Local Delivery of Hydrogel Encapsulated Vascular Endothelial Growth Factor for the Prevention of Medication-related Osteonecrosis of the Jaw

Overview

Journal Sci Rep

Specialty Science

Date 2021 Dec 4

PMID 34862395

Citations 6

Authors

Dileep Sharma

Stephen Hamlet

Cedryck Vaquette

Eugen Bogdan Petcu

Poornima Ramamurthy

Saso Ivanovski

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Ali-Erdem M, Burak-Cankaya A, Cemil-Isler S, Demircan S, Soluk M, Kasapoglu C . Extraction socket healing in rats treated with bisphosphonate: animal model for bisphosphonate related osteonecrosis of jaws in multiple myeloma patients. Med Oral Patol Oral Cir Bucal. 2011; 16(7):e879-83. DOI: 10.4317/medoral.17150. View

Allen M, Burr D . Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg. 2008; 66(5):987-94. PMC: 2464292. DOI: 10.1016/j.joms.2008.01.038. View

Marx R . Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003; 61(9):1115-7. DOI: 10.1016/s0278-2391(03)00720-1. View

Wehrhan F, Stockmann P, Nkenke E, Schlegel K, Guentsch A, Wehrhan T . Differential impairment of vascularization and angiogenesis in bisphosphonate-associated osteonecrosis of the jaw-related mucoperiosteal tissue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011; 112(2):216-21. DOI: 10.1016/j.tripleo.2011.02.028. View

Toole B . Hyaluronan in morphogenesis. J Intern Med. 1997; 242(1):35-40. DOI: 10.1046/j.1365-2796.1997.00171.x. View

Vincenzi B, Napolitano A, Zoccoli A, Iuliani M, Pantano F, Papapietro N . Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw. J Hematol Oncol. 2012; 5:56. PMC: 3472182. DOI: 10.1186/1756-8722-5-56. View

Ruggiero S, Dodson T, Fantasia J, Goodday R, Aghaloo T, Mehrotra B . American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 2014; 72(10):1938-56. DOI: 10.1016/j.joms.2014.04.031. View

Oh J, Kim S . Collagen sponge and rhBMP-2 improve socket healing in rats treated with zoledronic acid. Braz Oral Res. 2017; 31:e99. DOI: 10.1590/1807-3107bor-2017.vol31.0099. View

Subramanian G, Cohen H, Quek S . A model for the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw and teriparatide's potential role in its resolution. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011; 112(6):744-53. DOI: 10.1016/j.tripleo.2011.04.020. View

10.

Liu L, Thompson A, Heidaran M, Poser J, Spiro R . An osteoconductive collagen/hyaluronate matrix for bone regeneration. Biomaterials. 1999; 20(12):1097-108. DOI: 10.1016/s0142-9612(99)00006-x. View

11.

Valluru M, Brown N, Cross S, Reed M, Staton C . Blood vessel characterization in human dermal wound repair and scarring. Br J Dermatol. 2011; 165(1):221-4. DOI: 10.1111/j.1365-2133.2011.10327.x. View

12.

Street J, Lenehan B . Vascular endothelial growth factor regulates osteoblast survival - evidence for an autocrine feedback mechanism. J Orthop Surg Res. 2009; 4:19. PMC: 2701940. DOI: 10.1186/1749-799X-4-19. View

13.

Torsney E, Charlton R, Parums D, Collis M, Arthur H . Inducible expression of human endoglin during inflammation and wound healing in vivo. Inflamm Res. 2002; 51(9):464-70. DOI: 10.1007/pl00012413. View

14.

Ferretti G, Fabi A, Carlini P, Papaldo P, Fei P, Di Cosimo S . Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients. Oncology. 2005; 69(1):35-43. DOI: 10.1159/000087286. View

15.

Street J, Bao M, deGuzman L, Bunting S, Peale Jr F, Ferrara N . Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002; 99(15):9656-61. PMC: 124965. DOI: 10.1073/pnas.152324099. View

16.

Parasuraman S, Raveendran R, Kesavan R . Blood sample collection in small laboratory animals. J Pharmacol Pharmacother. 2011; 1(2):87-93. PMC: 3043327. DOI: 10.4103/0976-500X.72350. View

17.

Duff S, Li C, Garland J, Kumar S . CD105 is important for angiogenesis: evidence and potential applications. FASEB J. 2003; 17(9):984-92. DOI: 10.1096/fj.02-0634rev. View

18.

Perrin R, Konopatskaya O, Qiu Y, Harper S, Bates D, Churchill A . Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia. 2005; 48(11):2422-7. DOI: 10.1007/s00125-005-1951-8. View

19.

Schwartz Z, Goldstein M, Raviv E, Hirsch A, Ranly D, Boyan B . Clinical evaluation of demineralized bone allograft in a hyaluronic acid carrier for sinus lift augmentation in humans: a computed tomography and histomorphometric study. Clin Oral Implants Res. 2007; 18(2):204-11. DOI: 10.1111/j.1600-0501.2006.01303.x. View

20.

Biguetti C, Oliva A, Healy K, Mahmoud R, Custodio I, Constantino D . Medication-related osteonecrosis of the jaws after tooth extraction in senescent female mice treated with zoledronic acid: Microtomographic, histological and immunohistochemical characterization. PLoS One. 2019; 14(6):e0214173. PMC: 6568384. DOI: 10.1371/journal.pone.0214173. View