Computational simulations predict a key role for oscillatory fluid shear stress in de novo valvular tissue formation

Previous efforts in heart valve tissue engineering demonstrated that the combined effect of cyclic flexure and steady flow on bone marrow derived stem cell-seeded scaffolds resulted in significant increases in engineered collagen formation [Engelmayr et al. Cyclic flexure and laminar flow synergistically accelerate mesenchymal stem cell-mediated engineered tissue formation: Implications for engineered heart valve tissues. Biomaterials 2006; 27(36): 6083-95]. Here, we provide a new interpretation for the underlying reason for this observed effect. In addition, another related investigation demonstrated the impact of fluid flow on DNA content and quantified the fluid-induced shear stresses on the engineered heart valve tissue specimens [Engelmayr et al. A Novel Flex-Stretch-Flow Bioreactor for the Study of Engineered Heart Valve Tissue Mechanobiology]. Annals of Biomedical Engineering 2008, 36, 1-13]. In this study, we performed more advanced CFD analysis with an emphasis on oscillatory wall shear stresses imparted on specimens when mechanically conditioned by a combination of cyclic flexure and steady flow. Specifically, we hypothesized that the dominant stimulatory regulator of the bone marrow stem cells is fluid-induced and depends on both the magnitude and temporal directionality of surface stresses, i.e., oscillatory shear stresses (OSS) acting on the developing tissues. Therefore, we computationally quantified the (i) magnitude of fluid-induced shear stresses as well as (ii) the extent of temporal fluid oscillations in the flow field using the oscillatory shear index (OSI) parameter. Noting that sample cyclic flexure induces a high degree of OSS, we incorporated moving boundary computational fluid dynamic simulations of samples housed within a bioreactor to consider the effects of: (1) No Flow, No Flexure (control group), (2) Steady Flow-alone, (3) Cyclic Flexure-alone and (4) Combined Steady flow and Cyclic Flexure environments. Indeed we found that the coexistence of both OSS and appreciable shear stress magnitudes explained the high levels of engineered collagen previously observed from combining cyclic flexure and steady flow states. On the other hand, each of these metrics on its own showed no association. This finding suggests that cyclic flexure and steady flow synergistically promote engineered heart valve tissue production via OSS, so long as the oscillations are accompanied by a critical magnitude of shear stress.