Local delivery of hydrogel encapsulated vascular endothelial growth factor for the prevention of medication-related osteonecrosis of the jaw

Dileep Sharma,Stephen Hamlet,Cedryck Vaquette,Saso Ivanovski,Poornima Ramamurthy,Eugen Bogdan Petcu

doi:10.1038/s41598-021-02637-w

Abstract

The anti-angiogenic effects of bisphosphonates have been hypothesized as one of the major etiologic factors in the development of medication-related osteonecrosis of the jaw (MRONJ), a severe debilitating condition with limited treatment options. This study evaluated the potential of a gelatine-hyaluronic acid hydrogel loaded with the angiogenic growth factor, vascular endothelial growth factor (VEGF), as a local delivery system to aid in maintaining vascularization in a bisphosphonate-treated (Zoledronic Acid) rodent maxillary extraction defect. Healing was assessed four weeks after implantation of the VEGF-hydrogel into extraction sockets. Gross examination and histological assessment showed that total osteonecrosis and inflammatory infiltrate was significantly reduced in the presence of VEGF. Also, total vascularity and specifically neovascularization, was significantly improved in animals that received VEGF hydrogel. Gene expression of vascular, inflammatory and bone specific markers within the defect area were also significantly altered in the presence of VEGF. Furthermore, plasma cytokine levels were assessed to determine the systemic effect of locally delivered VEGF and showed similar outcomes. In conclusion, the use of locally delivered VEGF within healing extraction sockets assists bone healing and prevents MRONJ via a pro-angiogenic and immunomodulatory mechanism.

Highlights

The anti-angiogenic effects of bisphosphonates have been hypothesized as one of the major etiologic factors in the development of medication-related osteonecrosis of the jaw (MRONJ), a severe debilitating condition with limited treatment options
There was a rapid release (18–28%) of total vascular endothelial growth factor (VEGF) that peaked at 12 h in both the 100 and 200 ng VEGF-loaded gels
By the end of 3 days, 25–30% of the VEGF had been released from the 100 ng gel and 38–42% from the 200 ng gel

Summary

Introduction

The anti-angiogenic effects of bisphosphonates have been hypothesized as one of the major etiologic factors in the development of medication-related osteonecrosis of the jaw (MRONJ), a severe debilitating condition with limited treatment options. BP therapy has proven to be one of the most efficient ways to treat benign and malignant diseases characterized by high bone turnover, such as metastatic bone diseases (breast cancer, prostate cancer and multiple myeloma primary sites), osteoporosis, Paget’s disease and pediatric osteogenesis imperfecta[4,5,6] Notwithstanding these therapeutic effects, BP use has been associated with significant adverse effects that occur selectively in jaw bones often but not always, following tooth extraction and surgical procedures. Genetic polymorphisms within VEGF genes have been associated with increased risk of MRONJ20 These findings provide a sound biological rationale for the clinical application of a local angiogenic agent such as vascular endothelial growth factor (VEGF), to counter the local anti-angiogenic effect of BPs, resulting in an enhanced quality and rate of tissue healing. Direct association between local angiogenesis and bone growth during the formative stages of bone development, callous formation during fracture repair and distraction osteogenesis have all been well d ocumented[23,24,25]

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