Physical cues influence the construction of the osteoimmune microenvironment: focus on the hematoma period

Hematoma formation represents one of the earliest biological events during bone healing after bone injury or biomaterial implantation, a process that involves coagulation, provisional matrix formation, innate immune activation and early adaptive immune signaling. During this stage, the hematoma is rapidly infiltrated by neutrophils, monocytes/macrophages, dendritic cells and lymphocytes, which collectively construct the initial osteoimmune microenvironment that modulates subsequent angiogenesis, osteogenesis and osseointegration. Therefore, a systematic elucidation of the hematoma formation process and the regulatory factors governing hematoma behavior provides an important foundation for designing immunomodulatory bone implants. However, most current research has focused primarily on the modulation of macrophages by surface characteristics, relying heavily on simplified in vitro monoculture systems, with limited in vivo temporal characterization of the intact hematoma microenvironment. Insufficient investigation of other immune cells and the regulation of hematomas limits our in-depth understanding of the interplay between hematomas and immunity. This review focuses on the hematoma as a spatiotemporally regulated immune niche and summarizes how material-derived biophysical cues, including surface topography, porosity, wettability and mechanical stiffness, may influence hematoma evolution and the downstream establishment of the osteoimmune microenvironment. This review also discusses the current challenges and future research directions in unraveling the complex material-hematoma-immunity axis, aiming to provide a conceptual framework for the development of translationally relevant immunomodulatory biomaterials for both physiological and pathological bone repair.