Gerontas, S.; (2007) Bioreactor design for the controlled formation of engineered tissues. Doctoral thesis , University of London.

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Abstract

The availability of large numbers of engineered organs would offer significant benefits to the clinical management of surgery. Tissue engineering offers the potential of providing tissues that can mimic the morphology, function and physiologic environment of native ones. Cells could grow in vitro within a biodegradable polymer to construct tissue for implantation. However no generic bioreactor design currently exists. There is now a need to establish a robust process for the production of engineered tissues using autologous cells. A key challenge will be the prediction of the supply of nutrients and removal of metabolites. Models of transport phenomena were developed in order to predict the fluid flow and mass transfer requirements of a prototype bioreactor for the formation of engineered tissues. These models were solved to generate windows of operation which relate key operating parameters with the feasibility of tissue preparation. Examples highlight how the windows of operation can be used to visualize rapidly the region of operating conditions that satisfy the design constraints. The impact of the cell concentration, tube geometry, alginate diffusivity, substrate and metabolite concentration levels, feed and recycle rate on the design of the bioreactor is illustrated. The result of this analysis determines the best configuration of the bioreactor which can meet the cellular transport requirements as well as being reliable in performance whist seeking to reduce the amount of valuable nutrients to be used. Micro scale experiments were designed in order to evaluate from measurements, effective diffusivities of substrates and metabolites in alginate matrices as well as substrate consumption and metabolite production rates in matrices with immobilized growing cells. The oxygen diffusivity and oxygen uptake rate of alginate immobilized neonatal fibroblasts were evaluated using integrated oxygen sensor spots. Additionally, alginate cylindrical constructs with immobilized neonatal fibroblasts were prepared in transwells in order to evaluate the effective diffusivities of glucose and lactate as well as the glucose consumption and lactate production rate. The advantage of such micro scale experiments was that greater data sets could be generated with the small number of cells available but in a way which predicts the larger scale. The database which was created was used to construct the windows of operation to give quantitative solutions of how engineered tissues may be prepared and to visualize process operability in a more explicit way.

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