conidiospores. distinct properties of plant cell cultures have to be considerate in bioreactor design including: large cell size and complex morphology.P. shoots or roots as the final product). Bioreactors for Plant Cells Cultures The interest in plant cell cultures for the production of valuable natural products such as pharmaceuticals. end of the process. time-dependent rheological behavior. 2011). the produced heat is difficult to remove. However. For large-scale culturing plant cells a variety of bioreactors are usually described according three classes of culture systems: • Bioreactors for biomass production (cells or organonic or embryogenic propagules. The conventional stirred tank reactor (STR) for microbial cultures have been modified to allow better conditions to plant cell cultures. tendency for aggregation. The inferior part has 3. The goal in bioreactor design and operation is to provide a prolonged and sterile culture environment with efficient mixing and oxygen exchange in an effort to support optimized cell growth and achieve high productivity. The studies were carried out in a stirred tank bioreactor equipped with centrifugal impeller and compared with similar bioreactor with a setric impeller to investigate the role of O2 transfer efficiency of centrifugal impeller bioreactor on overall culture metabolism. with two compartments. balloon type bubble bioreactor- BTBB). with the air entrance. easy operation.5 cm height. The authors investigated the effect of elicitation with linoleic and α-linolenic fatty acids in Panax ginseng C. bubble column bioreactor.071 and 0. particularly for long term cultures. Bubble Column Bioreactor Bubble columns are suitable for plant cell cultures due to low shear stresses. Application of Different Types of Bioreactors in Bioprocesses 73 . The equipment is made with cylindrical Blindex® glass. the hydrodynamics of the liquid phase has a strong influence on column performance and cell response. The equipment works with an interlinked system with hoses of flexible rubber. air-lift bioreactor.5 g/L (by dry cell weight) and corresponding azadirachtin concentrations were 0. Soccol et al (2008) developed a Bioreactor of Immersion by Bubbles. .05 g/L. mechanical simplicity. and good mixing. All the internal components are made of stainless steel. Stirred-Tank Bioreactor (STR) Prakash and Srivastava (2007) successfully scaled-up Azadirachta indica suspension culture for azadirachtin production in a stirred tank bioreactor with two different impellers. respectively. but can be changed according to the needs of the process. pneumatically agitated and non-agitated bioreactors (simple aeration bioreactor. This type of bioreactor was used by Wu et al (2009).7 and 15. The bioreactor totalizes 28 cm height with 90 mm of diameter. angle of 120º and the sieves (mash 18). In bubble columns. The maximum cell mass for centrifugal impeller bioreactor and stirred tank bioreactor (with setric impeller) were 18. divided transversally by a porous plate with 170 a 220 µm.Meyer adventitious roots cultured in balloon-type bioreactor.A. The superior part has 24. It was used to produce many plant species.5 cm height and at this compartment are placed the tripods with 2 to 5 cm height each. through which the plant tissues receive air and nutritive solution by bubbling (Figure 3). 74 M. . reduced foaming. resulting in extracellular product titre close to 250 mg/L and 4–10% of the extracellular total soluble protein. Ramy3D. Front view (A) and side view (B) of a Bioreactor of Immersion by Bubbles. Figure 3. McDonald et al (2005) applied a membrane bioreactor for the production of recombinant human alpha-1-antitrypsin (AAT) using transgenic rice cell culture with a rice alpha amylase promoter. 2009). Pedroni Medeiros et al. (5) support brackets. membrane bioreactors result in less shear stress to cultivated cells. nutrient supply. or product separation. grape and apple suspension cells have been demonstrated.B. However. Spier. de Souza Vandenberghe. They are designed to retain cell biomass and also possibly recombinant protein product in a cell compartment. easy operation and low risk of contamination. (3): metallic perforated trays. Eibl and Eibl (2006) achieved high plant cell (V. Membrane Bioreactors Membrane bioreactors utilize specialized membranes with specific molecular weight cutoff for either in situ aeration.P. (1): Air exausting. Other advantages of wave bioreactors include time savings (the cleaning and sterilization processes are not needed). (4): porous plate distribution.R. (2) screws. (6) Air inlet.day) with a doubling time of 2 days and observed that there was no significant change in cell morphology when compared to cultivations in stirred-tank bioreactors. L. Source: Soccol et al (2008). Although. A. studies indicated that mass transfer is an important consideration even for relatively slow growing plant cells (Huang & MacDonald. Novel Bioreactors Types Wave Bioreactors The potential application of wave bioreactors for cultivating tobacco. vinifera) biomass productivities of 40 g/(L. the membrane bioreactor is primarily used for small scale processes and is difficult to scale up for large-scale applications. Another study pointed out. This will give rise to different cell behaviour in different spatial locations in the culture and will also reduce culture reproducibility. These static systems have limitations that arise from their non-homogeneous nature. such as hollow fiber which exhibit two functional compartments. Tissue culture traditionally follows the methods of batch or semi- batch culture. a biaxial rotating bioreactor with fluidics through in-silico modelling was applied to generate osteogenic bone graft using polycaprolactone-tricalcium phosphate scaffolds seeded with human fetal mesenchymal stem cell. Disposable bioreactors are usually made of FDA-approved biocompatible plastics such as polyethylene. A homogeneous mix of adult liver cells from organ collagenase digestion containing parenchymal hepatocytes. clean-up and re-sterilization steps are eliminated and associated risks with culture contamination are reduced (Xu et al. nutrients. Without mixing. This bioreactor reached cellular confluence earlier (day 7) compared to static culture (day 28). non-steady state process where biological parameters. reminiscent of the native liver (Gerlach et al. Bioreactors provide a manner for efficient exchange of nutrients and mechanical stimulus necessary for tissue engineered bone grafts. In studies reported by Zhang et al (2009). 