Dexamethasone-loaded nanoparticles promote angiogenesis and pro-regenerative macrophages polarization in the presence of titanium debris: a rabbit critical defect model.

Abstract

OBJECTIVE: Surgical treatment of peri‑implantitis sometimes encompasses bone regeneration procedures performed in junction with implantoplasty. Hence, the aim of this study was to evaluate if titanium debris (Tid) produced by abrasion of dental implants may alter the cellular response, the osteogenic capacity and vascularization in a critical-size calvarial bone defect model in rabbit. It was also assessed if dexamethasone-doped polymeric nanoparticles, combined with calcium phosphate, may help to overcome these impairments. METHODS: Four critical bone defects were performed on six New Zealand-bred rabbit skulls. In each of the four bone defects, the following materials were placed: 1) unfilled (control), 2) calcium phosphate particles (CaP), 3) CaP and Tid, 4) CaP and Tid with dexamethasone-doped polymeric nanoparticles (Dex-NPs) loaded onto the CaP. After six weeks, animals were euthanized and both cellularity (osteoblasts, osteocytes, osteoclasts, fibroblasts, M1 and M2 macrophages) and vasculature were characterized and quantified using toluidine-blue (TB)-stained sections. RESULTS: Bone defects treated with CaP attained the highest numbers of osteocytes and osteoblasts, and the lowest numbers of osteoclasts, among groups. In the presence of Tid, the bone defects treated with CaP showed the highest numbers of M1, and Dex-NPs reduced the number of M1 cells. The CaP+Tid group attained the highest M1/M2 ratio, but significantly lower than that attained in the unfilled group. Both CaP and CaP+Tid+Dex-NPs produced the highest number of blood vessels among groups. CONCLUSIONS: Tid tended to increase the M1/M2 ratio, leading to a pro-inflammatory cellular profile. Dex-NPs with CaP prompted the M1/M2 ratio decrease in the presence of Tid. Hence, reducing Tid-induced inflammation and osteolysis and thus gaining both osteoconductivity and neovascularization within the bone defect. CLINICAL SIGNIFICANCE: The presence of Tid reduces osteogenesis and angiogenesis, and upregulated osteoclastogenesis. Incorporation of Dex-NPs in the graft material, at the bone defect, reverted the previous findings, favoring macrophages polarization into a regenerative profile, increasing the osteogenic potential and, consequently, refining the bone defect closure.