Abstract
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 (Ly6Chi), 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 (Ly6Clo), 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.