The concept of“osteoimmunomodulation”and its application in the development of“osteoimmune-smart” bone substitute materials

The traditional biological principle for developing bone biomaterials is to directly stimulate the osteogenic differentiation of osteoblastic lineage cells, the direct effector cells for osteogenesis. This strategy has been successful for the development of bone biomaterials. However, recent progress in bone biology has revealed the vital role of the local bone microenvironment, especially the immune environment, in controlling osteogenesis. Interdisciplinary osteoimmunology has found that the osteoimmune and skeletal systems are closely related, sharing numerous cytokines and regulators. In addition, immune cells play an important role in the physiological and pathological processes of the skeletal system, suggesting that neglecting the importance of the immune response is a major shortcoming of the traditional strategy. Based on this principle, we propose a novel“osteoimmunomodulation”-based strategy to meet the strict requirements of new-generation bone biomaterials: instead of directly regulating the osteogenic differentiation of osteoblastic lineage cells, we should focus more on manipulating the responses of immune cells and developing biomaterials to induce an immune environment that provides conditions that balance osteogenesis and osteoclastogenesis for optimal osseointegration. This article reviews the recent progress on osteoimmunology and immunomodulatory biomaterials for the generation of the“osteoimmunomodulation”concept. Additionally, the outcomes of“osteoimmunomodulation”-related studies have been summarized to guide the development of advanced“osteoimmune-smart”bone substitute materials.