Vascularized bone organoids: current advances and a biomimetic platform for osteonecrosis of the femoral head

Osteonecrosis of the femoral head (ONFH) is a devastating ischemic bone disease. Its pathogenesis is multifactorial, including impaired bone remodeling, chronic inflammation, dysregulated lipid metabolism, and bone marrow edema, all intrinsically linked to vascular dysfunction. However, conventional experimental models fail to fully capture the complex pathophysiology of ONFH. Animal models suffer from interspecies differences and are inherently limited in investigating bone marrow edema and femoral head collapse. Therefore, the complex pathogenesis of ONFH remains poorly understood due to the limitations of existing models. Recently, organoids have emerged as a powerful tool for complex and biomimetic disease modeling, with vascularization strategies developed to enhance their structural and functional maturity. The central role of vascular dysfunction in ONFH underscores the value of vascularized bone organoids (VBOs) as a biomimetic model. In this review, we summarize vascularization strategies for bone organoids, including in vitro approaches, in vivo integration, and bioengineering technologies. For ONFH, VBOs provide an advanced experimental model for elucidating disrupted angiogenesis-osteogenesis coupling, inter-tissue crosstalk, and alterations in intraosseous pressure. VBOs also hold significant value for evaluating pro-angiogenic therapies, advancing regenerative medicine, and guiding personalized treatment. Overall, VBOs offer a promising platform for advancing mechanistic insights and therapeutic development in ONFH.