Characterization and in vivo biocompatibility analysis of synthetic hydroxyapatite compounds associated with magnetite nanoparticles for a drug delivery system in osteomyelitis treatment Dayana A.C. Ferreira-Ermita, Fabrício L. Valente, Emily C. Carlo-Reis, Fabiana R. Araújo, Iara M. Ribeiro, Cristiane C.V. Cintra, Andr ea P.B. Borges * Federal University of Viçosa, Viçosa, MG, Brazil ARTICLE INFO Keywords: Biomaterials Regeneration Bioceramics Biodegradation ABSTRACT This work aimed to characterize six compounds formulated with hydroxyapatite (HAP), magnetite nanoparticles (Fe 3 O 4 ) and ciprofloxacin, using scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS), in addition to describing their in vivo biocompatibility and biodegradation processes, aiming their subsequent use for treatment and bone regeneration in osteomyelitis cases. Six New Zealand white rabbits were used for the biocompatibility study, in which four samples of the same compound were surgically implanted in each rabbit, between the fascia and muscle tissue. After 15, 30, 60 and 90 days, biopsies of one sample from each animal were performed, comprising the implants and adjacent tissues. The analyzed compounds are biocompatible and biodegradable, with an absorption time of more than 90 days. In addition, according to the results obtained by SEM, they have a complex microtopographical surface and structural and morphological characteristics required to its use as bone implants. In three compounds, EDS analysis showed homogenous relative proportions of Ca:Fe throughout their surface, and at the other three the Ca:Fe ratios were not shown to be homogenous at different points of the same compound. Based on the obtained results, the subsequent use of these materials for the evaluation of bone regeneration in infection cases is indicated. 1. Introduction An adequate characterization and evaluation of safety of implantable biomaterials is essential as these compounds are designed to have direct contact with living tissues, once they must perform properly without causing undesirable reactions and remain for the required period for bone regeneration to occur [1]. Therefore, a compound is biocompatible when it does not exhibit toxicity, nor causing any sort of injure to the tissue or living system in which it remains in contact, neither causing immunological rejection. Furthermore, the compound must support a cell-biomaterial interaction with the tissue in which it was implanted [2, 3]. The biocompatibility of a compound is dependent on material related factors, such as shape, size, surface chemistry, roughness, porosity, composition, sterility, duration of contact and degradation; on the host related factors, as the species and the genetic inheritance and; on the implant site, such as tissue characteristics and microenvironment [1]. In this sense, the International Organization of Standardization 10,993 (ISO 10993) describes official standards for evaluation of biocompatibility of medical devices [4]. Because of its proven biocompatibility, bioceramics based on hy- droxyapatite (HAP) and their calcium phosphate compounds have been widely used in the medical areas for osseointegration, and its use has been improved during the last decades [5–8]. The HAP is the main inorganic component of the bone matrix and its synthetic form is chemically similar to the bone mineral phase, fulfilling important bio- logical prerequisites for their interaction with organic media [5,6]. The magnetite nanoparticles (Fe 3 O 4 ) are among the most widely used nanoparticles in biomedical engineering [9] for their capacity to trans- port drugs for delivery directly in the target tissue. However, concerns related to the safety of these compounds and the risks of their use as biomaterials have been highlighted. Mahmoudia et al. [10] e Watanabe et al. [11] demonstrate that tissue exposure to Fe 3 O 4 nanoparticles can cause oxidative stress and imbalance of homeostasis in the human body, leading to cellular toxicity effects. Bioactive coatings have been used in order to improve the biocompatibility of Fe 3 O 4 . In this context, * Corresponding author. E-mail address: andrea@ufv.br (A.P.B. Borges). Contents lists available at ScienceDirect Results in Materials journal homepage: www.journals.elsevier.com/results-in-materials https://doi.org/10.1016/j.rinma.2020.100063 Received in revised form 13 December 2019; Accepted 28 December 2019 Available online 28 January 2020 2590-048X/© 2020 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Results in Materials 5 (2020) 100063