Development of the HA Composite for the Prevention of BRONJ
Development of the HA composites for the prevention of BRONJ
Atsuko Miyazawa, Tomonori Matsuno, Kazunari Asano, Izumi Mataga
Department of Oral and Maxillofacial Surgery, The Nippon Dental University, School of Life Dentistry at Tokyo, JAPAN
Objectives:
Currently, there are over 10 million osteoporotic patients accompanied by the aging society in Japan. In addition, bisphosphonate (BP) formulations are regarded as first-line therapy for osteoporosis. However, Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) occurs with increasing frequency if the BP formulations are taken by the osteoporotic patients (1). Therefore, many researches about the treatment of BRONJ have been done, though the pathogenesis of BRONJ is not still revealed (2).
The objective of this study is to investigate the promotion of the bone formation and the angiogenesis by the grafting material dual releasing simvastatin and bFGF for the prevention of bisphosphonate related osteonecrosis of the jaw (BRONJ). In this study, the composites materials containing simvastatin (ST), bFGF, hydroxyapatite (HA) and gelatin hydrogel (GH) were prepared (ST+bFGF+HA/GH). In addition, we tied to investigate the effect of controlled release simvastatin and bFGF from the ST+bFGF+HA/GH to evaluate the osteoblastic differentiation and the angiogenesis.
Materials and Methods:
Firstly, simvastatin was incorporated into the micelles of gelatin grafted with L-lactic acid oligomers (LAo) for the water-solubilization. Secondly, the solution of simvastatin micelles (ST Mi) and the gelatin solution were mixed into the HA glanules, followed by the chemical crosslinking to form the composites of ST+HA/GH. After that, the composites of ST+HA/GH was overnight impregnated with the solution of bFGF to form the composites of ST+bFGF+HA/GH. After the preparation of the composites, the surfaces of the composites were evaluated by SEM images. In addition, the evaluation of release test and GH degradation test were performed. In vitro experiments, the effects of MC3T3E1 cell differentiation were evaluated with DNA assay, alkaline phosphatase (ALP) activity, and bone morphogenetic protein (BMP)-2 production to culture with the composites of ST+bFGF+HA/GH. As for the effect of the angeogenesis, the vascular endothelial cell growth factor (VEGF) production was evaluated by ELISA. All the data were analyzed statistically by Tukey honestly significant difference test for multiple comparisons, and statistical significance was accepted at p<0.05. The experimental results are expressed as the mean±the standard deviation.
Results:
The composites of ST+bFGF+HA/GH has an advantagerous surface for the cell attachment. In addition, the releases of ST and bFGF from the composite of ST+bFGF+HA/GH were governed by the degradation of the composites of ST+bFGF+HA/GH. The in vitro experiments indicated that the dual controlled release of ST and bFGF enhanced the differentiation and the promotion of angiogenesis compared with the free ST and bFGF.
Conclusion:
The composites of ST+bFGF+HA/GH is a promising material for the prevention of BRONJ by dual controlling release of ST and bFGF.
References:
(1) Bisphosphonate-related osteonecrosis of the jaws (Bronj).
Med Oral Dental Oral Cir Bucal. 2013 Sep 1;18(5):e752-8
(2) Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model.
Dentomaxillo fac Radiol. 2014;43(1):20130144. doi: 10.1259/dmfr.20130144.