Restoring anisotropy in living tissues 'in situ'

Regenerative Medicine aims to restore the composition and organisation of damaged tissues of the human body to regain tissue functionality. When regenerating tissues inside the body (in situ), however, restoration of tissue structural organisation is commonly overlooked. This is particularly problematic for the heart, where functional performance is inseparable from its structurally aligned (= anisotropic) organisation at length scales from the cell to the organ. Two decades of cell-, gene- and material-based therapies to regenerate the damaged heart have mainly targeted the restoration of tissue composition, so far with limited success. I hypothesise that synergistic restoration of tissue anisotropy will radically improve therapy outcomes as it provides the proper environment for cell function, will promote coordinated contraction and halt adverse effects like fibrosis and inflammation. With my team I will test this hypothesis and explore an entirely new concept for restoring cardiac tissue anisotropy remotely using ultrasound. We will create living model systems at the cell and tissue level that recapitulate the increasing heterogeneity of damaged cardiac tissue following cardiac infarction, offer control of cardiac dynamics, and allow manipulation of structural organisation to delineate the interplay between (an)isotropy and cell and tissue functions. By integrating mechanistic understanding from cell and tissue level with multi-scale computational modelling in comparison with an ex vivo living heart model, we will rationally design strategies to mechanically RE-ALIGN diseased, disorganised cardiac tissue at the organ level and evaluate to what extend this can be achieved using ultrasound. By focusing on regenerating structure-function properties in situ, this multidisciplinary, technology-driven project provides unique insights and novel tools that may open up new therapeutic concepts for Regenerative Medicine in general and Cardiac Regeneration in particular.