Safety and efficacy of hydroxyapatite scaffold in the prevention of jaw osteonecrosis in vivo Adriana Duarte de Almeida, 1 Fernanda Gomes Leite, 1 Marco Vin  ıcius Chaud, 2 M arcia de Ara  ujo Rebelo, 2 Liliane Cristine Ferreira de Souza Borges, 2 Fabia Judice Marques Viroel, 1 Alessandre Hataka, 3 Denise Grotto 1 1 Laboratory of Toxicological Research, University of Sorocaba (Uniso), Sorocaba, S~ ao Paulo, Brazil 2 Laboratory of Biomaterials and Nanotechnology, University of Sorocaba (Uniso), Sorocaba, S~ ao Paulo, Brazil 3 Department of Veterinary Clinical Sciences, School of Veterinary Medicine and Animal Science, S~ ao Paulo State University (UNESP), Botucatu, S~ ao Paulo, Brazil Received 25 April 2017; revised 9 August 2017; accepted 28 August 2017 Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.b.33995 Abstract: Two scaffolds of chitosan/sodium alginate/hydroxy- apatite (Ch/NaAlg/Hap) 1:1:0.2 and 1:1:0.6 were evaluated in the prevention of bisphosphonate-induced jaw osteonecrosis. Two groups of rats (n 5 24, according to the euthanasia time: 15 or 30 days after the last Zoledronic acid (ZA) administra- tion) were subdivided in four subgroups (n 5 6): I – Control (saline 1 teeth extraction); II – ZA 0.6 mg/kg 1 teeth extraction; III – ZA 1 teeth extraction 1 scaffold 1:1:0.2; IV – ZA 1 teeth extraction 1 scaffold 1:1:0.6. Jaws were evaluated histologi- cally and blood was evaluated for hematological and bio- chemical parameters. Histopathology showed significant osteonecrosis in AZ group. The scaffold’s implantation, despite the inflammatory process, were able to prevent the osteonecrosis. In the 15-day euthanasia group, an increase in red blood cells and platelets was observed in the subgroup II. Hemoglobin and hematocrit decreased in subgroup IV compared to II. Hepatic transaminases and creatinine concen- tration increased significantly in subgroup II. Calcium concen- tration increased in subgroup IV compared to II. In the 30-day euthanasia group, no differences among the groups were observed for any parameter. Scaffolds proved to be efficient and safe to liver and kidney function. Some hematological parameters were altered by the scaffold, but returned to nor- mal concentrations over time. V C 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000–000, 2017. Key Words: zoledronic acid, osteonecrosis, scaffold, hydroxy- apatite, bone regeneration How to cite this article: de Almeida, AD, Leite, FG, Chaud, MV, Rebelo, MA, Borges, LCFS, Viroel, FJM, Hataka, A, Grotto, D 2017. Safety and efficacy of hydroxyapatite scaffold in the prevention of jaw osteonecrosis in vivo. J Biomed Mater Res Part B 2015:00B:000–#000. INTRODUCTION The bone is a rigid tissue and its functions are support, pro- tection and locomotion. 1 This tissue is in constant remodel- ing through the reabsorption and formation of new bone tissue. The bone formation begins with osteoclasts, respon- sible for bone resorption, and osteoblasts, responsible for bone formation. During resorption, the bone structure is dissolved and digested by the acids and proteolytic enzymes produced by the osteosclasts, to remove the aged bone. 2,3 Bisphosphonates (BPs) are drugs prescribed in the treat- ment of bone diseases such as cancer-induced hypercalcaemia, bone pain, reduction of skeletal complications in patients with bone metastases or multiple myeloma, Paget’s disease, osteopo- rosis, among others. 4,5 BPs bind strongly to the hydroxyapatite of the bone surface and act preferentially in sites of great bone formation and remodeling. BPs can inhibit the precipitation of calcium phosphates, cause regression of the transformation from of the amorphous hydroxyapatite to the crystalline hydroxyapatite, and inhibition of hydroxyapatite dissolution. 6 BFs can be divided into two subgroups: with or without nitrogen in its chemical structure. Nitrogen compounds, such as zoledronic acid (ZA), are the most recent and potent BPs. They induce osteoblasts to produce an osteosclast inhibitory agent, decreasing bone resorption. 7–9 Oral complications resulting from BPs treatment have been a major challenge for dentists and researchers, among them the bisphosphonate-related osteonecrosis of the jaw (BRONJ). 10–12 The jaw has a high turnover and a strong ten- dency to accumulate phosphorus, is less vascularization, and presents the terminal part of the mandibular artery, which jus- tifies the preferential lesion at this area. 13 Thus, BRONJ is the incapacity of the bone tissue to repair and remodel in inflam- matory conditions due to physiological stress (chewing), iatro- genic trauma (improperly adapted prosthesis, e.g.), surgical procedures or odontogenic infections. 10,14 After BRONJ is diagnosed, there is a limitation in the best therapeutic approach. In asymptomatic cases, antimi- crobial and strict clinical and radiographic control are Correspondence to: D. Grotto; e-mail: denise.grotto@prof.uniso.br V C 2017 WILEY PERIODICALS, INC. 1