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 Zn 2+ /Sr 2+ 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.

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Zinc substituted hydroxyapatite/silk fibroin composite coatings were deposited on titanium substrates at room temperature by electrophoretic deposition. Microscopic characterization of the synthesized composite nanoparticles revealed that the particle size ranged 50-200 nm, which increased a little after zinc substitution. The obtained coatings maintained the phase of hydroxyapatite and they could induce fast apatite formation in simulated body fluid, indicating high bone activity. The cell culturing results showed that the biomimetic hydroxyapatite coatings could regulate adhesion, spreading, and proliferation of osteoblastic cells. Furthermore, the biological behavior of the zinc substituted hydroxyapatite coatings was found to be better than the bare titanium without coatings and hydroxyapatite coatings without zinc, increasing MC3T1-E1 cell differentiation in alkaline phosphatase expression.

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Cancer recurrence and metastasis after surgical resection is a vital reason of treatment failure. The modification of immune cells through implanted biomaterials is a promising postoperative immunotherapy. Herein, an injectable hydrogel scaffold loaded with engineered exosome mimetics that in vivo recruits and programs endogenous macrophages into M1 binding with anti-CD47 antibody (M1-aCD47 macrophages) for postoperative cancer immunotherapy is developed. Briefly, M1 macrophages-derived exosome mimetics co-modified with vesicular stomatitis virus glycoprotein (VSV-G) and aCD47 (V-M1EM-aCD47) are encapsulated in injectable chitosan hydrogel. Such hydrogel recruits inherent macrophages in situ and releases V-M1EM-aCD47 that programs M2 to M1-aCD47 macrophages. M1-aCD47 macrophages own dual-functions of tumor-homing and enhanced phagocytosis. They can actively target to tumor cells for delivery of aCD47 that blocks the "don't eat me" signal, thereby promoting phagocytosis of macrophages to cancer cells. Furthermore, V-M1EM-aCD47 hydrogel implanted into resection site of 4T1 breast tumor inhibits tumor recurrence and metastasis by phagocytosis of M1-aCD47 macrophages and T cell-mediated immune responses. The findings demonstrate that biomaterials can be designed in vivo to program inherent macrophages, thereby activating the innate and adaptive immune systems for prevention of postoperative tumor recurrence and metastasis.

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