Miniaturized Bioreactors

Miniaturized bioreactors can be divided into two categories based on scale microreactors and nanoreactors. These bioreactors present several fundamental advantages and open new venues. Miniaturized reactors allow for bench-scale chemical and biochemical production, which can be used by researchers. They also allow for cost-effective production when smaller quantities of a chemical are required. Other larger bioreactors are often not feasible because the production is not cost effective if the product is not very valuable or if the production is not consistent or pure enough for higher value chemicals. Miniaturized bioreactors, however, provide a great deal of conpol over reaction kinetics and hydrodynamics. 

With miniaturized bioreactors, however, scale-up is a much simpler process. The procedure involves putting miniaturized bioreactors into series and/or parallel in order to produce larger output quantities. This approach keeps the reaction kinetics and hydrodynamics predictable for each component regardless of plant scale. Hence, the process is often referred to as numbering-up. In other words, the laboratory bioreactor is very similar to the industrial production, with the bioreactor quantity and controls being the most significant differences. This property keeps the start-up and development costs lower and more flexible (Ehrfeld et al., 2000 Watts and Wiles, 2007). 

The numbering-up method also introduces another potential advantage. The scaled model operates as a continuous bioreactor rather than batch while providing the operator with the same control advantages of the batch operation at the same time. Therefore, the process time is expected to be shorter with miniaturized bioreactors since most standardized bioreactors use a process time that is longer than the kinetic minimum. Safety is also increased tremendously since the process can be stopped at any point in the process flow (Ehrfeld et al., 2000). These controls can be instituted automatically without the need for human supervision. 

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Miniaturization in biocatalysis and fermentation is another necessary step. This will allow continuous processes with the benefits that could derive in terms of process intensification and reduction of waste. Miniature (less than 10 mL) stirred reactors and microtiter plates (MTP) have been introduced mainly with the idea of allowing high-throughput screening to speed up bioprocess development, even though they are available now also for production uses [172-174]. Notably, problems emerge with these miniature bioreactors (MBRs), such as evaporation and surface tension, which determine the performances, but which are masked in larger bioreactors. 

Another very important advantage of miniaturized bioreactors is that scale-up takes on a different form. The scale-up procedure for standard bioreactors and miniaturized bioreactors is compared in Figure 10.5. The scale-up procedure for standard bioreactors involves a complicated iteration processes. A laboratory bioreactor is designed as a proof-of-concept. Next, an experimental-scale bioreactor is designed to ensure production viability. After a few iterations, a small-scale pilot plant is constracted to test and finalize the production process, equipment placement, and economic viability. Once this step is accomplished, a large-scale... 

Mohr and his colleagues reported a continuous recirculating two-phase flow miniaturized bioreactor for biocatalytic transformations with the enzyme... 

The hydrogel-EAP composites include other implications such as, application towards biosensors, DNA hybridizations, micro-surgical tools and miniature bioreactors and may be utilized to their full potential in the form of injectable devices... 

Betts JI, Baganz F. 2006. Miniature bioreactors current practices and future opportunities. Microbial Cell Factories 5 21. 

Isett K, George H, Herber W, AmanuUah A. 2007. Twenty-four-weU plate miniature bioreactor high-throughput system assessment for microbial cultivations. Biotechnol Bioeng 98(5) 1017-1028. 

Further miniaturization and lower-cost sensors will put an instrumented bioreactor in every scientist s reach. If this effort succeeds, it should be possible to instrument shake flasks at low cost. Since this is the most widely used bioreactor of any kind and the bulk of basic research as well as the annual screening of hundreds of thousands... 

Gloeckner, H. Lemke, H.-D. New miniaturized hollow fiber bioreactor for in vivo like cell culture, cell expansion, and production of cell derived products. Biotechnol. Prog. 2001, 17, 828-831. 

The miniaturization of biomedical and biochemical devices for bioMEMSs has gained a great deal of attention in recent years. Products include biochips/ biosensors, drug delivery devices, tissue scaffolds, and bioreactors. In the past, MEMS devices have been fabricated almost exclusively in silicon, glass, or quartz... 

Clark GJ, Langley D, BushneU ME (1995) Oxygen limitation can induce microbial secondary metabolite formation investigations with miniature electrodes in shaker and bioreactor culture. Microbiology 141 663 - 669... 

Microreactors are defined by their size rather than construction. Microreactors are miniaturized with channels between the (sub-)millimeter scale and nanometer scale. Microreactors mix the gas and liquid phases pneumatically or mechanically. The size of the complete bioreactor construction is less important. A microreactor example is shown in Figure 10.6. Microreactors are generally compounded into microreactor elements, which are placed into nuxing units. These units are placed into microreactor devices, which have inputs and outputs for all the microreactor units placed within it. Microreactor devices are placed in parallel or in series in order to achieve the necessary conversion. Finally, the output is treated... 

Novel bioreactors can be represented by many different designs and variations, but the most novel and promising approach may turn out to be miniaturized reactors. 

Novel mechanical or bubble-induced flow designs are not trendsetters nor do they solve many of the and gas-liquid mass transfer problems. Miniaturized reactors, however, could decrease process design and implementation signiflcantly. The numbering-up method for these reactors reduces the time and amount of work necessary for scale-up the process is determined for one experimental unit and then the unit is copied multiple times. The rest of the work is spent on the industrial and economic problems rather than hydrodynamic and gas-liquid mass transfer issues commonly found in scale-up issues for other bioreactors. 

One additional area that is on the horizon is the potential to optimize biologically based processes with microscale equipment. An approach developed by BioProces-sors is a Simcell platform, which is an automated miniaturized system for cell culture development. This platform is capable of running and monitoring hundreds of complex bio-reactions. This automated platform has been used to conduct high-throughput cell culture experiments for process development purposes. The system performs bioreactor operations such as cell inoculation and culture monitoring and control. 

Microfluidic bioreactors are miniaturized systems that are designed to perform a biological transformation on a sample. For instance, a bioreactor with an enzyme will convert the substrate into product when the substrate is present in the sample. Specifically, a protylytic enzyme can be placed in a microfluidic device in order to digest analyte proteins... 

There is presently a move towards biosensors that are multiparametric, miniaturized, and portable. The pharmaceutical industry is particularly difficult to penetrate there are a limited number of bioreactors, the products are expensive, and the analytical methods used are often very sophisticated (for example, chromatography or HPLC). In contrast, biosensors have a large number of applications and a promising future in the areas of environment and defense, in which a number of sensors in different sites can increase the efficiency of protection. 

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