How hydrogel inclusions modulate the local mechanical response in early and fully formed post-infarcted myocardium

Abstract

Expansion of myocardium after myocardial infarction (MI) has long been identified as the primary mechanism that drives adverse left ventricular (LV) remodeling towards heart failure and death. Direct injection of hydrogels into the myocardium to mechanically constrain the infarct has demonstrated promise in limiting its remodeling and expansion. Despite early successes, there remain open questions in the determination of optimal hydrogel therapies, key application characteristics for which include injected polymer volume, stiffness, and spatial placement. Addressing these questions is complicated by the substantial variations in infarct type and extent, as well as limited understanding of the underlying mechanisms. Herein, we present an investigation on how hydrogel inclusions affect the effective tissue-level stiffness and strain fields in myocardium using full three-dimensional (3D) finite element simulations at early and late post-MI time points. We calibrated our simulations to triaxial mechanical and structural measurements of cuboidal LV myocardial specimens of post-infarcted myocardium, 0 and 4 weeks post-MI, injected with a dual-crosslinking hyaluronic acid-based hydrogel. Simulations included multiple deformation modes that spanned the anticipated physiological range in order to assess the effects of variations in inclusion size, location, and modulus on tissue-level myocardial mechanics. We observed significant local stiffening in the hydrogel-injected specimens that was highly dependent on the volume and mechanical properties of the injected hydrogel. Simulations revealed that the primary effect of the injections under physiological loading was a reduction in myocardial strain. This result suggests that hydrogel injections reduce infarct expansion by limiting the peak strains over the cardiac cycle. Overall, our study indicated that modulation of local effective tissue stiffness and corresponding strain reduction are governed by the volume and stiffness of the hydrogel, but relatively insensitive to its transmural placement. These findings provide important insights into mechanisms for ameliorating post-MI remodeling, as well as guidance for the future design of post-MI therapies.