Heart Scar-In-A-Dish: Tissue Culture Platform to Study Myocardial Injury and Mechanics In Vitro.

Abstract

Myocardial Infarction (MI) occurs when blood flow is blocked to a portion of the left ventricle and leads to necrosis and scar formation. Many therapies are under development to improve infarct healing, and 3-dimensional engineered heart tissues (EHTs) offer an in vitro drug screening option to help reduce, refine, and potentially replace animal testing. Unfortunately, existing EHTs over-simplify cardiac mechanics and neglect the spatial variations of the infarcted ventricle in vivo, wherein the passive infarct zone is cyclically stretched under tension as the remote zone cyclically contracts with every heartbeat. We present an in vitro 3-dimensional tissue culture platform focused on mimicking the heterogeneous mechanical environment of post-infarct myocardium. Herein, EHTs were subjected to a cryo-wound injury to induce localized cell death in a central portion of beating tissues composed of neonatal rat cardiomyocytes and fibroblasts. After injury, the remote zone continued to contract (i.e., negative strains) while the wounded zone was cyclically stretched (i.e., positive tensile strains) with intermediate strains in the border zone. We also observed increased tissue stiffnesses in the wounded zone and border zone following injury, while the remote zone did not show the same stiffening. Collectively, this work establishes a novel in vitro platform for characterizing myocardial mechanics after injury with both spatial and temporal resolution, contributing to a deeper understanding of MI and offering insights for potential therapeutic approaches.