The effect of a single injection of uniform-sized insulin-loaded PLGA microspheres on peri-implant bone formation

Titanium implants are widely used treatment modalities, with a long list of clinical successes in orthopaedics, orthopedics and maxillofacial surgery. However, early implant loss occurs in 4.4% of patients, and to overcome this issue, bioactive factors have been generally used for improving peri-implant bone formation. Recently, the role of insulin in the improvement of bone development and physiology has attracted considerable attention. Nevertheless, one injection of insulin could not have a persistent effect in the site for bone formation because of its fast metabolism and instability, leading to limited efficacy. Moreover, the wider size distribution of microspheres frequently leads to uncontrollable insulin release, which affects preparation repeatability, drug efficacy and reliability. Herein, we developed uniform-sized insulin-loaded poly(dl-lactic-co-glycolic acid) (PLGA) microspheres for injection around the metal implant. The results demonstrated that the microspheres had narrow size distribution (Span < 0.7) and bioactive insulin was sustainedly released from the microspheres over 45 days. These insulin-loaded PLGA microspheres exhibit good bioactivity to facilitate the proliferation of human bone marrow mesenchymal stromal cells (BMSCs). Expressions of ALP, OCN and mineralized matrix formations in the insulin-loaded PLGA group were significantly higher than those in other groups. Furthermore, in rabbit mandible models, a single injection of insulin-loaded PLGA microspheres around the titanium implant showed higher peri-implant bone formation and better osseointegration, as observed by histological analysis, micro-CT and biomechanics.