Macrophages play a pivotal role in the immunological cascade activated in response to biomedical implants, which predetermine acceptance or rejection of implants by the host via pro‐ and anti‐inflammatory polarisation states. The role of chemical signals in macrophage polarisation is well‐established, but how physical cues regulate macrophage function that may play a fundamental role in implant‐bone interface, remains poorly understood. Here we find that bone marrow‐derived macrophages (BMDM) cultured on polyacrylamide gels of varying stiffness exhibit different polarisation states. BMDM are ‘primed’ to a pro‐inflammatory M1 phenotype on stiff substrates, while to an anti‐inflammatory M2 phenotype on soft and medium stiffness substrates. It is further observed that matrix stiffening increases Piezo1 expression, as well as leads to subsequent activation of the mechanotransduction signalling effector YAP, thus favouring M1 polarisation whilst suppressing M2 polarisation. Moreover, upon treatment with YAP inhibitor, we successfully induce macrophage re‐polarisation to the M2 state within the implant site microenvironment, which in turn promotes implant osseointegration. Collectively, our present study thus characterises the critical role of the Piezo1‐YAP signalling axis in macrophage mechanosensing and stiffness‐mediated macrophage polarisation and provides cues for the design of immuno‐modulatory biomaterials that can regulate the macrophage phenotype.

As clusters of peptides or steroids capable of high-efficiency information transmission, hormones have been substantiated to coordinate metabolism, growth, development, and other physiological processes, especially in bone physiology and repair metabolism. In recent years, the application of hormones for implant osseointegration has become a research hotspot. Herein, we provide a comprehensive overview of the relevant reports on endogenous hormones and their corresponding supplementary preparations to explore the association between hormones and the prognosis of implants. We also discuss the effects and mechanisms of insulin, parathyroid hormone, melatonin, vitamin D, and growth hormone on osseointegration at the molecular and body levels to provide a foothold and guide future research on the systemic conditions that affect the implantation process and expand the relative contraindications of the implant, and the pre-and post-operative precautions. This review shows that systemic hormones can regulate the osseointegration of oral implants through endogenous or exogenous drug-delivery methods.