Micro/nano-structured titanium surfaces promote endothelial responses and angiogenic activity under zoledronic acid exposure

Dental implants are widely used to restore oral function, maintain mastication, and improve long-term quality of life. However, patients receiving high-dose bisphosphonates (BPs), such as zoledronic acid (ZOL), are considered clinically high-risk due to the potential development of medication-related osteonecrosis of the jaw (MRONJ). Impaired angiogenesis caused by BPs is a key pathogenic factor of MRONJ and an essential role for early wound healing, infection control, and long-term osseointegration of dental implants. Therefore, understanding whether titanium micro/nano-scale topographies can promote angiogenic responses under ZOL exposure is essential for improving implant outcomes in this high-risk population. Two micro/nano-structured surfaces were fabricated on selective laser melting (SLM) titanium: (i) SAH: sand-blasted alkali-heated; (ii) SAO: sand-blasting and acid-etching (SLA) followed by anodic oxidation. Conventional SLA surface served as positive control. Under 5 µM ZOL exposure, endothelial morphology, viability, cytoskeletal organization, tube-forming ability, and angiogenic gene and protein expressions were evaluated on different titanium surfaces in vitro. A rat model receiving high-dose intravenous ZOL was used to assess peri-implant vascularization and early osseointegration among mini-implants with different surface topographies in vivo. Micro/nano-structured (SAH and SAO) surfaces comparably improved endothelial spreading, cytoskeletal integrity, viability, and tube formation compared with SLM and SLA surfaces in the presence of ZOL. Consistently, both SAH and SAO surfaces upregulated the expression of angiogenesis-related genus, including PECAM-1, ICAM-1, vWF, and Ang-1. At the protein level, Ang-1 expression was upregulated on these micro/nano-structured surfaces, while apparent differences in PECAM-1 levels were not observed. In vivo, micro/nano-structured implants showed a higher density of CD31-positive microvessels and a tendency toward improved bone-implant contact and early bone formation despite high-dose ZOL administration. Micro/nano-structured titanium surfaces can enhance endothelial function and promote peri-implant angiogenesis under ZOL exposure challenge. These findings suggest their potential to support better peri-implant vascularization and safer implant rehabilitation for patients receiving high-dose bisphosphonates.