Three-Dimensional Paper-Based Model for Cardiac Ischemia

In vitro models of ischemia have not historically recapitulated the cellular interactions and gradients of molecules that occur in a 3D tissue. This work demonstrates a paper‐based 3D culture system that mimics some of the interactions that occur among populations of cells in the heart during ischemia. Multiple layers of paper containing cells, suspended in hydrogels, are stacked to form a layered 3D model of a tissue. Mass transport of oxygen and glucose into this 3D system can be modulated to induce an ischemic environment in the bottom layers of the stack. This ischemic stress induces cardiomyocytes at the bottom of the stack to secrete chemokines which subsequently trigger fibroblasts residing in adjacent layers to migrate toward the ischemic region. This work demonstrates the usefulness of patterned, stacked paper for performing in vitro mechanistic studies of cellular motility and viability within a model of the laminar ventricle tissue of the heart. A paper‐based 3D cell culture system recapitulates certain aspects of cardiac ischemia, including gradients of nutrients and migration of fibroblasts. Stacking multiple thin (≈200 μm) layers of paper into thicker (≈1 mm) tissue‐like constructs enables precise positioning of different types of cells, tracking of migratory cells between layers, and analysis of cells in specific regions of the stack.