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A bioreactor can be defined as a device that uses mechanical means to influence biological processes.

In tissue engineering bioreactors can be used to aid in the in vitro development of new tissue by providing biochemical and physical regulatory signals to cells and encouraging them to undergo differentiation and/or to produce extracellular matrix prior to in vivo implantation. This chapter discusses the necessity for bioreactors in tissue engineering, the numerous types of bioreactor that exist, the means by which they stimulate cells and how their functionality is governed by the requirements of the specific tissue being engineered and the cell type undergoing stimulation.

Challenges and Opportunities: Artificial tissues/ organ for transplantation that are under active development include skin, liver, pancreas, kidney, bone marrow, cartilage, blood cells. Despite significant advances have made in tissue engineering, there are a number of challenges biological as well as engineering challenges that need to be solved. These barriers include the lack of a renewable source of functional cells that are immunologically compatible with the patient; the lack of biomaterials with desired properties; and the inability to generate cells in large number. Every organ/ tissue has different architecture; it requires different microenvironments for regeneration, including the employment of scaffolds with optimal pore sizes and optimal surface are to volume ratio. Electrospinning is the novel approach, as it produces continuous fibres in the nano and micro range, create the correct physical environment to promote cell migration and new tissue formation. Electrospinning offers another advantage to co-spin polymers with various additives. By modifying variables such as the distance to collector, magnitude of applied voltage, or solution flow rate can change the overall scaffold architecture. Another principal constraints is how polymers is going to promote blood vessel network formation in the tissue specially in the case of bone. The solution for this may be inducing the angiogenesis process by incorporating the growth factors, such as vascular endothelial cell growth factor (VEGF) or fibroblast growth factor (FGF). Growth factor supply has also been needed for guiding and controlling the cellular behaviour. Polymer-surface engineering is an important tool to improve scaffold multifunctionality and to design biomimetic materials to interact with the surrounding environment by biomolecular recognition. The discovery of adhesion domains in fibronectin and other extracellular matrix glycoproteins containing the amino acid sequence Arg-Gly-Asp (RGD) has enabled the design of synthetic materials that can modulate cell adhesion. Bioactive ligands, such as peptides and polysaccharides, may either be adsorbed or covalently grafted onto the surface to promote specific cell adhesion, proliferation and differentiation. These strategies take advantage of the specific interactions between ECM protein ligands and integrin cell surface receptors. It may prove to be a cost-effective strategy eliminating the need for cells or growth factors. Another important critical issue for engineering 3D tissues in vitro is scale-up for clinical use. Hundreds or thousands of tissues must be grown and cryopreserved under sterile conditions. Bioreactors simulate the in vivo environment and are designed to provide cells seeded deep within a scaffold with all necessary nutrients and biological cues to survive, proliferate, differentiate, and produce ECM. The properties of animal cells set certain constraints on the design of animal cell bioreactor. Hollow fiber bioreactor, packed bed, plug flow and membrane bioreactors are the under development stage.

Bioreactor Design and Cell Culturing Techniques If the great variety of potentially commercial bioprocesses are to be developed and applied, then bioreactors must be designed in which the environment can be controlled precisely to maximize process efficiency. The design of a bioreactor requires a basic understanding of both chemical reactor design and cell biology. First, designers must understand the effects of reaction rates and stoichiometry, mass transfer, heat transfer, and turbulence and mixing on product distribution, reactor productivity and size, and operational characteristics. These phenomena need to be expressed in accurate but tractable models that can be used for design and optimization calculations. In order to develop effective cell culturing techniques, designers also must have basic knowledge of cellular functions and protein chemistry. They should understand the molecular, genetic, and metabolic processes involved in the growth of cells and the expression of cellular products; and structure/function relationships in the use of proteins for biochemical conversions. Separation and Purification

The separation and purification of materials produced in a bioreactor is a critical part of a manufacturing operation. The biological products involved range from high-value-added substances used as pharmaceutical agents (e.g., insulin) to lowercost products including commodity chemicals (e.g., ethanol). High-value bioproducts are usually fragile molecules, such as proteins or peptides that require highly specialized and mild processing conditions and may need to be separated from a complex mixture of molecules, including cell debris. This combination of factors makes separation difficult. At present, most separation schemes are scaledup laboratory procedures; research is needed to improve their performance. Biological processes one day may offer economical alternatives to current, petrochemically based methods for manufacturing organic acids and alcohols. However, before these bioprocesses can become commercially viable, nontraditional, lower-cost separation methods need to be developed. Research is under way to develop extracting solvents, resins (separation media), and sorbents that are more selective and have a higher capacity than do current materials. Reversible extraction systems are needed that respond to changes in temperature, pressure, or acidity. Combinations of conventional separation methods and biological methods are being explored to reduce product inhibition, which often occurs in fermentations that produce alcohols and solvents. In addition, mathematical models of separation steps need to be developed to help reconcile regulatory requirements with basic process conditions during early stages of process development, and to meet the demands of a competitive business environment. Modeling enables scale-up considerations to be estimated very

quickly, a capability needed in order to commercialize a bioprocess in an industry where being the "first to market" is a critical element of success.
In conclusion, tissue engineers are an eclectic group which includes chemical engineers, chemists, cell biologists, and surgeons. The field draws upon the chemical engineer's expert knowledge of fluid dynamics, mass transport, process modeling, materials design, and chemistry. Chemical engineers are designing biocompatible casings for cell transplants, polymer composites for patching wounds, scaffolds that guide and encourage cells to form tissue, bioreactors for large-scale production of therapeutic cells, and experimental and mathematical models to predict cell behavior. However, there are still many challenges that need to be overcome. Some include missing information on how to develop universal donor cells that could be given to any recipient, how to stimulate regeneration of complex multicellular structures in vivo, or how an organ directs the function of its cells. Therefore, success in Tissue Engineering is going to require interdisciplinary participation and determination.