2011). stellate cells. Bioreactors for Mamalian Cell Culture Animal and human cells are extremely sensitive to fluctuations in culture environment and the traditional depletion and toxic by-product accumulation associated with batch culture can adversely affect them. A spontaneous reassembly of primary cells inoculated into a bioreactor established of a scaffold or biomatrix. Some bioreactors used in mammalian models and in vitro are presented in Table 3. that four bioreactor compartments are necessary to enable integral oxygenation and distributed mass exchange with low gradients. with the carbon source present at the start of the culture. toxins. physical rate process and the local mechanical environment are continually changing with time – in essence tissue engineering is a 4D challenge. The majority of 2D tissue culture systems are T-flasks and well-plates in which cells are grown statically without any mixing. such as neo-sinusoidal structures and neo-spaces of Dissé. 2010).. and liver progenitor cells) will restructure after injection into specific bioreactors to form well-defined liver structures. Tissue growth is dynamic. 2008). 2001) and can be used for growing liver progenitors (Table 3).. Bioreactors are currently used for primary liver cell culture and clinical liver support as showed in Tabela 3. It has been documented that the behaviour of cells in 2D can be very different in 3D culture (Abbott. Since the bioreactor vessel is pre-sterilized and discarded after harvest. and allowed the maintenance of cellular viability . Application of Different Types of Bioreactors in Bioprocesses 75 Disposable Bioreactors The use of disposable bioreactors for large-scale plant cell culture with a goal of reducing production costs and minimizing validation efforts under GMP regulations. concentration gradients of pH. polytetrafluorethylene. 1998). non-parenchymal cells (such as sinusoidal endothelial cells. polystyrene. 2003) and this has important implications for the in vitro generation of functional human tissues. polypropylene and ethylene vinyl acetate (Eibl et al. A specific bioreactor was developed for clinical liver support that accommodated 400–800 g of primary cells (Gerlach et al. gases and growth factors will occur in the culture medium (Collins et al. human Christiansen et al (1953) malignant epithelial cells. for bone marrow expansion: AastromReplicell Hollow fiber-based bioreactor Human leukemic cell lines Gloeckner & Lemke (2001) with integral oxygenation Hollow fiber-based bioreactors Mouse fibroblasts.76 M. Chinese Rose (1954) hamster cells. miniPERM Bioreactor. Sartorius AG. VectraCell gas-permeable bags. Cartwright (1994) . CELLine.P. CellMax. 1983) Human hepatocytes Coaxial hollow fiber-based Rat hepatocytes Macdonald et al (2001) bioreactor with integral oxygenation Hollow fiber-based bioartificial Porcine and human liver cells Gerlach et al (2003) liver with integral oxygenation Sauer et al (2002) Flat sheet and hollow fiber-based Porcine hepatocytes Flendrig et al (1997) bioartificial liver with integral oxygenation Titanium mesh bioreactor Rat bone marrow stromal Bancroft et al (2003) osteoblasts Flat membrane bioreactor with Porcine hepatocytes De Bartolo et al (2000) integral oxygenation Source: Gerlach et al (2008).. with increased proliferation and osteogenic differentiation both in vitro and in vivo. beyond the limits of conventional diffusion. Spier. Wave bioreactor. L. for non-adherent cells: Synthecon. Wave Biotech LLC. de Souza Vandenberghe. Knazek et al (1972) Human choriocarcinoma cells. Rotary Cell Culture System. Tecnomouse Integra Biosciences AG Commercially available system Hematopoetic stem cells Aastrom Biosciences. hybridomas Freed (1963) Katinger (1985) Commercially available Bone marrow-derived osteoblasts Minucells & Minutissue perfusion chambers Vertriebs GmbH Commercially available systems Hybridomas Diagnostic Chemicals Limited. Table 3. Spectrum Laboratories. Pedroni Medeiros et al.R. A. Inc. Inc. Hager et al (1978. Wolf & Munkelt (1975) Reuber hepatoma cells. Inc. Integra Biosciences AG.B. Bioreactors used in animal models and in vitro Technology Cell type Reference Stirred tank for the production of Namalwa Cartwright (1994) alpha-interferon to the clinical use in cancer and viral infection Stirred tank for producing tissue CHO Cartwright (1994) plasminogen activator used for thrombolysis Roller bottles CHO Cartwright (1994) Hollow fiber-based bioartificial Porcine liver cells Gerlach et al (2001) liver with integral oxygenation Janke et al (1999) Spirally wound flat sheet and Porcine hepatocytes Flendrig et al (1999) hollow fiber-based bioartificial liver with integral oxygenation Flat plate bioartificial liver with Porcine hepatocytes Shito et al (2003) integral oxygenation Hollow fiber-based renal tubule Human renal tubule cells Humes et al (2002) assist design Early perfusion chambers Chick heart fibroblasts. In general. 1992. requirement of large areas of land. which are offered by different types of closed photobioreactors applied outdoors. seaweed type photobioreactors. which is necessary for efficient operation of mass algal cultures. which diminishes the chance of contamination and facilitates harvesting. bubble column. Park et al (2011) produced algal biomass for conversion to biofuels with minimum environmental impact using wastewater by Chlorella sp. in the field of aquaculture. is that the light path length is noticeably reduced leading to higher cell densities. helical tubular. but presents some limitations such as poor light utilization by the cells. Flat-Plate Bioreactors In this type of photo bioreactor the photosynthetic microorganisms are cultivated in a large illumination surface area. stirred-tank. tubular. The proposed device can be used with any exhaust gas stream with higher concentrations of CO2 in conjunction with raceways for optimizing algae production. their mass transfer rates are very poor resulting to low biomass productivity (Ugwu et al. Open Ponds Open ponds are easy to construct and operate. flat-plate. 1996. Application of Different Types of Bioreactors in Bioprocesses 77 Photobioreactors Although some models of photo bioreactors have been proposed. 