Laser-modified titanium surfaces induce sex-dimorphic secretion of angiogenic factors by gingiva-derived mesenchymal stromal cells.

Background/purpose: Dental implants have been applied to restore missing dentition for more than fifty years. However, whether different surface modification on implant provide topographical cues that alter sex-specific effect on peri-implant angiogenesis remains unclear. This study aimed to investigate whether titanium surface modifications influence sex-specific chromatin accessibility, gene expression, and angiogenesis-related functions in human gingiva-derived mesenchymal stromal cells (GMSCs). Materials and methods: We collected health gingival tissues from sixteen subjects (eight females and eight males) and isolated primary GMSCs. The primary GMSCs were cultured on three types of titanium surfaces: machined, lasered, and SLA (sand-blasted, large-grit, acid-etched). Chromatin accessibility and gene expression were assessed via ATAC-seq and RNA-seq, respectively, with further validation through qRT-PCR, ELISA, and western blot. Functional angiogenic potential was evaluated using both direct and indirect tube formation assays. Results: Our findings revealed that titanium surface modifications induce sex-dimorphic effects on the secretion of angiogenic factors CCN1 and EDIL3. Laser-modified titanium significantly increased the secretion of extracellular vesicles enriched with both CCN1 and EDIL3 compared to machined surfaces. Interestingly, female GMSCs secreted higher levels of EDIL3, while male GMSCs secreted more CCN1 on lasered titanium surfaces. Moreover, lasered titanium demonstrated superior angiogenic potential in both direct and indirect tube formation assays compared with machined and SLA titanium. Conclusion: This study suggests that laser-modified microchannels on titanium surfaces provide bioactive topographical cues that enhance the secretion of extracellular vesicles enriched with angiogenic factors-particularly CCN1 and EDIL3-by GMSCs, which may play key roles in promoting angiogenesis and supporting early-stage osseointegration.