3D bioprinting of human iPSC-derived cardiac constructs with microvascular network support for improved graft survival <i>in vivo</i>

Cardiac tissue engineering is a rapidly growing field that holds great promise for the development of new therapies for heart disease. While significant progress has been made in the field over the past two decades, engineering functional myocardium of clinically relevant size and thickness remains an unmet challenge. A major roadblock in this respect is the current difficulty in incorporating efficient vascularization into engineered constructs. One potential solution involves the use of microvascular fragments from adipose tissue, which have demonstrated encouraging results in improving vascularization and graft survival following transplantation. However, this method lacks precise control over the vascular architecture within the constructs. Here, we set out to investigate the use of 3D bioprinting for the fabrication of human cardiac tissue constructs composed of human induced pluripotent stem cell derivatives, while allowing for the precise control of the distribution and density of microvessel fragments within the bioprinted constructs. We carefully selected and optimized bioink compositions based on their printability, biocompatibility, and construct stability. Following transplantation into immunodeficient mice, 3D bioprinted cardiac constructs containing microvessel fragments exhibited rapid and efficient vascularization, resulting in prolonged graft survival. Overall, our studies underscore the advantages of employing engineering design and self-assembly across different scales to address current limitations of tissue engineering, and highlight the usefulness of 3D bioprinting in this context.