2008). one of the major factors that limit their practical application in algal mass cultures is mass transfer. Some of these reactors include open ponds. Putt et al (2011) studied a system for carbonation and got a high biomass production during algae culture. Due to inefficient stirring mechanisms in open cultivation systems. only a few of them can be practically used biomass from algae. evaporative losses. flat-plate. Hu & Richmond. for the production of fine chemicals and as useful supplements in humans and animals. Generally. Studies of vertical alveolar panels designs and flat plate reactors for mass cultivation of different algae were reported (Tredici & Materassi. And besides. and Spirulina sp. involving vegetable biomass growth or microalgae growth under controlled conditions. and contamination by predators and other fast growing heterotrophy. reducing one of the limitations of the open pond photobioreactor. The same author describe that the advantage of closed as compared to open ponds or tanks. The photo bioreactors range from laboratory to industrial scale models and besides they are classified in closed photo bioreactor. for biosorption of heavy metals. CO2 fixation. Zhang et al (2001). The main applications of photo bioreactors are in photosynthetic processes. conical. The biomass from algae is commonly used in water treatment. reduces evaporative losses and temperature can be more easily controlled (Tredici. flatplate . laboratory-scale photobioreactors are artificially illuminated using fluorescent or other light lamp distributors. The introduction of more sophisticated cultivating methods of microalgae with higher productivities and capable of avoiding contamination. open ponds. horizontal/serpentine tubular airlift and inclined tubular photobioreactors (Ugwu et al. difficulty in CO2 diffusion. 2008). airlift column. 2004). 2002). in open ponds photobioreactor. Hoekema et al. According to Ugwu et al (2008). diffusion of CO2 to the atmosphere. torus. a marine unicellular photoautotrophic alga producer of EPA (eicosapentaenoic acid. horizontally serpentine. cultive.4cm (outer diameter 7. It requires a relatively small ground area. Spier. m2. The tubes had an inner diameter of 6. 2011). utilizing strong light very effectively by having a large illuminated surface to volume ratio (i.1 mL/L/h and a photochemical conversion efficiency of 0. A. near horizontal photobioreactors. This bioreactor was made of number of units (8-10 mm thick glass plates each unit). Efficient light distribution to the cells can be achieved by improving the mixing system in the tubes (Ugwu et al. L. Flat plate photobioreactors are very suitable for mass cultures of algae.B.78 M. Tubular Photobioreactors Tubular photobioreactor is a type of reactor for outdoor biomass cultures with high surface area for illumination. Pedroni Medeiros et al. 2001).e. conical. while the second turbulent culture mixing was achieved by a circulating gas-lift system that is operated with a customised liquid diaphragm pump. The reactor tested consisted by horizontal serpentine-like. which resulted in the highest observed photochemical efficiencies.. 20:5w3). photobioreactors are made of transparent of transparent materials for maximum utilization of solar light energy. They can be in form of inclined.P. . constructed with glass or plastic tube. It has been reported that with flat plate photobioreactors. The cultures are re-circulated either with pump or preferably with airlift system. An illustrative H2 production experiment achieved a H2 yield of 105 ml/L at a maximum H2 production rate of 1. This work showed that outdoor tubular photobioreactor seemed to be particularly sensitive to the variable conditions outdoors and we suggest that new designs of closed photobioreactor try to achieve more stable and homogeneous conditions throughout the system and over the daily cycle (Bergeijk et al. 110 cm high protected and sustained by dividers. de Souza Vandenberghe.24% (Tamburic et al. high photosynthetic efficiencies can be achieved (Richmond & Cheng-Wu. measuring 200 cm long. This photobioreactor was divided in two compartments: the first compartments holds the algal culture and provide control measurements. An outdoor tubular photobioreactor were used for biomass culture of Isochrysis sp. The investment cost per liter culture was US$ 4 L-1 considered one of the lowest available for large-scale operation (Cheng-Wu. A flat plate photobioreactor was applied for Nannochloropsis sp. The inside width composed by 10 cm light-path and form a 500 to 1000 L unit developed for outdoor production. 60m (10m×6m) of acrylic tubes connected with 180 fits (photostage amounting to 200 L) and a 400-L fibreglass gas exchange tank (culture volume 200 L). 2005). considering the area of all the illuminated reactor surfaces. Accumulation of dissolved oxygen concentrations in flat-plate photobioreactors is relatively low compared to horizontal tubular photobioreactors.R.0 cm) and were submerged in a water bath in order to mitigate temperature variations. The flat-plate reactor geometry was chosen by Tamburic et al (2011) for H2 production due to its superior surface-to volume ratio. a microalgae rich in docosahexaenoic fatty acid (polyunsaturated). 50 L. 2001). 2010). air pump. This reactor consisted in a draft- tube internal-loop type made of Pyrex glass. 2010). Air and CO2 are also supplied to the cultures.19m in diameter can attain a final biomass concentration and specific growth rate that is comparable to values typically reported for narrow tubes (e. 2008). 2011). 2002).03m in diameter) of conventional horizontal tube reactors. feeding and sampling. The airlift photobioreactor was study by Ranjbar et al (2008) for cultivating Haematococcus pluvialis cells and astaxanthin production. exposed to certain light/dark cycles and by light intensity distribution and mixing inside the photobioreactor. top head plastic cover with four ports for plastic tubes. gas outlet. The increase of light intensity during the accumulation of astaxanthin resulted in a better result (600 mg L-1. Pigment-rich biomass is generated in light-limited culture. The biomass concentration of Chlorella sp. four plastic tubes with a diameter of 6 mm which were used for gas inlet. Sánchez Mirón et al (2002) studied relatively large outdoor bubble column and airlift bioreactors that were compared for monoseptic fed-batch culture of the microalga Phaeodactylum tricornutum and concluded that the three photobioreactors produced similar biomass versus time profiles and final biomass concentration. and the regular light/dark cycles and laminar flow had a positive effect on the astaxanthin accumulation.. The good performance of the large-diameter vertical reactors was explained by an absence of photoinhibition and photo-oxidation of the biomass and also the biomass in vertical reactors does not experience oxygen inhibition of photosynthesis (Sánchez Mirón. The carotenoids contents in P. intermixing occurs between the riser and the downcomer zones of the photobioreactor through the walls of the draft tube. they are very promising for large- scale cultivation of biomass algae. with a working volume of 1. The authors achieved the highest ever reported cell numbers (7x106 cells mL-1) after 300 h cultivation. This type of photobioreactor can also utilize solar light. In the case of draft tube photobioreactors. Some bubble column photobioreactors are equipped with either draft tubes or constructed as split cylinders. at the end of exponential phase was approximately 1. was cultivated in 2 L bubble-column photobioreactor and investigated for biodiesel production. It has doubling time of approximately 15 h during the exponential phase (Rasoul-Amini et al. 0.9 g/L. and easy to operate monoseptically (Sanchez Miron et al. 2002). low-cost. Bubble column and airlift photobioreactors of up to 0. Chlorella sp. Glassmade cylinder. This equipment is equipped with impellers for agitation of the algal cultures.) of this pigment. The photobioreactor consisted of different parts.0 liter. Application of Different Types of Bioreactors in Bioprocesses 79 Vertical-Column Photobioreactors Vertical-column photobioreactors are compact. Furthermore. which was several times higher than previously reported values (Ranjbar et al. mainly fluorescent lamps. This type of photobioreactor has good light– dark cycling and low surface/volume (Mata et al. Some photobioreactors can be internally illuminated with artificial light. tricornutum are much more sensitive to available light in light-limited culture than are the chlorophyll contents. 