Advanced Tissue Engineering, Bioprinting, and 5D Optogenetics for Arrhythmia Investigation and Treatment

Ziel

Cardiac arrhythmias like atrial fibrillation (AF) and scar/fibrosis related ventricular arrhythmias (VA) are responsible for significant morbidity and mortality. Yet, the mechanisms underlying their initiation and perpetuation are, in many cases, unclear and their treatments inadequate. These limitations stem, in part, from the lack of suitable complex human arrhythmia models and the inability to introduce reversible targeted functional interventions in the system. Here we propose to develop advanced 3D human cardiac tissue models that can recapitulate the patient-specific structural and electrophysiological substrate and combine them with novel optogenetic interventions to study cardiac arrhythmias. Specifically, we propose to combine patient-specific engineered human induced pluripotent stem cell (hiPSC) derived cardiac cell subtypes with photolithography micropatterning, decellulrization/recellularization, and 3D bioprinting to establish advanced tissue models (Aim 1). Novel optogenetic tools and concepts will then be developed to facilitate modeling of the underlying arrhythmia substrate, for robust and reproducible arrhythmia induction (“arrhythmia printing”), to decipher the mechanisms and to identify critical sites for arrhythmia maintenance; and to introduce new therapeutic concepts (Aim 2). These tools, together with clinical imaging/pathological samples serving as templates, will be used to generate models of the ventricular infarct border-zone (and other fibrosis patterns) to study VA (Aim 3) and the healthy and diseased atria to study acquired and inherited AF (Aim 4). Lessons learned from these studies will be evaluated in relevant animal models. The described approach represents a paradigm shift in the way cardiac arrhythmias can be studied and treated. If successful, it will provide a tailored approach towards novel mechanistic insights into different rhythm disorders, allow patient-specific risk-stratification and provide novel therapeutic options.

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