Hard tissue organoids: From concept to practice

Hard tissues are core components maintaining the mechanical integrity and physiological functions of organisms but have limited self-repair capacity. Traditional clinical strategies for hard tissue healing or regeneration face challenges, including donor scarcity. As engineered 3D cell culture systems that recapitulate tissue/organ-specific structures and functions, organoids outperform conventional 2D cell culture systems and animal models, thereby holding substantial potential for hard tissue healing or regeneration. Regrettably, constructing desired hard tissue organoids is highly demanding, as simulating the intricate structures and mechanical properties of native hard tissues is inherently challenging. Recently, hard tissue organoids have gradually transformed from a conceptual framework into tangible research objects. Focusing on this challenging yet promising field, this review comprehensively delineates the desired features and corresponding viewpoints of hard tissue organoids. It then systematically summarizes the design and construction strategies for organoids, the specific advances in hard tissue organoid development, and their diverse biomedical applications. Furthermore, contemporary challenges and prospective directions in the development and translational application of hard tissue organoids are thoroughly discussed. The summarized insights and proposed perspectives aim to guide the design and engineering of next-generation, or even ideal hard tissue organoids. This review may further facilitate the widespread application and efficient use of hard tissue organoids, as well as related advanced matrix technologies, in drug screening and hard tissue regeneration. STATEMENT OF SIGNIFICANCE: As engineered 3D systems recapitulating tissue/organ-specific structures and functions, organoids outperform conventional 2D cell cultures and animal models. Regrettably, constructing desired hard tissue organoids remains demanding, as simulating the intricate structures and superior mechanical properties of native hard tissues is inherently challenging. Focused on this promising field, this review comprehensively outlines the desired features and corresponding viewpoints of hard tissue organoids. It also summarizes the design and construction strategies for organoids, the latest advances in hard tissue organoid development, and their diverse biomedical applications. Finally, current challenges and prospective directions in their development and translational application are thoroughly discussed, with a focus on multidimensional biomimicry, simulation of typical gradient features, and integrated assembly of adjacent tissue organoids.