2002).g.19 m in diameter) can attain a final biomass concentration and specific growth rate that are comparable to values typically reported for narrow tubular photobioreactors (Sanchez Miron et al. It was reported that bubble-column and airlift photobioreactors (up to 0. porous bulk stone which was used for bubbling the air. . Tissue Engineering. Vermette. algae. 424. P. 2008b. 41–46. P. internal optical fibers for light distribution have been reported for scale up photobioreactors. However. Mikos. VI. 379–387. 870-872. It is necessary more efforts to improve bioreactor technologies and performance during operations. 2008.P. Bancroft. Vermette. Biochemical Engineering Journal. A. 9. 2003. Even fermentation processes such as submerged and solid state fermentation are commonly used using microbial cells (bacteria. Ahamed. AG.80 M. Nature. 40. 42. P. L. microbial and mammalian cells or its culture for obtain interest products. Culture-based strategies to enhance cellulase enzyme production from Trichoderma reesei RUT-C30 in bioreactor culture conditions. Enhanced enzyme production from mixed cultures of Trichoderma reesei RUT-C30 and Aspergillus niger LMA grown as fed batch in a stirred tank bioreactor. depending to the application and the nature of the cell culture. Ahamed. Pedroni Medeiros et al. Biochemical Engineering Journal. several photobioreactors have been proposed for small scale. 549-554. . yeast and fungi) aim biomolecules or metabolic for commercial purposes. Besides. Biochemical Engineering Journal. References Abbott. Effect of mechanical agitation on the production of cellulases by Trichoderma reesei RUT-C30 in a draft-tube airlift bioreactor. A . Most of them are projected for maximize processes conditions. Conclusion Several operation models of bioreactor permit to cultivate since vegetable. Sikavitsas. 2003. but each of them presents limitations.R. The establishment of a more sustainable future industrial production is the key to develop new and innovative industrial bioprocesses. 49. technical costs of construction and low energy losses should be considered. A. but most of them present limitations or difficulties to scale-up. although these fibers are expensive and may present technical problems. Vermette. 2010. A. .B. GN. an appropriate method for harvesting the solar energy and distributing the light inside the photobioreactor is required. Scale-up success depends on the good light supply to the cultivation of photosynthetic organisms. Scale Up of Photobioreactors For photobioreactor scale-up. 399–407. Biology´s new dimension. de Souza Vandenberghe. Spier. Future Perspectives Bioreactor design and the association with process optimisation are essential for transfering the parameters obtained from lab or pilot scale experiments to efficient production processes in industrial large scale bioreactors. even if the product has high-value aggregated. Ahamed. A . Design of a flow perfusion bioreactor system for bone tissue-engineering applications. According to Ogbonna et al (1996). 375 p. Sarrà. Dussap. JP. . Babitha. Production of microbial alginate in a membrane bioreactor. Stirred culture of peripheral and cord blood hematopoietic cells offers advantages over traditional static systems for clinically relevant applications. TK. CR. E. 660–622 Blánquez. M . 38. Chaudhuri. Bioreactors: Functions in fermentation processes.. P . M . Binod. Dhulster. World Journal of Microbiology and Biotechnology. 2009. 2010. Bhattacharyya. Morcellet. G . Belghith. Soccol. CG (Editors). 2005. Dussap. 34. galbana (T-iso) in outdoor tubular photo bioreactors. 59. AGIMAX®. 2002. Cañavate. Singhania. 13. Vicent. Bioreactors: Functions in fermentation processes. A. Hepatology 2001. Low and variable productivity and low efficiency of mass cultures of the haptophyte Isochrysis aff. 2001. Brozzoli. 656–661. Netherlands: Springer. C. Biotechnology and Bioengineering. SN. A. M . Facciotti. 8. S. Petruccioli. Collins. X . Bhatia. Alatorre.. Animal cells as bioreactors. MCR . Available in: http://www. Bhatia. Bioreactors for tissue engineering: Principles.18. SA. Caminal. Bergeijk. F . Assessment of olive-mill wastewater as a growth medium for lipase production by Candida cylindracea in bench-top reactor. Inc.br/pdfs/Agimax. A. 43. 2004.Enzyme and Microbial Technology. Escamilla-Silva.pdf. 1998. JC. Junter. Vallarino. CR. Cheze-Lange. Soccol. JW. T. Journal of Biotechnology. WM. Allen. Ellouz-Chaabouni. In: Pandey. Inc. Badino Jr. EM. 2008. Pandey. S. 2001. Application of Different Types of Bioreactors in Bioprocesses 81 Allen. Schmidell. Caze. 1994. 855–860. Mechanism of textile metal dye biotransformation by Trametes versicolor. 24. Kinetic of the gibberellic acid and bikaverin production in an airlift bioreactor. Soccol. 2010. D . Aquacultural Engineering. Blánquez. 2002. pigment production and culture morphology of Monascus purpureus in solid-state fermentation. IG . C. S . Gabarrell. et al. 2008. 172-201. Larroche. 43(1). M . D . Industrial Enzymes. 447–54. 3395– 3402. Sarrá. Al-Rubeai. Ghosh. I . W. 2008. Sampedro. Banerjee. 14-23. Gabarrell. Olive oil mill waste waters decoloration and detoxification in a bioreactor by the white rot fungus Phanerochaete flavido-alba. AC. 2002. CR. Gonzalez-Ortega. M. Salas-Leiton.com. JW. MT. Negrete-Rodríguez. H . A. Biotechnology Progress. P . BOMAX DO BRASIL®. Soccol. 30. Bioresource Technology. 257–62. RR. New Delhi: Asiatech Publishers. 89. A . 291-320. Chavez-Parga. GG . 447–55. A-M . Gargouri. N . Advances in bioartificial liver devices. BC. 111–119. D’Annibale. P. X. Cell & Dev Biol. 184 p. Agitadores e misturadores verticais. 2008. Advances in Fermentation Technology. Carvalho. PC. Advances in Fermentation Technology. J. G-A. 2166–2172. Beunard. Hassanein. V . Casas. Process Biochemistry. Miller.bomaxdobrasil. Cartwright. S . Crognale. 2671–2675. Cambridge University Press. Biochemical Engineering Journal. New Delhi: Asiatech Publishers. Biostoning of denims by Penicillium occitanis (Pol6) cellulases. SN. Guillochon. 