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 days in vivo. This work shows the successful bioprinting and implementation of cECM-hCPC patches for potential use in repairing damaged myocardium.

Cell therapy is an emerging paradigm for the treatment of heart disease. In spite of the exciting and promising preclinical results, the benefits of cell therapy for cardiac repair in patients have been modest at best. Biomaterials-based approaches may overcome the barriers of poor differentiation and retention of transplanted cells. In this study, we prepared and tested hydrogels presenting extracellular matrix (ECM)-derived adhesion peptides as delivery vehicles for c-kit cardiac progenitor cells (CPCs). We assessed their effects on cell behavior in vitro as well as cardiac repair in rats undergoing ischemia reperfusion. Hydrogels presenting the collagen-derived GFOGER peptide induced cardiomyocyte differentiation of CPCs as demonstrated by increased expression of cardiomyocyte structural proteins. However, conditioned media obtained from GFOGER hydrogels showed lower levels of secreted reparative factors. Interestingly, following injection in rats undergoing ischemia-reperfusion, treatment with CPCs encapsulated in nonadhesive RDG-presenting hydrogels resulted in the preservation of cardiac contractility and attenuation of postinfarct remodeling whereas the adhesion peptide-presenting hydrogels did not induce any functional improvement. Retention of cells was significantly higher when delivered with nonadhesive hydrogels compared to ECM-derived peptide gels. These data suggest that factors including cell differentiation state, paracrine factors and interaction with biomaterials influence the effectiveness of biomaterials-based cell therapy. A holistic consideration of these multiple variables should be included in cell-biomaterial combination therapy designs.

Developing a suitable cell source is a critical component for the success and durability of tissue engineered heart valves. The significance of this study is the generation of iPSCs-derived mesenchymal stem cells (iMSCs) that have the capacity to mature into valve interstitial-like cells when introduced into a 3D cell culture designed to mimic the layers of the valve leaflet. iMSCs were generated using a feeder-free protocol, which is one major advantage over other methods, as it is more clinically relevant. In addition to generating a potential new cell source for heart valve tissue engineering, this study also highlights the importance of a 3D culture environment to influence cell phenotype and function.

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Tissue engineered heart valves (TEHVs) have the potential to address the shortcomings of current implants through the combination of cells and bioactive biomaterials that promote growth and proper mechanical function in physiological conditions. The ideal TEHV should be anti-thrombogenic, biocompatible, durable, and resistant to calcification, and should exhibit a physiological hemodynamic profile. In addition, TEHVs may possess the capability to integrate and grow with somatic growth, eliminating the need for multiple surgeries children must undergo. Thus, this review assesses clinically available heart valve prostheses, outlines the design criteria for developing a heart valve, and evaluates three types of biomaterials (decellularized, natural, and synthetic) for tissue engineering heart valves. While significant progress has been made in biomaterials and fabrication techniques, a viable tissue engineered heart valve has yet to be translated into a clinical product. Thus, current strategies and future perspectives are also discussed to facilitate the development of new approaches and considerations for heart valve tissue engineering.

Heart valve tissue engineering has the potential to allow the development of living heart valves comprised of cells and biomaterials, and to make them be anatomically patient‐specific. This Review (article No. https://doi.org/10.1002/adhm.201700918) describes the current valve prosthesis and its design criteria, and discusses current strategies and future perspectives for valve tissue engineering. The cover image shows a patient with a “living valve implant” that was engineered using 3D bioprinting, biomaterial scaffold, and cells.