Zn/Sr dual ions-collagen co-assembly hydroxyapatite enhances bone regeneration through procedural osteo-immunomodulation and osteogenesis

Zhenyu Zhong; Xiaodan Wu; Yifan Wang; Mengdie Li; Yan Li; XuLong Liu; Xin Zhang; Ziyang Lan; Jianglin Wang; Yingying Du; Shengmin Zhang

doi:10.1016/j.bioactmat.2021.09.013

Zn/Sr dual ions-collagen co-assembly hydroxyapatite enhances bone regeneration through procedural osteo-immunomodulation and osteogenesis

Bioact Mater. 2021 Sep 16:10:195-206. doi: 10.1016/j.bioactmat.2021.09.013. eCollection 2022 Apr.

Authors

Zhenyu Zhong^{1

2}, Xiaodan Wu^{1

2}, Yifan Wang^{1

2}, Mengdie Li^{1

2}, Yan Li^{1

2}, XuLong Liu^{1

2}, Xin Zhang^{1

2}, Ziyang Lan³, Jianglin Wang^{1

2

4}, Yingying Du^{1

2

4}, Shengmin Zhang^{1

2

4}

Affiliations

¹ Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan, 430074, China.
² Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China.
³ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA.
⁴ Institute of Regulatory Science for Medical Devices, Huazhong University of Science and Technology, Wuhan, 430074, China.

Abstract

The immune microenvironment induced by biomaterials played vital roles in bone regeneration. Hydroxyapatite (HA) and its ion-substituted derivates represent a large class of core inorganic materials for bone tissue engineering. Although ion substitution was proved to be a potent way to grant HA more biological functions, few studies focused on the immunomodulatory properties of ion-doped HA. Herein, to explore the potential osteoimmunomodulatory effects of ion-doped HA, zinc and strontium co-assembled into HA through a collagen template biomimetic way (ZnSr-Col-HA) was successfully achieved. It was found that ZnSr-Col-HA could induce a favorable osteo-immune microenvironment by stimulating macrophages. Furthermore, ZnSr-Col-HA demonstrated a procedural promoting effect on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. Specifically, the osteo-immune microenvironment acted as a dominant factor in promoting osteogenic gene expressions at the early stage through OSM signal pathway. Whereas the direct stimulating effects on BMSCs by Zn²⁺/Sr²⁺ were more effectively at the later stage with Nfatc1/Maf and Wnt signals activated. In vivo study confirmed strong promoting effects of ZnSr-Col-HA on critical-sized cranial defect repair. The current study indicated that such a combined biomaterial design philosophy of dual ion-doping and biomimetic molecular co-assembly to endow HA applicable osteoimmunomodulatory characteristics might bring up a new cutting-edge concept for bone regeneration study.

Keywords: Biomimetic co-assembly; Hydroxyapatite; Osteoimmunomodulation; Strontium; Zinc.