Microvasculature functions at the tissue and cell level, regulating local mass exchange of oxygen and nutrient-rich blood. While there has been considerable success in the biofabrication of large- and small-vessel replacements, functional microvasculature has been particularly challenging to engineer due to its size and complexity. Recently, three-dimensional bioprinting has expanded the possibilities of fabricating sophisticated microvascular systems by enabling precise spatiotemporal placement of cells and biomaterials based on computer-aided design. However, there are still significant challenges facing the development of printable biomaterials that promote robust formation and controlled 3D organization of microvascular networks. This review provides a thorough examination and critical evaluation of contemporary biomaterials and their specific roles in bioprinting microvasculature. We first provide an overview of bioprinting methods and techniques that enable the fabrication of microvessels. We then offer an in-depth critical analysis on the use of hydrogel bioinks for printing microvascularized constructs within the framework of current bioprinting modalities. We end with a review of recent applications of bioprinted microvasculature for disease modeling, drug testing, and tissue engineering, and conclude with an outlook on the challenges facing the evolution of biomaterials design for bioprinting microvasculature with physiological complexity.

Cardiovascular disease is the leading cause of death worldwide and bears an immense economic burden. Late-stage heart failure often requires total heart transplantation; however, due to donor shortages and lifelong immunosuppression, alternative cardiac regenerative therapies are in high demand. Human pluripotent stem cells (hPSCs), including human embryonic and induced pluripotent stem cells, have emerged as a viable source of human cardiomyocytes for transplantation. Recent developments in several mammalian models of cardiac injury have provided strong evidence of the therapeutic potential of hPSC-derived cardiomyocytes (hPSC-CM), showing their ability to electromechanically integrate with host cardiac tissue and promote functional recovery. In this review, we will discuss recent developments in hPSC-CM differentiation and transplantation strategies for delivery to the heart. We will highlight the mechanisms through which hPSC-CMs contribute to heart repair, review major challenges in successful transplantation of hPSC-CMs, and present solutions that are being explored to address these limitations. We end with a discussion of the clinical use of hPSC-CMs, including hurdles to clinical translation, current clinical trials, and future perspectives on hPSC-CM transplantation.

Human cardiac organoids hold remarkable potential for cardiovascular disease modeling and human pluripotent stem cell–derived cardiomyocyte (hPSC-CM) transplantation. Here, we show cardiac organoids engineered with electrically conductive silicon nanowires (e-SiNWs) significantly enhance the therapeutic efficacy of hPSC-CMs to treat infarcted hearts. We first demonstrated the biocompatibility of e-SiNWs and their capacity to improve cardiac microtissue engraftment in healthy rat myocardium. Nanowired human cardiac organoids were then engineered with hPSC-CMs, nonmyocyte supporting cells, and e-SiNWs. Nonmyocyte supporting cells promoted greater ischemia tolerance of cardiac organoids, and e-SiNWs significantly improved electrical pacing capacity. After transplantation into ischemia/reperfusion–injured rat hearts, nanowired cardiac organoids significantly improved contractile development of engrafted hPSC-CMs, induced potent cardiac functional recovery, and reduced maladaptive left ventricular remodeling. Compared to contemporary studies with an identical injury model, greater functional recovery was achieved with a 20-fold lower dose of hPSC-CMs, revealing therapeutic synergy between conductive nanomaterials and human cardiac organoids for efficient heart repair.