100. Papoutsakis. Improving the next generation of bioartificial liver devices. CR. Federici. M . MLX . G . Pandey. Font. N . M . design and operation. Saude. Water Research. Effect of light on growth. Volumetric oxygen transfer coefficients (kLa) in batch cultivations involving non-Newtonian broths. 534-543. ET. T. CG (Editors). A. In: Pandey. Larroche. MC . P . H . Caminal. 337–342. 1991. 1944. S. Cheng-Wu. De la Broise. D. JV. A. 102-108. DIC. Birol. 36. 1994. de Souza Vandenberghe. Kaiser. . 43. Domínguez. H-B . Journal of Biotechnology. C-Y. Cinar. Laboratory scale bioreactor for solid state processes. 2001. Weinheim: Wiley-VCH Verlag. CP. 1995. PM. 504-509.P. 648 p. R.R. A. A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: Cell viability and tissue-specific functions. D. Allen. M. Parulekar. Biotechnology Advances. 86. Leinfelder. 1739-1748. J-M. T-W. Doran. Batch Fermentation: Modeling Monitoring and Control. 5. MJ. Blachère. A fiber-bed bioreactor for anchorage-dependent animal cell cultures: Part I. S. L. O. Cooper. Eibl. C. R. Disposable bioreactors: the current state-of-the-art and recommended applications in biotechnology. GA. Paecilomyces tenuipes C240 in stirred-tank and airlift reactors. Richmond. An industrial-size flat plate glass reactor for mass production of Nannochloropsis sp. S . 242 p. 97. MA. 8. Kopel. A. 2006. Lombriser R. Z.. Elsevier Science & Technology Books. Exp. Pan. A. 49. CM. 2008. Kim. Bioreactor Engineering: The Design and Optimization of Reactors with Living Cells. 13. Y. PJ. 195. 770–777. G. 2003. 2006.405– 409. SJ. Res. JL. Eibl. 6. Biochemical Engineering Journal. 10-15. Chen. Ind. Hwang. Pedroni Medeiros et al. Bioreactor designs for solid state fermentation Biochemical Engineering Journal. Murakami. Bader. Toca-Herrera. A. Fernstrom. Rodríguez Couto. 508 p. 755–761. Design and use of the wave bioreactor for plant cell culture. Cell. Christiansen. Dempsey. Eustigmatophyceae. Bioresource Technology. Chiou. CRC Press. Experimental study of gasinduced liquid-flow structures in bubble columns. Sanromán. Huang. 203–227. SA. 25.B. Chen. 59–66. A. Biofilms and Fluidized Bed Fermentation. 1913–1931. Dye decolourization by Trametes hirsuta immobilised into alginate beads. Eibl. 1988. 16. Durand. Miller. Biotechnology Progress. 37. C-J . R. Haverich. Couto. A . IJ. 2001. D. S. 2003. Liu. 2000. SR . Plant Tissue Culture Engineering. HJ. SW. Kao. H-C . 2010. L. A culture chamber for the continuous biochemical and morphological study of living cells in tissue culture. International Biodeterioration & Biodegradation. Applied Microbiology and Biotechnology. Biological reaction engineering: Dynamic modelling fundamentals with simulation examples. Spier. Dudukovic. 1953. 47. Xu. L. 113–125. Aquaculture. AIChE Journal. Degaleesan. Undey. Biotechnology and Bioengineering. Wang. Engasser. B. 21. JW. Bioreactor design and operations. P-M . Dunn. 35–49. Production of exopolysaccharides by submerged culture of an enthomopathogenic fungus. Eibl. Durand. Automatic Control of Bioprocess. Effects of using various bioreactors on chitinolytic enzymes production by Paenibacillus taichungensis.82 M. Dochain. De Bartolo. Chem. Danes. 2003. GS. Chemical Engineering Science. Bioprocess Engineering Principles. 1988. Yun. H. London: John Wiley and Sons. Schweder. C-J . 2007. A. 558–569. D. World J Microbiol Biotechnol 2005. Laccase production at reactor scale by filamentous fungi. Zmora. 41–9. Eng. 2010. Shieh. 223–229. Ladiges. H. GG . Turnea. Applied Microbiology and Biotechnology. D. RA. D. Gerlach. Kardassis. R. Neuhaus. Sauer. 2009. K. Haltrich. Efimov. H . Botsch. 78. D. 1999. Gerlach. 2003. Mieder. Biochemical Engineering Journal. 828-831. Freed. AA. 529–536. 2009. Kosan. Ingenlath. Increased production of laccase by the wood-degrading basidiomycete Trametes pubescens. TA . NC. J. 13. IM. Lemke. RV. Inc. Enhanced formation of laccase activity by the white-rot fungus Trametes pubescens in the presence of copper. Drew. MT. S. 85–94. Soe. 17. Sermanni. Biotechnology Progress.. M. Karlsen. Font. Garcia-Ochoa. Tietze. Gan. Vicent. yeasts and fungus broths. Gage. E. 56. V. Gabarrell. Experimental evaluation of a cell module for hybrid liver support. 100. Biochemical Engineering Journal. Acta Biotechnology. JC. MC . M. Flendrig. 30. Black liquor detoxification by laccase of Trametes versicolor pellets. P. S . Science. D'Annibale. F . P. C. A. Kraemer. A. A. Oniscub. Hout. Design and operation of an integrated membrane reactor for enzymatic cellulose hydrolysis. 59. Cascaval. WM. Galhaup. cell expansion. Bowee. D. Cell culture perfusion chamber: Adaptation for microscopy of clonal growth. R. S. 2001. C. Janke. Rossaint. Transplantation. Bachman. 1086-1105.. Puhl. Polidoro. 225–232. Galaction. Romero. In vitro evaluation of a novel bioreactor based on an integral oxygenator and a spirally wound nonwoven polyester matrix for hepatocyte culture as small aggregates. 2004. Mas. Prediction of oxygen mass transfer coefficients in stirred bioreactors for bacteria. 24. Journal of Hepatology. T. Steenbeek. 793-798. 781-786. USA: John Wiley & Sons. 1993. Mutig. IM. MM. SJ . A. J Chem Technol Biotechnol 2003. Biocatalysis. 2003. HD. 153–176. Efimova. Kosan. M. Jorning. F. Busse. X . 1334-1335. M. Sauer. Biotechnology Advances. Flickinger. P. Allen. K. 27. Zeilinger. 4493–4498. OT. Gomez. Gloeckner. 140. JW. C . J. JC. and Bioseparation. G. 2002. Lemmens. M. K. M. Q . M . JC. 2001. Roman. Patzold. G. Zeilinger. 77–85. Caminal. G. Submerged and solid-state production of laccase and Mn-peroxidase by Panus tigrinus on olive mill wastewater- based media. and production of cell-derived products. Belal. New miniaturized hollow-fiber bioreactor for in vivo like cell culture. Schrade. Taylor. Gerlach. Naumann. Haltrich. GG. E. 26. . E. JJ. 1379-1392. Journal of Biotechnology. LM. 548–554. 1963. Liver Cell-Based Therapy – Bioreactors as Enabling Technology. 20. Silveira. B. X . B. Pless. Sultmann. D. 1997. 100. Chamuleau. Principles of Regenerative Medicine. 12. Unger. Neuhaus. SW. Muller. 2002. Comparison of stirred tank and airlift bioreactors in the production of polygalacturonases by Aspergillus oryzae Bioresource Technology. G. Schon. Application of Different Types of Bioreactors in Bioprocesses 83 Fenice. RC . Gavrilescu. Hinterstoisser. International Journal of Artificial Organs. Fontana. M. Federici. Use of primary human liver cells originating from discarded grafts in a bioreactor for liver support therapy and the prospects of culturing adult liver stem cells in bioreactors: a morphological study. B . M. P. C . Grunwald. 2008. A-I . Bohmer. 76. Enzyme Microb Technol. K. J. 2001. Te Velde. Bioreactor scale-up and oxygen transfer rate in microbial processes: An overview. 