Bioprinting organoids for functional cardiac constructs: Progress and unmet challenges
Developing physiologically relevant cardiac-engineered in vitro models has been a longstanding challenge in cardiac tissue engineering. Bioprinting technologies have been utilized to recreate the complex architecture of the human heart via the precise placement of cells and biomaterials. Concurrently, self-organizing cardiac organoids have emerged as powerful tools for developing cardiac tissues accurately mimicking the heart’s biological composition. This review explores the merging of these two rapidly evolving fields to produce functionally mature engineered cardiac tissues. Together, bioprinting can provide spatial control and mechanical support to guide cardiac self-organization, including strategies to directly print cardioids or incorporate them as modular units, while cardioid differentiation protocols promote multi-cellular complexity and developmental relevance to improve the functionality of engineered cardiac constructs. In this review, we discuss the key processing challenges and goals across the bioprinting workflow—spanning pre-processing, processing, and post-processing—and evaluate how they intersect with cell viability, structural integrity, and electromechanical function. We then explore the formation and functional features of self-organized cardioids, outlining major differentiation protocols, signaling cues, and functional outcomes. Finally, we propose a convergence between bioprinting and cardioid technologies to produce the next generation of in vitro cardiac models.
1. Introduction
As the leading cause of death globally, cardiovascular disease (CVD) encompasses a range of disorders affecting the heart and blood vessels, including coronary heart disease, valvular heart disease, and congenital heart disease, claiming over 20 million lives annually.1 Over the past three decades, CVD-related deaths have increased by 60% and continue to rise.2 In the United States, more than half of the adult population experiences some form of CVD, ranging from early onset to late-stage disease.3 The heart’s minimal regenerative capacity makes it highly susceptible to irreversible damage, often leading to heart failure.4 Alarmingly, projections estimate that over 8 million people in the United States will suffer from heart failure by 2030.5 By 2050, the annual healthcare costs associated with CVD—currently $393 billion—are expected to rise to $1.49 trillion.6
As the CVD prevalence continues to rise, researchers have increasingly relied on advanced in vitro cardiac models as essential tools for developmental and disease modeling, drug testing, and regenerative medicine. Diverse cardiac tissue models—such as two-dimensional (2D) cultures, engineered three-dimensional (3D) constructs, and animal models—have been developed, but none fully replicate the structural and functional complexity of native heart tissues.7 The structural and biological complexity of the human heart presents significant challenges in engineering functional cardiac tissue.8 Technologies such as 3D bioprinting, an additive manufacturing process that deposits cells, biomaterials, and bioactive molecules in a spatially controlled manner, have been used to fabricate diverse cardiac constructs, ranging from simplified 2D myocardial sheets to complex 3D miniature hearts.9,10 Many bioprinting modalities have been explored in cardiac applications, each offering unique advantages depending on the intended application. However, regardless of modality, bioprinted cardiac constructs often fail to fully replicate native cardiac function due to limitations in cellular organization, vascularization, and functional maturation.7,9,10
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