The Strontium Ion Reprograms Monocyte Subsets via TRPM2 Channel Regulation to Enhance Osseointegration

Early immune homeostasis at the biomaterial-tissue interface is a critical engineering challenge for osseointegration success. While strontium (Sr)-modified biomaterials exhibit advantages in enhancing osseointegration, the immunomodulatory effects of localized Sr release, particularly on upstream monocytes, remain unelucidated. This study aims to delineate Sr-reprogrammed monocyte subset dynamics and the underlying mechanism. Here, we engineered Sr-doped sandblasted, large-grit, and acid-etched (Sr-SLA) titanium implants. Sr-SLA implants ameliorated the early inflammatory microenvironment and promoted osseointegration. To decipher the Sr-modulated immune microenvironment, we employed single-cell RNA sequencing, which revealed that monocytes constituted the largest proportion of cells surrounding implants, with subset distribution correlating with osteogenic efficiency. Notably, Sr-SLA implants suppressed the activation of pro-inflammatory classical monocytes (Ly6C^hi), with high transient receptor potential melastatin 2 (TRPM2) and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) expression, while promoting the expansion of regenerative nonclassical monocytes (Ly6C^lo), exhibiting low TRPM2 and NLRP3 levels. Further validation demonstrated that Sr ions inhibited NLRP3 inflammasome activation in monocytes via blocking TRPM2 expression and calcium influx, leading to reduced pro-inflammatory cytokine (interleukin-1β and interleukin-18) secretion. Meanwhile, a conditioned medium from Sr-SLA-cultured monocytes exerted robust osteogenic potential by markedly facilitating bone marrow mesenchymal stromal cells' osteogenic differentiation, due to a Sr-reshaped cytokine profile. Moreover, in vivo study corroborated that monocyte depletion impaired osseointegration, underscoring its indispensable role in implant-mediated bone regeneration. Collectively, Sr-SLA implants reprogrammed monocyte subsets via the TRPM2-Ca²⁺-NLRP3 axis, reshaping the early inflammatory microenvironment to enhance osseointegration. This study establishes a cascade linking material properties, early immune response, and bone regeneration, providing an engineerable target for designing immunomodulatory biomaterials.