P464Acute cardiac dysfunction induced by Ionizing radiation exposure: the mitochondrial side
Authors: M Ciccarelli, D Sorriento, A Fiordelisi, J Gambardella, A Franco, B Trimarco, G Iaccarino
Journal: Cardiovascular Research (2018)

Background: Classical cell therapy approaches for the injured heart still have therapeutic promise, but are limited by poor cell retention.Engineering native myocardial tissue, thereby recapitulating the structural organization, has therapeutic potential but is still a challenge.Recently, we developed a microfiber scaffold of a biodegradable polymer in combination with cardiac progenitor cells by using a novel technique, called Melt Electrowriting (MEW).Although successful, the limited dynamic mechanical properties of these scaffolds do not allow for deformation under heart contraction and consequently hinders functional integration.Purpose: We hypothesize that the fabrication of fiber scaffolds with non-linear hexagonal geometries will allow for variable mechanical properties.Moreover, combining these novel fiber scaffolds with human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) will enhance iPSC-CM function, thereby creating a compatible and clinically-relevant heart patch for cardiac regeneration.Methods: Using a custom-made MEW device, poly (e-caprolactone) (PCL) based scaffolds were fabricated with an internal hexagonal architecture.Scaffolds were manufactured with equilateral hexagons with different side lengths and then mechanically characterized under quasi static and dynamic loading conditions.Subsequently, scaffolds were seeded with iPSC-CMs encapsulated in a cardiac ECM-like hydrogel to create a functional cardiac patch.iPSC-CM viability, alignment, maturation and function were determined after 7 and 14 days in culture.To show minimally invasive application of the hexagonal scaffolds, injectability and shape-recovery was assessed in a large-animal (porcine) model.Results: Scaffolds with hexagonal geometries were successfully manufactured for the first time using MEW.The smallest hexagon pore resolution achievable was 400 mm (for microfibers Ø¼20-25 mm and scaffold thickness ¼ 300 mm).The hexagonal architecture allowed for better deformation recoverability (50% strain), compared to the linear architecture (5%).Additionally, hexagonal scaffolds showed improved recovery under dynamic loading conditions.The hexagonal cardiac patches showed increased beating rate (1.5 fold), enhanced cell alignment, sarcomere content, and Cx43 organization, and an increase in cardiac marker expression (cardiac Actin 1.5 fold, SERCA2a 2.1 fold, and PPARGC1a 3.1 fold), indicative of enhanced iPSC-CM maturation.Importantly, we showed successful minimally invasive epicardial delivery of the hexagonal patches on a porcine heart. Conclusion:The creation of MEW scaffolds with stretchable geometries composed of microfibers allows for the generation of in vitro cardiac constructs that better mimic the mechanical environment of endogenous cardiac tissue.By combining these flexible fiber scaffolds with clinically relevant human iPSC-CMs, we have produced a heart patch with superior features for cardiac tissue engineering.