At present, a large number of bioreactor types are available. This is due to the rapid development of biotechnological processes resulting from progress in genetic engineering and the bioreactor business boom since the 1970s.
Devising a classification of all these bioreactor configurations becomes extremely difficult. Some reported studies have dealt with classification trials based on whether the reaction occurs, the bioreactor operation, the way in which the culture grows, the reactor mixing characteristics, the basis of the reactor structure, and the energy input (23,27-33).
However, the energy input classification dominates in the literature. It should also be noted that only aerobic reactor systems with high energy input will be considered using the classical energy input classification. But anaerobic cultures, immobilized cultures, and animal as well as plant cell and tissue cultures require a lower energy input for mass and heat transfer processes. It should also be borne in mind that they often occur as cell aggregates and show shear and pressure sensitivity. In addition, systems for cell immobilization become necessary. Aerobic reactors with mechanical, hydraulic, and pneumatic energy input (lower energy input or adapted energy input) are suitable reactor systems for such biocatalysts. Bed reactors and membrane reactors represent further commonly applied reactor variants. Figure 2 illustrates the general bioreactor classification with given examples of bioreactor types.
The power input for mass and heat transfer is controlled mechanically in mechanically agitated reactors. There are mechanically driven or agitated reactors with rotating agitators and with nonrotating agitators producing a stirring effect through a vibrating or tumbling motion. The third type of mechanically driven reactors works without an agitator while the whole reactor vessel rotates. The mechanical energy input by agitators or self-motion should ensure homogeneity of mass and temperature as well as gas dispersion inside the reactor.
Because of aseptic design requirements for mechanically driven reac-
tors, one critical point is the seal between the reactor's inside and the rotating, tumbling, or vibrational shaft as well as the environment. The predominant current choice is a double mechanical seal for direct mechanical coupling of the shaft to the drive. Magnetic coupling has been recommended for alternative cases with high levels of containment. In addition, power transfer by magnetic drive is quite low (150 N m). Tumbling or vibrating stirrer shafts are sealed with a static seal such as a bellows or metal compensator (no mechanical seal). There is enormous know-how available on the design, scale-up, and operation of mechanically driven reactors. The most commonly used reactor type, applied in about 90% of all industrial processes, is the stirred reactor.
The working principles of hydraulically driven reactors are based on energy input produced by pumps. Special double-phase pumps guarantee fluid circulation in internal and external loops. Thereby the kinetic energy of the jet of liquid entering the medium after passing the nozzle (for example, slot nozzles, Venturi tubes, injectors, or ejectors) is used for gas distribution and liquid recirculation. Typical representatives of this reactor class are the deep-jet and the jet-loop reactor. The main advantages of hydraulically driven reactors are their simple design. They work without mechanical internals and seal shafts and show reduced shear forces, simple regulation of external loops, and the possibility to install heat exchangers in the external loop as well as to increase the number of loops.
The term pneumatically driven reactors covers reactors in which the energy input for mass and heat transfer takes place through a steam of gas or air. The effective differences in density between medium and gas lead to variations in fluid mixing and fluid dynamics influenced by viscosity, density difference, gas flow, and gas bubble size. The gas is usually injected by static gas distributors (diffuser stones, nozzles, perforated plates, diffuser rings) or dynamic gas distributors (slot nozzles, Venturi tubes, injectors or ejectors). Airlift reactors and bubble columns represent important pneumatically driven reactors. Although they are relatively simple in construction, sound design and operation are critical for optimal hydrodynamic behavior (31). If there are strong variations in biomass concentration, viscosity, surface tension, and ionic concentration, operational problems—for example, foaming, flotation, and bubble coalescence—will result.
