Bone organoid construction and evolution

Abstract

Organoids, generated through three-dimensional in vitro culture, are cellular aggregates that accurately mimic the complex microenvironment, cell-cell interactions, and signaling mechanisms of native tissues. These models offer transformative advantages in studying disease mechanisms, drug screening, and personalized medicine. Compared to traditional two-dimensional cell cultures and animal models, organoid systems exhibit higher physiological relevance, effectively mitigating species-specific discrepancies while significantly enhancing clinical translational feasibility. However, current organoid research primarily focuses on soft tissues such as the heart, liver, spleen, lungs, and kidneys, with limited progress in hard tissue organoids, particularly bone organoids. Given the pivotal role of bone tissue in clinical bone repair, disease mechanism elucidation, and drug screening, this field demands further investigation. Based on our previous research, this review introduces a five-stage iterative framework for bone organoid development: 1.0 (physiological model), 2.0 (pathological model), 3.0 (structural model), 4.0 (composite model), and 5.0 (applied model). This paper systematically reviews the technical pathways for bone organoid construction, highlights the core features and scientific value of each model iteration, and explores the current challenges and future directions in this emerging field. The goal is to provide theoretical and technological insights that advance bone organoid research, offering innovative solutions for bone-related disease studies and clinical applications. The translational potential of this article: This review provides a systematic overview of bone organoid development, highlighting their remarkable role in orthopaedic research and in clinical practice. Through the incorporation of advanced technologies like artificial intelligence and 3D bioprinting, bone organoids provide novel approaches to the development of regenerative medicine and customized orthopaedic treatments.

Keywords: Biomedicine; Bone organoid; Evolution.

Graphical abstract

Fig. 1

A brief history of organoids.

Fig. 2

Six key elements in the construction of physiological bone organoids. Oxygen supply: Ensures cellular metabolism and osteoblast differentiation while preventing hypoxia-induced necrosis; Angiogenesis: Facilitates oxygen and nutrient delivery, metabolic waste removal, and supports bone formation and remodeling; Immune regulation: Modulates inflammatory responses, promotes bone repair, and maintains the balance between osteogenesis and osteoclastogenesis; Extracellular matrix: Provides structural and biochemical support to regulate cell behavior and store/release growth factors; Osteogenic mineralization: Drives mineral deposition and bone matrix formation to achieve mechanical stability and remodeling; Neural innervation: Regulates bone cell activity via nerve signaling, enhancing regeneration and establishing bone-nerve feedback.

Fig. 3

(A) Pathological bone organoids and (B) structural bone organoids.

Fig. 4

(A) Composite bone organoids and (B) applied bone organoids.