1rst ed. Wagner. Monch. Encyclopedia of Bioprocess technology: Fermentation. Galhaup. G . C . 39. 231–237. K. USA. K . et al. Richmond A. Gerlach. JS. Productivity and photosynthetic efficiency of Spirulina platensis as affected by light intensity. G . Saxena. International Journal of Artificial Organs. Spier. 139-145. 168-184. Tramper. Journal Applied Phycology. H. Thermostable cellulases from Streptomyces sp. Anaerobe. An extremely thermostable cellulase from the thermophilic eubacterium Rhodothermus marinus. 2004. Kang. M. A . Stand. 2006. Rossaint. Humes. Hubbard. Fissel. Eggertsson. 3047–3049 Hu. Bubble column reactors. Svobodová. Kumar. SW .B. C . F. algal density and rate of mixing in a flat-plate photobioreactor. JM. Pedroni Medeiros et al. Sasek. 1999. Saran. J. Ju. Bioprocess Engineering. GO . 229–241. N. Biotechnology processes. Process Biochemistry. Weitzel. Metabolic replacement of kidney function in uremic animals with a bioartificial kidney containing human cells. John Wiley and Sons. 63-67. 62. CL. 570-576. KC . Leitner. Biol. Kaiste. 1992. RH A pneumatically agitated flat-panel photobioreactor with gas re-circulation: anaerobic photoheterotrophic cultivation of a purple non-sulfur bacterium. E. 2002. Janssen. Akron. L. Principles of animal cell fermentation. KO. Novotný. 99. Hreggvidsson. J. Chase. D W. 32. 1331-1338. Hager JC. A. B . New York: AIChE. M . 40. L . Galhaup. 2003. C . S. Scale-up and mixing. Lee. Celulase and Xylanase Production by Aspergillus niger KKS in Various Bioreactors. J. R. Jang. 1985.167–173 Katinger. Mackay. Chang. Ulge. Effect of a hybrid liver support system on cardiopulmonary function in healthy pigs. DS. K A. C . WF. Gummadi. LE et al. 45. 1996. Appl Biochem Biotech. 20. 6.. Hess. Dev. Enzyme Microbial and Technology. M. R. SW . Kasinath. Kristjansson AJ. Improved scale-up strategies of bioreactors. 12. Kulbe. pp. WH. DA. Bioresource Technology. HD. RK. 1987 Isar. Gutierrez. 27. Heinzle.R. 2263–2283. S. 8 49-53. New York: AIChE. SN . J. Hinterstoisser. . GG. Biotechnology Letters. Borak. E . AJ. 294 p. Agarwal.84 M. Bohmer. International Journal of Hydrogen Energy. 239–242. AP. Applied Environmental Microbiology. 2006. 168–184. Succinic acid production from Bacteroides fragilis: Process optimization and scale up in a bioreactor. Kardassis. L-K. Steinwender. Palsdottir. J . 2002. Bioresource Technology. 1996. Porter. 2008. 59. Huang. 1983.P. 2005. Patel. Bioreactor engineering for recombinant protein production in plant cell suspension cultures Biochemical Engineering Journal. Wijffels. 2002. 1078-1087. scale-up production in a 50-l fermenter. Buffington. Am. A . 27(11). Biwer. Cooney. de Souza Vandenberghe. SM. Neonatal hepatocyte culture on artificial capillaries: a model for drug metabolism and the artificial liver. ASAIO Journal. Decolorization of synthetic dyes by Irpex lacteus in liquid cultures and packedbed bioreactor. KD . 2009. McDonald. Development of sustainable bioprocesses: modeling and assessment. TK. 98. 195-209. 23rd Symposium on Biotechnology for Fuels and Chemicals. Enhanced formation of extracellular laccase activity by the white-rot fungus Trametes multicolor. Westover. C. 874–881. Hoekema. Holst. Janke. Kim. Kantarci. H. Q. O . 8. 26-35. Carman. 66. V. Kidney Dis. Batch and fed batch production of pectin lyase and pectate lyase by novel strain Debaryomyces nepalensis in bioreactor. 1997. Eds. J . Bijmans. D. Kim. Q. 183-189. P. 1ª ed. Food Technology and Biotechnology. Bad Abbach. A. DM. GM. 2005. JAC . C. Luo. KA. LM. Meng. coli in a bioreactor enhances undecylprodigiosin production.. Dedrick. 178. Effect of flow configuration and membrane characteristics on membrane fouling in a novel multicoaxial hollow-fiber bioartificial liver. Lau. 665–685. Kubota. USA. YI. Optimization of the production of aroma compounds by Kluyveromyces marxianus in solid-state fermentation using factorial design and response surface methodology. Macdonald. Vermette. Cell culture on artificial capillaries: an approach to tissue growth in vitro. 6. 45. characterization. USA: Wiley. 2010. J . 14. P. Hong. A . Freitas. Ruffieux. Encyclopedia of Bioprocess Technology: Fermentation. Production and Recovery of Aroma Compounds Produced by Solid-State Fermentation Using Different Adsorbents. SP. G. and Separation. Y-K . Vertriebs GmbH. Application of an anaerobic packed-bed bioreactor for the production of hydrogen and organic acids. and recent advances. 46. P. Barbozab. Enzyme and Microbial Technology.R. Leite. JA. 1244-1252. RJS. Cooney. McDonald. Yang. Zaiata. 2007. ED. Packed-bed bioreactors for mammalian cell culture: Bioprocess and biomedical applications. LPS. Fan. AIChE Journal. LM. X. BS . L. Hang-Sik Shin. 334- 343. Kraume. H-S . 2001. Reid. S-R. 281–285. Li. 1489 – 1512 Meuwly. P-A . 2000. Xie. Minucelis and Minutissue. A. M . Wolfe. KJK . Fernandes. Application of Different Types of Bioreactors in Bioprocesses 85 Knakek. Trombly. 2011. RA. Mirón. 728–734. CL.Y-Y . 65-66. González. AP. R. 44(1). ABP. Pandey. Renew Sustain Energy Rev. GM. . 217–32. 2005. U. Water Research. Kohler. Bioreactors for tissue mass culture: Design. RL. A . 26. 2008. 47–51. 2006. 21–27. Noike. Kadouri. Y. International Journal of Hydrogen Energy. Jackman. Production of human alpha-1-antitrypsin from transgenic rice cell culture in a membrane bioreactor. Recent advances in membrane bioreactors (MBRs): Membrane fouling and membrane material. Caetano NS. 944. Mavituna. 7481–7503. Gullino. Ann. M-S . H. Christen. NY Acad. 2008. Enhancement glucose oxidase production by solid-state fermentation of Aspergillus niger on polyurethane foams using mussel processing wastewaters. Medeiros. Pandey. AA. Microalgae for biodiesel production and other applications: a review. Medeiros. 53. Science. Biochemical Engineering Journal. Chae. LPS. von Stockar. ME. 33–39. Martin. PO. Biomaterials. Vandenberghe. Roy-Chowdhury. Germany. Oh. 45–56. 25. Murado. JM. PM. MA. International Journal of Hydrogen Energy. Science. F . Lee. C. Biocatalysis. Laska. A. CR. CR. Maximum stable bubble size and gas holdup in high-pressure slurry bubble columns. 579-589. T. ABP. Martins. Soccol. Khalid Jaber Kadhum Luti. 43. TM. Vandenberghe. E . 1999. Bianca. 34. M. Xylanase Production by Aspergillus niger LPB 326 In Solid –State Fermentation Using Statistical Experimental Designs. Soccol. F. 2009. 2009. Elicitation of Streptomyces coelicolor with E. F. Effect of iron concentration on continuous H2 production using membrane bioreactor. 46. F . Drews. Biotechnology Progress. Pastore. Maciel. D-Y . 21. Pandey. Pozzia. 2010. Biochemical Engineering Journal. 1972. Food Technology and Biotechnology. Biotechnology Advances. Yang. Soccol. M. Mata. 33. Vázquez. DJ. 1999 Lee. K . 1998. Giardina P.P. A. B . KY. M . Vaidya. YV . Larroche. 2009. Giri. Chakrabarty. 249-253. M . Okabez. R . 2008. EJ. Craggs. Prakash. T. Ishigaki. ML. Ohta. 61-67. 