Bed reactors are directly linked to the use of biocatalysts (enzymes, microorganism cells, plant cells, animal cells) occurring in the form of heterogeneous particles (e.g., floes, cell aggregates, immobilized cells or enzymes); biofilms as well as biocatalysts require an immobilization matrix. Bed reactors with a continuous gas phase or continuous liquid phase are available. According to the dependence on the bed containing the biocatalyst and the flow rate inside the bed, we distinguish between packed bed reactors and fluidized bed reactors. The term packed bed reactor is used to define the reactor systems composed of a solid phase with packed or immobilized biocatalysts. The biocatalysts are in continuous or periodic contact with air and nutrient medium. Commonly used packed bed reactors are the trickle bed reactor and biofilter. With respect to the high packing density of biocatalysts, the packed bed reactor is the bioreactor configuration with the highest achievable productivity per unit reactor volume. On the other hand, the height of the solid particles in a bed is influenced by the biocatalyst as well as the catalyst particles. These particles should be relatively incompressible and able to withstand their own weight in the bed without deforming and occluding liquid flow. Thus, crack formation and channeling inside the bed will be prevented. In fluidized bed reactors, the solid particles with the biocatalyst are maintained in fluidization by means of the circulation of the fluid phase (up-flow mode). Fluidization of the solid particles is reached when the fluid flow through the bed is high enough to compensate for their weight. The degree of internal mixing can vary to a great extent and depends on energy input. Configurations favoring complete liquid mixing are possible as well as configurations approaching plug flow. It is difficult to guarantee steady-state operation for fluidized bed systems with different biocatalyst densities and volumes.
Membrane reactors find application in procedures where separation is desired. Here membranes are used for immobilization of cells and enzymes, selective feeding and removal of medium components and metabolites, as well as separation of low- and high-molecular-weight nutrients. Applied membranes are dialysis, ultrafiltration, and microfiltration systems. The biocatalyst can be adsorbed in the form of a membrane layer or immobilized in the pores of the membrane. There are static membranes and dynamic membranes inside the reactor, external cross-flow systems, and special membrane reactors with medium circulation available. The most important advantage of membrane reactors is their recognition of specific culture conditions allowing biocatalyst usage without possible inactivation steps taking place. In membrane reactors the cells are retained by a membrane in a similar way to a natural cell (34). This ensures continuous or repeated operations. Principally, it is necessary to move the fluid on the pressure side to guarantee high filtration rates and long operational times.
Modern bioreactor configurations combine the working principles of a number of reactor basic configurations and are often equipped with external or internal reactor-separator systems (35,36). The eight main reactor types will be characterized briefly concerning the typical working principle in the following discussion.
The ordinary stirred reactor (Fig. 3a) is equipped with baffles, air sparger and radial flow impellers, axial flow impellers, and impellers distributing the power input over a large fraction of the total reactor volume (e.g., Rush-ton, marine, or Intermig impeller). Its typical fermenter geometry (fermenter height/diameter ratio) must be 2:1 or 3:1. Mixing and mass dispersion are achieved by mechanical agitation. Different flow patterns and shear rates inside the vessel will be produced by different impeller shapes, sizes, and spacing (multiple stirrers) as well as installation of a coaxial draught tube (Fig. 3b). It is also possible to design and operate stirred reactors in a multistage mode.
Mass and energy inputs are realized by drum self-rotation in the rotating drum reactor (Fig. 3c). Systems with one reactor-chamber work with a long axis designed as a hollow shaft for air and gas exchange. Transport processes inside the reactor can be varied by the drum rotation rate. If there is the demand for low hydrodynamic shear stress conditions and high oxygen transfer rates for non-Newtonian cultures, the rotating drum reactor should be preferred to standard stirred reactors (37,38).
The bubble column is another alternative to the stirred reactor that has no mechanical agitation and is structurally very simple (Fig. 4a). Mass and energy inputs are achieved only by pneumatic driving (gas sparging). Advantages of this reactor type are low capital cost and minimized problems of sterility based on lack of moving parts inside the reactor. Bubble columns can be divided into five main types of reactors on the basis of their structure: simple column reactors, multistage perforated plate column reactors as well as multistage column reactors with static mixers for repeated gas dispersion, and column reactors with nozzle aeration and tower reactors.
As in bubble columns, mass and energy input in airlift reactors is accomplished pneumatically without mechanical agitation and associated with significantly lower shear levels than in stirred reactors. It should be pointed out that airlift reactors generally provide better mixing conditions than the bubble columns described. The use of a draught tube divides the flow in a riser and downcomer, and the density difference enables the liquid to circulate
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