Tissue Engineering is an emerging field of medical research in which there is tremendous activity. Many of these products rely on the use of a cellular component co-formulated with a natural or synthetic biomaterial. At this time, though, there are no consensus safety or efficacy standards for tissue-engineered products. We describe general approaches for assessment of the safety and efficacy of cell-based tissue-engineered products which will lead to reliable medical products for human use. This article provides a general summary of the factors that should be considered in the design and development of cell- and tissue-based products. Seven areas are considered: cell and tissue sourcing; cell and tissue characterization; biomaterials testing; quality assurance; quality control; and nonclinical testing and clinical evaluation. Factors relevant to these areas have been discussed to provide a set of recommendations on which development of products can be standardized. Where relevant, the discussion has been separated in each area to issues that are independent or dependent on cell source. Also, examples are provided of how these guidelines would be applied to two product types that represent somewhat extreme ends of the spectrum for tissue engineering applications. The first example is a product whose mechanism of action is to provide locally-acting structural repair or enhancement in vivo. The second example is a product whose mechanism of action involves systemically distributed physiologically or pharmacologically active products. In general, we have limited the discussion of product types to those that are implanted into the patient for relatively long periods of time. We believe that adoption of these voluntary guidelines would lead to products that are more consistent in quality and performance as well as more rapidly developed.
The production of recombinant proteins by mammalian cells demands a highly controlled environment for cell cultivation. Temperature stress represents a commonly encountered disturbance in both research and process environments. In this study, we examined the effects of heat shock on the expression of recombinant human erythropoietin (EPO) in a Chinese hamster ovary (CHO) cell line. Biosynthetic radiolabeling experiments indicated that the cells exposed to a 42 degrees C/1-hour heat shock exhibit a transient reprogramming of transcription and translation characterized by the inhibition of protein synthesis and induction of heat shock proteins. The rate of protein synthesis decreased by 50% after the heat shock, while the rate of RNA synthesis increased by 50% initially and then quickly reduced to 80% of the control level. The protein and RNA synthesis rates were fully recovered in approximately 48 hours after the heat shock. However, we found that the expression of EPO was not arrested by the heat shock. The glycosylation patterns, as examined by isoelectric focusing, of either the culture supernatant or the purified EPO were not affected by the heat shock. In contrast, a 45 degrees C/1-hour heat shock terminated RNA and protein synthesis immediately and caused culture death in 12 hours. Cellular responses to temperature stress were affected by the metabolic state of the cells; cells maintained in serum-free medium were more sensitive than cells growing exponentially in the presence of serum. We have also examined the kinetics of metabolic responses of the cells to heat shock with respect to nutrient uptake and metabolite accumulation.
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