Improving in situ Heart Valve Tissue Engineering: Understanding Hemodynamics and Patient-Specific Host Response

Objective: In situ heart valve tissue engineering (TE) is an approach that aims to use the patient’s natural regenerative response to obtain living valve prostheses, starting from an off-the-shelf available resorbable synthetic scaffold. The in situ regenerative response is affected by the host inflammatory response to the scaffold.1 We aim to elucidate the difference in the inflammatory and regenerative responses underlying in situ heart valve TE between males and females under hemodynamic stimuli (e.g. cyclic strains). Methods: Macrophages, isolated from blood of male and female donors, were cultured on electrospun synthetic scaffolds as a model system for the initial inflammatory response, predictive for downstream tissue regeneration. Mechanical loading was applied in terms of cyclic strains with varying strain levels, i.e. 0%, 7% and 14%. In addition, sex-differences were studied through addition of varying hormone, i.e. testosterone and estrogen, concentrations. The macrophage response was evaluated in terms of polarization, cytokine production, tissue formation, and scaffold degradation. Results: High strain levels induced a pro-inflammatory gene expression and protein secretion, compared to low strain levels and static controls. In addition, early secretion and deposition of matrix proteins, such as elastin, by macrophages was demonstrated to be strain-dependent. The results on sex-differences are still under review. Conclusions: Our results demonstrate the influence of hemodynamics on the macrophage response to scaffolds. Our current focus lies on exploring the influence of cell intrinsic and hormonal difference between males and females on the response of macrophages to scaffolds for in situ heart valve TE. It is hypothesized that female macrophage and an estrogen-rich environment will display a more M2 dominated response, including increased phenotypical and remodeling markers.2,3 1. Wissing, T.B. et al. npj Regen. Med (2017). 2. Klein, S.L. & Flanagan, K.L., Nat. Rev. Immunol.(2016). 3. Toniolo, A. et al., J. Clin. Endocrinol. Metab.(2015).