197-205. 1997.N. 84(3). N . CR. Park. 93–97. Hahn. R . Kristiansen. Tissue and Organ Culture. 1995. 312 p. Park. Salatino P. Bhaskar. Olive mill wastewater remediation by means of Pleurotus ostreatus. Ramanaiah.R. KK . 287–300. A. Soccol. Advances in Fermentation Technology. Lee. G. Journal of Fermentation and Bioengineering. Han. (+)-Lactic Acid Production by Repeated Batch Culture of Rhizopus oryzae in Air-Lift Bioreactor. Journal of Fermentation Bioengineering. 2011. Azadirachtin production in stirred tank reactors by Azadirachta indica suspension culture. 1996. Marzocchella A. Juwarkar. JY. Mohan. K. Paek . New Delhi: Asiatech Publishers. 85(1). Oldshue. 2006. Pedroni Medeiros et al. . Papagianni. 1039–1054 Nag. 172-201. Laccase production using Pleurotus ostreatus 1804 immobilized on PUF cubes in batch and packed bed reactors: influence of culture conditions. Nishina. 2008. YAahiro. BR. Biochemical Engineering and Biotechnology. Pandey. SV . 1966. SV . A . Dixit. Journal of Fermentation and Bioengineering. Fermentation mixing scale-up technique. 8. B. J . Okabe. Olivieri G. Dussap. Kyz. 39. Bioreactors: Functions in fermentation processes. 102.Mattey. Plant Cell. Tanaka H. Friedrich. Masui H. 2005. Bhatt. 82(1). S. 79. SP . Biotechnology Bioengineering. L. M.. Mirro. C . Application of bioreactor systems for large scale production of horticultural and medicinal plants. 51. 1998. 81. 443-448. K . Biofuels refining and performance. 2. Ogbonna JC. Enhanced Production of L(+)-Lactic Acid from Corn Starch in a Culture of Rhizopus oryzae Using an Air-Lift Bioreactor. 52-57 Mohorčič. S . Voll. Park. Yada H. Prasad. Kabe. C. Spier. A. Decolorization of acid black 52 by fungal immobilization. R . Pavko. Chapter 7. 3-24. 180–7. 43. Padoley. Park. Srivastava . 31. Biochemical Engineering Journal. EJ . Biochemical Engineering Journal. Yahiro. Citric acid production and morphology of Aspergillus niger as functions of the mixing intensity in a stirred tank and a tubular loop bioreactor. Yahiro. JBK. M. Shilton A. Y. A. 91. Sannia G. McGraw-Hill Professional. P . Satpute. Ghasem D. 2006. Inc. p. 301–307. de Souza Vandenberghe. 2008. Park. Which Impeller Is Right for Your Cell Line? A Guide to Impeller Selection for Stirred-Tank Bioreactors. 7. 2005. Najafpour. 35–42. Acta Chim Slov. Kim. Bioreactors for treatment of VOCs and odours – A review. A. Enzyme Microbial and Technology. 2007. BioProcess International. 42. GD . J.86 M. Journal of Microbiology. Journal of Fermentation Bioengineering. Yin. D . CG (Editors). K. Pandey. P. Process Biochemistry. 96-100. Ashok. Yin. Cennamo G. Decoloration of the diazo dye Reactive Black 5 by immobilised Bjerkandera adusta in a stirred tank bioreactor. Lee. M. N.B. 2004. B . RJ. Y. Journal of Environmental Management. Wastewater treatment high rate algal ponds for biofuel production. Pati. 371–374. K. D. P. 619–628 Mudliar. 2010. Comparison of Neomycin Production from Streptomyces fradiae Cultivation Using Soybean Oil as the Sole Carbon Source in an Air-Lift Bioreactor and a Stirred-Tank Reactor. Bioresource Technology. reesei. Letters Applied Microbiology. 2008. Ultra Clean Magnetic Mixer®. 2002. FG. Rep. Schaechter.premiertec. Applied Energy. N. Sanromán. 37. 2006. . 1–9. ZS . Applied Biochemestry and Biotechnology. Hoseini-Alhashemi. Rodríguez Couto. ST. Lorenzo. Das. RRM . C. Mobasher. S. 2005. A. 612–616 Rose. The Desk Encyclopedia of Microbiology. Sánchez-Mirón. Bioresource Technology. Katsuda. J. R. A . 57. 31(7).. Biol. T. Fiber bed reactor design for animal cell culture. New York: Elsevier Academic Press. French Patent no. Optimization of a flat plate glass reactor for mass production of Nannochloropsis sp. 1068–1074. CR. Y. Rodríguez. 2004. 106(2). Reczey. Gerlach. Ryan. 259-269. S . Camacho. Chisti. Chinnasamy. Soccol. Lima. 2010. 1149 p. 39. 1221–1228. S . High efficiency production of astaxanthin in an airlift photobioreactor. Paterson. Cellulase production by T. 42:. Teixeira. 12. M . Application of Different Types of Bioreactors in Bioprocesses 87 Perry. G. Biotechnology Bioengineering. I. 2002. S. 703-706. Reddy. P . Putt. Zacchi. 1954. Á . Wang. 85(3). Molares. Pandey. H. R . Process Biochemistry. Lederberg. Art. PREMIERTEC®. Teodoro. Modeular extracorporeal liver support. V . MC. Leukes. Journal of Biotechnology. Cheng-Wu. A. A separable and multipurpose tissue culture chamber. Process Biochem. 25–30 Reddy.net/Ultra_Clean_Magnetic_Mixer/Ultra_Clean_Magnetic_Mixer. Sauer. Journal of Bioscience and Bioengineering. 1015-1023. García. N . R. 2001. DIC. outdoors. 76-06-677 (1976) Rancaño. Improvement on Citric Acid Production in Solid-state Fermentation by Aspergillus niger LPB BC Mutant Using Citric Pulp. EM. 72–87. Katoh. Available from: http://www. htm Raimbault. Enzyme and Microbial Technology. G . An efficient system for carbonation of high- rate algae pond water to enhance CO2 mass transfer. Germon. 2009. Richmond. Szengyel. KC. J. WD .: A new strain with highly saturated fatty acids for biodiesel production in bubble-column photobioreactor. 467– 473 Ranjbar. Manjinder. Chlorella sp. Pillay. S. Rodríguez Couto. 1989. MA. Available online 8 Jan 2011. S . Effect of aeration on the production of hemicellulases by T. Montazeri-Najafabady. 2003. 3240–3245. 34. S. Biotechnology Progress. In Press. Med. S. 21. J. Org. B . 1996. K . JA. Eklund. 2011.G. 204-207. 102. lanuginosus SSBP in a 30 l bioreactor. Rasoul-Amini. N . Tex. 158. M. 2002. Growth and biochemical characterization of microalgal biomass produced in bubble columnand airlift photobioreactors: studies in fed-batch culture. Rodrigues. High laccase activity in a 6 l airlift bioreactor by free cells of Trametes hirsuta. R. Grima. LPS. Singh. 1074-1083. Burton. Vandenberghe. DR . Production of laccase by Trametes versicolor in an airlift fermentor. Procédé d’enrichissement en proteins de produits comestibles solides. SG. Yamaji.. M. Ghasemi. JC. 26. Inoue. Bioresour Technol. Fungal bioremediation of phenolic wastewaters in an airlift reactor. Z. A. Mulimani. Jones. spores by solid state fermentation in different types of bioreactors. Pettersson. 13–18. R. Phytase produced on citric byproducts: purification and characterization. Cellulase fermentation on a novel substrate (waste cardboard) and subsequent utilization of homeproduced cellulase and commercial amylase in a rabbit feeding trial. Tamburic. 111. 2009. Crudge. Soccol. Natural and recombinant fungal laccases for paper pulp bleaching.R. GT. Bioresource Technology. 20. CS. Guizelini. 346–352 Smith. Szijarto. M. Electron Journal of Biotechnology. GC. 2003. FW. 2004. Johansson G. PJ. Noseda. T . V. Vandenberghe. E. Pandey. Réczey. SK. Levasseur.. Maitland. A. Boom. Patel. Recent advances in solid-state fermentation. van den Hondel. Yarmuch. Sigoillot. RI. M. JJ. A. JL. Sella. World Journal of Microbiology and Biotechnology (2011) 27:267–274 Stanbury. de Souza Vandenberghe. IK. Soccol. Bersény. 