Design of three-dimensional bioartificial stretchable scaffolds through additive manufacturing for an in vitro model of fibrotic cardiac tissue

Cardiac fibrosis typically arises as a result of myocardial infarction, causing the irreversible loss of billions of cardiomyocytes and progressive heart failure. New regenerative medicine approaches are under investigation to reduce heart failure or revert cardiac fibrosis. In vitro testing platforms able to mimic the mechanical behavior of pathological cardiac tissue allow to reduce in vivo trials on animal models in agreement with the 3Rs principle. State of the art literature reports in vitro models mainly based on hydrogels, which however have different drawbacks: they lack structural biomimetic cues for cell guidance, cannot bear the cyclic deformations of cardiac tissue and have short degradation times (< 1 month). The aim of this thesis was the design of mechanically stretchable scaffolds with biomimetic composition to be exploited for in vitro engineering of human cardiac fibrotic tissue, reproducing different pathological conditions through their architecture and allowing long-term testing. Scaffolds were fabricated by additive-manufacturing from a synthetic biocompatible polymer providing proper mechanical resistance and slow degradation times. Scaffold pores were filled with natural polymer hydrogels, mimicking extracellular matrix-like microenvironment. The stiffness of hydrogels was tuned by their concentration. Highly stretchable scaffolds were obtained by tailoring fiber diameter and mesh geometry and size, to mimic cardiac fibrotic tissue stiffness and maximum elastic deformation. Scaffolds were fabricated by fused deposition modeling (FDM) and melt-electrowriting (MEW). FDM was employed to optimize the geometry and mechanical behavior while MEW allows to print scaffolds with closer and thinner filaments, suitable to support future long-term cell colonization. Static and fatigue cyclic tensile tests on final scaffolds showed a close behavior to the mechanical properties of fibrotic cardiac tissue. In the future such models will be used for in vitro drug screening and preclinical validation of cardiac regenerative therapies, with the advantage to allow long-term testing. The work has been part of BIORECAR ERC project (772168).