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After seeding of cells onto scaffolds, a period of growth in vitro is often required prior to implantation. Static cell culture conditions generally have proven suboptimal for the development of engineered neotissues because of limitations on seeding efficiency and transport of nutrients, oxygen, and wastes. Bioreactor systems have been designed to overcome these difficulties and to facilitate the reproducible production of tissue-engineered constructs under tightly controlled conditions. The rapidly developing field of reactors for regenerative medicine applications has been reviewed recently (I. Martin et al., 2004; Portner et al., 2005; Visconti et al., 2006; Wendt et al., 2005). Future advances will likely come through improved understanding of the requirements for tissue development, coupled with increasingly sophisticated reactor engineering.

One area in which basic knowledge must increase is the level of oxygen most appropriate for formation of particular tissues. Contrary to conventional wisdom, for some tissues or cell types it appears that low oxygen tension is important for optimal growth and specialized function. For example, in tissue engineering of cartilage, whereas aerobic conditions are essential for adequate tissue production (Obradovic et al., 1999), cultivation in bioreactors at reduced oxygen tension (e.g., 5% instead of the 20% found in room air) improves the production of glycoasminoglycans and the expression of additional characteristic phenotypic markers and functions (Kurz etal., 2004; Mizuno and Glowacki, 2005; Saini and Wick, 2004). Growth of stem and progenitor cells at reduced oxygen tension also may enhance the production of differentiated derivatives (Betre et al., 2006; Grayson et al., 2006; D. W. Wang et al., 2005).

It has become increasingly clear that, in addition to regulating mass transport, bioreactors may be used to enhance tissue formation through mechanical stimulation. For example, pulsatile flow helps the maturation of blood vessels (Niklason et al., 1999), while mechanical stretch improves engineered muscle (Barron et al., 2003). Engineering of bone, cartilage, blood vessels, and both skeletal and cardiac muscle all are likely to continue to advance, in part through more sophisticated mechanical conditioning of developing neotissues.

A third area of great importance will be the use of bio-reactors to improve the manufacture of engineered grafts for clinical use (I. Martin et al., 2004; Naughton, 2002; Wendt et al., 2005). Key goals will be to standardize production in order to eliminate wasted units, to control costs, and to meet regulatory constraints, including good manufacturing practice (GMP) regulations.

The direct interface between man and bioreactors represents another significant challenge in the bioreactor field. On one hand, the patient is increasingly viewed as a potential in vivo bioreactor, providing an optimal environment for cell growth and differentiation to yield neotissues (Warnke et al., 2006). There also are circumstances in which a bioreactor may serve as a bioartificial organ, attached directly to a patient's circulation. The most significant case is the effort to develop a bioartificial liver that can be used to sustain life during acute liver failure, until the patient's endogenous organ regenerates or can be replaced by orthotopic transplantation (Jasmund and Bader, 2002; Sauer et al., 2001, 2003). Most designs to date have focused on the use of hollow-fiber bioreactors seeded either with human hepatic lineage cell lines or xenogeneic (e.g., porcine) hepa-tocytes. Despite intensive efforts, leading to at least nine clinical trials, no bioartificial liver assist device has yet achieved full regulatory approval (Park and Lee, 2005). However, improved bioreactor systems and the use of primary human hepatocytes show promise for enhanced functionality that may lead to clinical success (Gerlach, 2005; Guthke et al., 2006; Zeilinger et al., 2004).

The creation of a robust bioartificial pancreas to provide a physiologically responsive supply of insulin to diabetes patients represents a comparable major challenge for bio-reactor development. Despite three decades of effort, no design has yet proved entirely successful (Kizilel et al., 2005; A. I. Silva et al., 2006), but recent reports offer encouragement (Ikeda et al., 2006; Pileggi et al., 2006). If bioartificial organ technology continues to advance, the demand for new sources of functional human cells such as hepatocytes and pancreatic P-cells will expand dramatically.

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