Biomaterial systems for evaluating the influence of ECM mechanics on anti-fibrotic therapeutic efficacy

•Fibrotic therapies are often tested on biomaterial platforms which do not mimic in vivo mechanics.•In these studies, we use various viscoelastic substrates to mimic healthy and fibrotic cardiac tissue and evaluate the efficacy of a novel anti-fibrotic therapy on relevant cardiac cell types.•Cellular responses were evaluated on soft and stiff polyacrylamide substrates and compared to responses on high and low loss tangent microgel thin films.•In the presence of Y-27632 containing nanogels, a reduction of fibrotic marker expression was noted on linear elastic healthy and fibrotic cardiac mimetics.•Cellular responses differed on nonlinear elastic mimetics, where early treatment with the ROCK inhibitor increased fibrotic marker expression. Cardiac fibrosis is characterized by excessive accumulation and deposition of ECM proteins. Cardiac fibrosis is commonly implicated in a variety of cardiovascular diseases, including post-myocardial infarction (MI). We have previously developed a dual-delivery nanogel therapeutic to deliver tissue plasminogen activator (tPA) and Y-27632 (a ROCK inhibitor) to address MI-associated coronary artery occlusion and downregulate cell-contractility mediated fibrotic responses. Initial in vitro studies were conducted on glass substrates. The study presented here employs the use of polyacrylamide (PA) gels and microgel thin films to mimic healthy and fibrotic cardiac tissue mechanics. Soft and stiff polyacrylamide substrates or high and low loss tangent microgel thin films were utilized to examine the influence of cell-substrate interactions on dual-loaded nanogel therapeutic efficacy. In the presence of Y-27632 containing nanogels, a reduction of fibrotic marker expression was noted on traditional PA gels mimicking healthy and fibrotic cardiac tissue mechanics. These findings differed on more physiologically relevant microgel thin films, where early treatment with the ROCK inhibitor intensified the fibrotic related responses.