Development of Integrative Platforms with Engineered Cardiomyocyte-Fibroblast Interactions for Cardiac Tissue Engineering Applications

Cardiovascular disease, particularly myocardial infarction (MI), leads to irreversible cardiomyocyte (CM) loss and fibrotic remodeling, driven by complex interactions among CMs, cardiac fibroblasts (CFs), and immune cells. This dissertation presents a series of engineered in vitro platforms to investigate these multicellular dynamics and explore their applications in disease modeling and biological computation. A two-dimensional micropatterned CM–CF system was developed to study synchronization between physically separated CM clusters connected by CFs. By integrating microtopographic features with microelectrode arrays, the platform enabled real-time analysis of intercellular coupling and rhythm coordination. To investigate immune contributions to fibrosis, a macrophage-integrated CM–CF model was created. Introducing distinct macrophage phenotypes revealed how pro-inflammatory versus reparative immune cells influence CF activation, extracellular matrix production, and CM electrophysiology. Expanding to a three-dimensional context, a cardiac fibrosis-on-a-chip microfluidic device was developed to mimic the spatial heterogeneity and immune dynamics of the infarcted heart. This platform allows for region-specific cell patterning and immune stimulation, enabling detailed study of localized cardiac-immune interactions. Finally, leveraging the synchronized beating of CM clusters, a cardiac cell-based biocomputing platform was designed to solve the vertex coloring problem. This biologically inspired system uses the phase dynamics of beating cells to approximate solutions to complex optimization problems with minimal energy input. Together, these platforms advance our understanding of cardiac pathology and demonstrate the potential of living systems in both therapeutic modeling and unconventional computing.