Quercetin-loaded nanocomposite microspheres for chronologically promoting bone repair via synergistic immunoregulation and osteogenesis

Biomaterial implantation for bone defect repair is a complex cascade reaction process, which mainly includes early inflammatory response and subsequent osteogenic repair. In this work, quercetin / nano-hydroxyapatite / poly (glycolide-co-epsilon-caprolactone) (Que/n-HA/PGCL) nanocomposite micro -spheres were successfully prepared by airflow shearing method, possessing interconnected porous struc-ture with unique "eyeball-like" surface morphology. The encapsulation efficiency of microspheres reaches as high as 80 % and Que release was stable and continuous, only released 7.5 % at 120 h in the 4 wt% group. Moreover, Que-loaded microspheres triggered positive immunomodulation via upregula-tion of M2 macrophage polarization evidenced by decreased expression of pro-inflammatory cytokines TNF-alpha, iNOS and the increased expression of anti-inflammatory cytokines Arg1, IL-10 in RAW264.7 cells, which was beneficial to BMSCs osteogenic differentiation in the co-culture system. Meanwhile, the capa-bility to directly promote osteo-differentiation was manifested by upregulation of Runx2, ALP, OPN, OCN gene expression and the increase of differentiation markers. Furthermore, the assessment of Que/n-HA/ PGCL microspheres in vivo confirmed desirable bone repair contributed to efficient immunomodulation and excellent osteo-differentiation. Thus, the Que/n-HA/PGCL microspheres could serve as potential func-tional filling materials for bone repair, which could be applied to efficient drug delivery platform in the future clinical applications. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).