Living tissue engineered heart valves (TEHV) may circumvent ongoing problems in pediatric valve replacements, offering optimum hemodynamic performance and the potential for growth, remodeling, and self-repair [1]. Although a myriad of external stimuli are available in current bioreactors (e.g. oscillatory flows, mechanical conditioning, etc.), there remain significant bioengineering challenges in determining and quantifying parameters that lead to optimal ECM development and structure for the long term goal of engineering TEHVs exhibiting tissue architecture functionality equivalent to native tissue. It has become axiomatic that in vitro mechanical conditioning promotes engineered tissue formation (Figure 1), either in organ-level bioreactors or in tissue-level bioreactors with idealized-geometry TE constructs. However, the underlying mechanisms remain largely unknown. Efforts to date have been largely empirical, and a two-pronged approach involving novel theoretical developments and close-looped designed experiments is necessary to reach a better mechanistic understanding of the cause-effect interplay between MSC proliferation and differentiation, newly synthetized ECM, and tissue formation, in response to the controllable conditions such as scaffold design, oxygen tension, nutrient availability, and mechanical environment during incubation. We thus evaluate the influence of exterior flow oscillatory shear stress and dynamic mechanical conditioning on the proliferative and synthetic behavior of MSCs by employing a novel theoretical framework for TE. We employ mixture theory to describe the evolution of the biochemical constituents of the TE construct and their intertwined biochemical reactions, evolving poroelastic models to evaluate the enhancement of nutrient transport occurring with dynamic mechanical deformations, and computational fluid dynamics (CFD) to assess the exterior flow boundary conditions developed in the flex-stretch-flow (FSF) bioreactor [4–6].

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