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In vitro and in vivo evaluations of nanocrystalline Zn-doped carbonated hydroxyapatite/alginate microspheres: zinc and calcium bioavailability and bone regeneration

Authors Martinez-Zelaya VR, Zarranz L, Herrera EZ, Alves AT, Uzeda MJ, Mavropoulos E, Rossi AL, Mello A, Granjeiro JM, Calasans-Maia MD, Rossi AM

Received 13 December 2018

Accepted for publication 1 March 2019

Published 10 May 2019 Volume 2019:14 Pages 3471—3490

DOI https://doi.org/10.2147/IJN.S197157

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Govarthanan Muthusamy

Peer reviewer comments 3

Editor who approved publication: Dr Thomas J Webster


Victor R Martinez-Zelaya,1 Laila Zarranz,2 Edher Z Herrera,1 Adriana T Alves,2 Marcelo José Uzeda,2 Elena Mavropoulos,1 André L Rossi,1 Alexandre Mello,1 José M Granjeiro,2,3 Monica D Calasans-Maia,2 Alexandre M Rossi1

1Department of Condensed Matter, Applied Physics and Nanoscience, Brazilian Center for Research in Physics, Rio de Janeiro, RJ, Brazil; 2Dental Clinical Research Center, Oral Diagnosis Department and Oral Surgery Department, Dentistry School, Fluminense Federal University, Niteroi, RJ, Brazil; 3National Institute of Metrology, Quality and Technology, Duque de Caxias, RJ, Brazil

Background: Zinc-doped hydroxyapatite has been proposed as a graft biomaterial for bone regeneration. However, the effect of zinc on osteoconductivity is still controversial, since the release and resorption of calcium, phosphorus, and zinc in graft-implanted defects have rarely been studied.
Methods: Microspheres containing alginate and either non-doped carbonated hydroxyapatite (cHA) or nanocrystalline 3.2 wt% zinc-doped cHA (Zn-cHA) were implanted in critical-sized calvarial defects in Wistar rats for 1, 3, and 6 months. Histological and histomorphometric analyses were performed to evaluate the volume density of newly formed bone, residual biomaterial, and connective tissue formation. Biomaterial degradation was characterized by transmission electron microscopy (TEM) and synchrotron radiation-based X-ray microfluorescence (SR-μXRF), which enabled the elemental mapping of calcium, phosphorus, and zinc on the microsphere-implanted defects at 6 months post-implantation.
Results: The bone repair was limited to regions close to the preexistent bone, whereas connective tissue occupied the major part of the defect. Moreover, no significant difference in the amount of new bone formed was found between the two microsphere groups. TEM analysis revealed the degradation of the outer microsphere surface with detachment of the nanoparticle aggregates. According to SR-μXRF, both types of microspheres released high amounts of calcium, phosphorus, and zinc, distributed throughout the defective region. The cHA microsphere surface strongly adsorbed the zinc from organic constituents of the biological fluid, and phosphorus was resorbed more quickly than calcium. In the Zn-cHA group, zinc and calcium had similar release profiles, indicating a stoichiometric dissolution of these elements and non-preferential zinc resorption.
Conclusions: The nanometric size of cHA and Zn-cHA was a decisive factor in accelerating the in vivo availability of calcium and zinc. The high calcium and zinc accumulation in the defect, which was not cleared by the biological medium, played a critical role in inhibiting osteoconduction and thus impairing bone repair.

Keywords: zinc-doped carbonated hydroxyapatite, nanocomposite, synchrotron radiation-based X-ray microfluorescence, zinc/calcium bioavailability, bone regeneration


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