48. Research. 2007. Desalination. ML. 27. Desalination. K. Punt. CR. Membrane applications for antibiotics production. Mohan. Medeiros. 2000. G. Soccol. BP. Design of a novel flat- plate photobioreactor system for green algal hydrogen production. Santos. Xia. 205–218. Ma. A . Mézesc. U. RC. Lilly. 2009. 49–57. 236. 273. CR. Hellgardt. 958–961. JL. 1990. Van Roon. Keshavarz. Optimized cellulase production by Phanerochaete chrysosporium: control of catabolite repression by fed-batch cultivation. RG. Process Biochemistry. K.VH. Biotechnology and Bioengineering. SRBR. A. Shito. Szabo. RM. MD. Record. CAMJJ.P. Lab-Scale production of Bacillus atrophaeus&apos. AK. Brazilian Archives of Biology and Technology. W . Scheidt GN .B. MR . SJ. Production and immobilization of cellobiase from Aspergillus niger ZU-07. 2011. AL. 39. Oxford: Pergamon Press. RR. Enzyme Microbial and Technology. Soccol. 44. Fournel. Fendrich. 1011. L. C. Toner. M. Brazilian Patent (PI0801454-0). Membrane bioreactors: Two decades of research and implementation. Spier. Zemichael. 2008. X. L. ABP. 1363–1367 Schroën. 2011. B. AW. 98. SoccoL. Spier. Ind Crops Prod. Principles of Fermentation Technology. Beefink. Leontievsky. Shankar. IJ.88 M. CR. 35. Belle. 64. α-Galactosidase production by Aspergillus oryzae in solid-state fermentation. Transformation and degradation of the disazo dye Chicago Sky Blue by a purified laccase from Pycnoporus cinnabarinus. CR. Singhania. Greiner. 148–154 Sedarati. Transformation of high concentrations of chlorophenols by the white-rot basidiomycete Trametes versicolor immobilized on nylon mesh. Asther. J. 78–84 Sigoillot. Desenvolvimento de um biorreator do tipo imersão por bolhas (BIB) para as técnicas de micropropagação e cultura de células vegetais. 52. 100–7 Shen. Robert. CGPH. A. Journal of Surg. Konietzny. Woiciechowski . LPS. VT. Tramper. K. Journal of Biotechnology. Baker. Efficacy of an extracorporeal flat-plate bioartificial liver in treating fulminant hepatic failure. M. Tillers. Biochemical Engineering Journal. P C. Vandenberghe. Biochemical Engineering Journal. 104–114 Schliephake. Pedroni Medeiros et al. LPS. Fox. 6578-6591. PF. Mainwaring. WL. Evans. 2004. 36. 53-62. 2003. 13. Faigl Z. International Journal of Hydrogen Energy. 159-170. R. 1995. 2004. AA . 2009. Lonergan. Overview of applied solid-state fermentation in Brazil. M. Tompkins. CR. Applied Microbiology Biotechnology. HH. M R. . Almeida. Judd. IA. P. 6. Soccol. N. 221–230. 2003. JC. 1996. DE. Geng. Merchuk. H. New York: Academic Press. 2004. JJ. CU. Wolf. 1992a. Xavier. KY. 547– 554 Ugwu. Kadouri. 16-27. L. editors. Bioresource Technology. Handbook of Microalgal Culture: Biotechnology and Applied Phycology. Tredici. Griffiths G. 30. Iowa. Applied Biochemistry Biotechnology. Wang. 178–214. 40(11). Li. 3880–3893. Water Reseach. 2005. Biochemical Engineering Journal. Soccol. Pirbazari. Zhang. VWl. 47. 2007. A. Bioresource Technology. 1992b. EJ. 175-178. 4. Tanaka. South Africa. 2007. Solid State fermentation for the synthesis of citric acid. SZ. D. Membrane bioreactor process for removing biodegradable organic matter from water. 21. D. 221–231. CR. Freedman. LPS. Williams. Linoleic and α-linolenic fatty acids affect biomass and secondary metabolite production and nutritive properties of Panax ginseng adventitious roots cultured in bioreactors. BE. Soc. Characterization of light utilization and biomass yields of Chlorella sorokiniana in inclined outdoor tubular photobioreactors equipped with static mixers. EQ. Cytotechnology. Application of Different Types of Bioreactors in Bioprocesses 89 Tavares. Modeling of rotating drum bioreactor for anaerobic solid-state fermentation. USA. R. Wang. (Ed. Uchiyama. 2006. Ogbonna. Wu. MSM. 41–49. Optimization and modeling of laccase production by Trametes versicolor in a bioreactor using statistical experimental design. G. Gray. Ben Aim. 99. Vandenberghe. Ramsay. 2000. Freedman. Coelho. W. Wang. MR. Li. Am. CF. 2000. University of the Free State. Applied Energy. Tao. 80. 134. Eppstein. W. MacDonald D. JC. Master Thesis. 2839–2845. Lebeault. Growth and laccase production kinetics of Trametes versicolor in a stirred tank reactor. 460–464. Ugwu. Materassi. Aoyagi. 1992. Tredici. C. Organs. Uhl. Thiruchelvam. 1– 48. 2010. In: Spier RE. H. A. Membrane separation bioreactors for wastewater treatment. Blackwell Publishing. APM. G. 2008. 41. MR. Kadouri. Popova. MAS. In: Richmond. C. Parameswaran. Mixing: Theory and Practice. MD. Animal cell technology: developments: process and products. A. 3406-3411. AT. AMRB. JB. 9. JAP.). Bilirubin conjugation by an artificial liver composed of cultured cells and synthetic capillaries. L. Mass production of microalgae: photobioreactors. Munkelt. Department of Microbiology and Biochemistry. Biotechnology and Bioengineering. Oxford: Butterworth-Heinemann. X. X. Critical Review Environmental Science Technology. Agapito. Bloemfontein. 156-168. TC. H. Photobioreactors for mass cultivation of algae. J. Hahn. 1975. Applied Microbiology Biotechnology. 109–115. Paek. Simulation of algae growth in a bench-scale bubble column reactor. Process Biochemistry. Journal of Applied Phycology. Trans. A. K. EV. Pandey. JA. Zhang. . Continuous production of monoclonal antibodies in CelliGen packed bed reactor using Fibracel carrier. Eppstein. Intern. Coutinho. 2009. 1966. 74. Production of laccase by the white rot fungus Pycnoporus sanguineus. JC. Modified CelliGen- packed bed bioreactors for hybridoma cell cultures. Artif. L. M. 4021–4028. Jacklin. From open ponds to vertical alveolar panels: the Italian experience in the development of reactors for the mass cultivation of phototrophic microorganisms. Wu. Van der Merwe. R. 2002 Visvanathan. 2002. CH. 233– 248. 87. CU. O. Pedroni Medeiros et al. . 270. A. Ge. 30. 2694–2704. X.B. Zmora. AY. MC. de Souza Vandenberghe. An industrial-size flat plate glass reactor for mass production of Nannochloropsis sp. 29. 195.. Biomaterials. Spier. Biochemical Engineering Journal. Xu. 2007. 2006. 35-49. 2011. CW. 278–299. Zhang. Cicek. R. Kopel. State-of-the-art of membrane bioreactors: Worldwide research and commercial applications in North America. Production of lactic acid from renewable materials by Rhizopus fungi. A.90 M. Food. J. A biaxial rotating bioreactor for the culture of fetal mesenchymal stem cells for bone tissue engineering. N. Richmond. Dolan. Aquaculture. Zhang. Towards high-yield production of pharmaceutical proteins with plant cell suspension cultures. Biotechnology Advances. JM. 2001. Jerry Chan. Kelly. WS. J . Chng. TT. 251–263. Chong. Zhang. Ilg. L. (Eustigmatophyceae). Yang. SH. Mahesh Choolani. 35.R. 2009. YC.. Journal of Membrane Science. ZY.P. Jin. Teoh. 201–211. B. W.