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.

生物材料诱导的免疫微环境在骨再生中起着至关重要的作用。羟基磷灰石 (HA) 及其离子取代衍生物代表了一大类用于骨组织工程的核心无机材料。尽管离子置换被证明是赋予 HA 更多生物功能的有效方法，但很少有研究关注离子掺杂 HA 的免疫调节特性。在此，为了探索离子掺杂的 HA 的潜在骨免疫调节作用，成功实现了锌和锶通过胶原模板仿生方式（ZnSr-Col-HA）共组装成 HA。研究发现，ZnSr-Col-HA 可以通过刺激巨噬细胞来诱导有利的骨免疫微环境。此外，ZnSr-Col-HA 表现出对骨髓间充质干细胞 (BMSCs) 成骨分化的程序性促进作用体外。具体而言，骨免疫微环境在通过 OSM 信号通路促进早期成骨基因表达中起主导作用。而Zn ²⁺ /Sr ²⁺对BMSCs的直接刺激作用在后期随着Nfatc1/Maf和Wnt信号的激活更为有效。体内研究证实了 ZnSr-Col-HA 对临界尺寸颅骨缺损修复的强烈促进作用。目前的研究表明，这种双离子掺杂和仿生分子共组装相结合的生物材料设计理念赋予HA适用的骨免疫调节特性，可能为骨再生研究带来新的前沿概念。