BIOPRINTED CARDIAC PATCH COMPOSED OF CARDIAC PROGENITOR CELLS AND EXTRACELLULAR MATRIX FOR HEART REPAIR AND REGENERATION

Congenital heart defects are present in 8 of 1000 newborns, and palliative surgical therapy has increased survival rates. Despite improved outcomes, many children develop reduced cardiac function and go on to heart failure and transplantation. Human cardiac progenitor cell (hCPC) therapy has the potential to repair the pediatric myocardium through reparative factor release but suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) has improved heart function in adults while also improving CPC functionality in 2D and 3D culture. This work focuses on developing a bioprinted cardiac patch composed of native cECM and pediatric hCPCs, for use as an epicardial device in repairing the damaged myocardium. First, a method to print patches with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA) is developed. Patch assessments include bioink printability, cellular functionality, and mechanical properties in vitro. To further tailor the reparative potential of cardiac patches, modifying patch components, particularly cell age, matrix composition, and oxygen growth conditions are evaluated. Finally, the implantation of patches in vivo towards improvements to cardiac function in a rat model of right ventricular heart failure, compared to sham controls and cell-free patches, is evaluated. Assessments include hCPC retention, right ventricle function, and tissue level parameters (vessel density, cardiomyocyte hypertrophy, and fibrosis) across all treatments. The animal model evaluation shows that cell-free and neonatal hCPC-laden cECM-GelMA patches improve right ventricle function and tissue level parameters compared to other patch groups and surgical controls. cECM inclusion into patches may be the most influential parameter driving therapeutic improvements. Additionally, child hCPC patches require cECM incorporation to improve right ventricle function, compared to cECM-free child hCPC patches. Altogether, this study paves the way for clinical trials in treating pediatric heart failure using the bioprinted hCPC-GelMA-cECM patches.Ph.D

A bioprinted cardiac patch composed of cardiac-specific extracellular matrix and progenitor cells for heart repair

Congenital heart defects are present in 8 of 1000 newborns and palliative surgical therapy has increased survival. Despite improved outcomes, many children develop reduced cardiac function and heart failure requiring transplantation. Human cardiac progenitor cell (hCPC) therapy has potential to repair the pediatric myocardium through release of reparative factors, but therapy suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) improves heart function in animals, and human trials are ongoing. In the present study, a 3D-bioprinted patch containing cECM for delivery of pediatric hCPCs is developed. Cardiac patches are printed with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA). GelMA-cECM bioinks print uniformly with a homogeneous distribution of cECM and hCPCs. hCPCs maintain >75% viability and incorporation of cECM within patches results in a 30-fold increase in cardiogenic gene expression of hCPCs compared to hCPCs grown in pure GelMA patches. Conditioned media from GelMA-cECM patches show increased angiogenic potential (>2-fold) over GelMA alone, as seen by improved endothelial cell tube formation. Finally, patches are retained on rat hearts and show vascularization over 14 d in vivo. This work shows the successful bioprinting and implementation of cECM-hCPC patches for potential use in repairing damaged myocardium