A Dynamic Hydrogel Platform to Model Cardiac Tissue Development and Disease

Heart disease is currently the leading cause of death in the United States, and is most often caused by myocardial infarction (MI). There is a desire to create novel therapies and treatments. However, due to a lack of fundamental understanding of the heart’s inflammatory response to infarction, the development of new therapies is both time consuming and costly. In this work, we report a novel biomaterial platform to mimic dynamic changes in the heart tissue during MI. We believe that our platform enables dynamic control of cardiac cell alignment and matrix stiffness (from healthy to fibrotic tissue) to investigate cardiac tissue development and disease.<br/><br/>In this study, we report a novel dynamic hydrogel platform enabling spatiotemporal control of cellular alignment and matrix stiffness (from healthy to fibrotic tissue stiffness). Our approach involves: (i) fabrication of polydimethylsiloxane (PDMS) based elastomeric film displaying lamellar wrinkling patterns with user defined and spatiotemporally controlled pattern amplitude and wavelength, and (ii) chemically grafting a hydrogel film allowing light-induced stiffening from healthy to fibrotic stiffness, matching values reported in the literature. In our approach, methacrylated alginate (MeAlg) hydrogel films are first fabricated using Michael-type addition crosslinking using dithiothreitol (DTT) to form hydrogels with healthy stiffness (~15 kPa), during which it is also chemically tethered to the PDMS substrate. When needed, hydrogels can be stiffened in situ when exposed to UV or blue light in the presence of a photo initiator to reach to fibrotic stiffness (~55 kPa). Using this platform, we first investigate the effect of pattern size (amplitude and wavelength) on cardiac cell alignment. We then report the effect of matrix stiffness on cardiac cell function. Human cardiac fibroblasts (hCFs, Normal Human Ventricular Cardiac Fibroblasts, NHCF-V, CC-2904, Lonza, United States), human cardiomyocytes (hCMs, AC16 Human Cardiomyocyte Cell, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) (iCell Cardiomyocytes 01434, FUJIFILM Cellular Dynamics, Inc.) were used in this study. <br/><br/>In the first part, we show that the degree of cellular alignment for hCMs and hCFs is controlled by the pattern dimensions, such that higher degree of alignment is obtained for higher pattern amplitudes or smaller wavelengths. Spatial control of lamellar patterns allows us to create distinct regions with tunable patterns or continuous patterns with gradient dimensions. In the second part, we show that hydrogels are capable of being stiffened dynamically during the culture (confirmed by AFM and rheology), and gel integrity can be maintained for up to 21 days of culture. In addition, iPSC-CMs cultured for up to 21 days show distinct changes in their sarcomere expression and beating frequency in response to changes in stiffness and alignment. We plan to conclude with our approach to use this platform to mimic the dynamic changes in the ECM post-MI to develop a drug screening platform.