A new paradigm in bone tissue biomaterials: Enhanced osteogenesis-angiogenic coupling by targeting H-type blood vessels.

Bone defects resulting from trauma or osteoporosis remain a significant clinical challenge due to the limited regenerative capacity of affected tissues. Traditional therapeutic approaches are often associated with complications such as donor site morbidity and immune rejection, underscoring the necessity for the development of advanced strategies. This review examines H-type blood vessels, a recently identified subtype that plays a pivotal role in linking osteogenesis and angiogenesis. These vessels are distinguished by specific functional phenotypes and are characterized by high co-expression of CD31 and endomucin (Emcn). While various strategies have been explored to enhance osteogenesis, inadequate vascularization remains a major obstacle in effective bone defect repair. Here, we categorize and critically evaluate biomaterials based on their compositions, which facilitate the formation of H-type vessels in the bone microenvironment by modulating key signaling pathways that promote osteogenic-angiogenic coupling. The integration of findings from diverse animal models provides valuable insights into the design principles of materials that optimize the formation of vascular networks alongside bone regeneration. This review also discusses the persisting challenges and potential future directions for the development of clinically translatable biomaterial therapies aimed at achieving functional restoration of vascularized bone tissue. These advancements not only enhance our understanding of H-type vessels biology but also provide a strategic framework for addressing the critical limitation of vascular insufficiency in bone repair.