Effect of Local Delivery of VEGF-loaded Hydrogel on Bone Healing in Rat Medication Induced Osteonecrosis Model - A Pilot Study

Abstract

Objectives: Zoledronic acid (ZA), a potent bisphosphonate is used in bone depleting conditions like metastatic bone cancer, Paget's disease and osteoporosis. However, ZA is known to cause a debilitating side-effect in jaw bones termed medication-related osteonecrosis of jaws (MRONJ), especially after surgical manipulations. A significant pathogenic mechanism involved is aberrant angiogenesis, with reduction of VEGF levels both locally and in systemic circulation. This study aims to evaluate the effect of locally delivered VEGF-loaded Hydrogel in a rat MRONJ model.

Methodology: Sprague Dawley rats were exposed to weekly, intraperitoneal ZA administration over three weeks, and the maxillary molars were extracted to induce MRONJ. Immediately following extraction, hydrogel containing VEGF was placed in the tooth socket. ZA was continued until the rats were sacrificed. Gross healing was assessed over 4 weeks followed by sacrifice and harvesting of the maxillae. MicroCT was carried out to evaluate socket bone healing and histological evaluation was performed on decalcified paraffin sections.

Results: On gross evaluation, control maxillae showed significantly altered bone wound healing with signs of bone necrosis. In contrast, complete wound closure was evident in maxillae which received VEGF hydrogel. MicroCT confirmed significant bone destruction in the control group and normal bone healing in the VEGF hydrogel group. Also, initial histological evaluation showed signs of osteonecrosis including sequestration and diminished vascularity in the no gel controls compared to the gel group.

Significance: Locally delivered VEGF-containing hydrogel could be a valuable approach in preventing medication-induced osteonecrosis in patients who require dental manipulation while on anti-resorptive medications.