Quercetin-Loaded Nanocomposite Microspheres for Chronologically Promoting Bone Repair Via Synergistic Immunoregulation and Osteogenesis

Abstract

Biomaterials 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 microspheres were prepared successfully by airflow shearing method. The as-prepared microspheres possessed interconnected porous structure with unique “eyeball-like” surface morphology. The encapsulation efficiency of microspheres was as high as 80% and Que release was stable and continuous, especially in the 4 wt% group that only released 7.5% at 120 h. Moreover, Que-loaded microspheres triggered positive immunomodulation via upregulation of M2 macrophage polarization evidenced by decreased expression of pro-inflammatory cytokines TNF-α, 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 ability to directly promote osteo-differentiation was manifested by upregulation of Runx2, ALP, OPN, OCN gene expression and the increase of differentiation markers. Furthermore, in vivo assessment of Que/n-HA/PGCL microspheres confirmed desirable bone repair contributed to efficient immunomodulation and excellent osteo-differentiation. Thus, the Que/n-HA/PGCL microspheres could serve as potential functional filling materials for bone repair, which could be applied to efficient drug delivery platform in the future clinical applications.

Note:

Funding Information: This work was financially supported by National Natural Science Foundation of China (52173146), Industrial Technology Research and Development Project of Jilin Development and Reform Commission (No.2021C042-2), Medical and Health Project of Jilin Department of Science and Technology (No.20210204111YY), Dengfeng Projects of Foshan Hospital of Traditional Chinese Medicine (No.202100046), Key Projects of Military Logistics Opening Research (N0. BLB20J011).

Declaration of Interests: The authors declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval Statement: Animal experiments were approved by the Institutional Animal Care and Use Committee of Jilin University (IACUC). Animal maintenance and all experimental procedures were done in accordance with the National Institutional Guidelines for Care and Use of Laboratory Animals.

Keywords: Drug delivery, macrophages polarization, BMSC differentiation, osteoimmunology, bone regeneration