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A barrier membrane is a major component of guided bone regeneration (GBR), which is traditionally viewed as a physical barrier. Due to its "foreign body" nature, the implantation of a barrier membrane would inevitably modulate immune response and subsequently affect bone dynamics, which has long been neglected. To bridge this knowledge gap, we investigated the osteoimmunomodulatory effects of barrier collagen membranes. It is found that barrier collagen membranes elicit significant effects on modulating the osteoimmune response of macrophages, by upregulating the expression of pro-inflammatory cytokines (TNFα, IL-1β, IL-6, and IL-18) and osteogenic factors (BMP2/6, WNT10b, OSM). The modulated-osteoimmune environment was beneficial for the osteogenic differentiation of BMSCs, due to the activation of BMP, canonical WNT/β-catenin, and OSM signalling pathways. The membrane-mediated osteoimmunomodulation was further modulated to show whether osteogenesis could be enhanced via manipulating the membrane-mediated osteoimmunomodulation. The membrane-mediated osteoimmune response was successfully tuned through coating the collagen membranes with nanometer-sized bioactive glass Ca2ZnSi2O7 by pulsed laser deposition, which is indicated from the change in the expression profile of inflammatory cytokines and the upregulated expression of osteogenic factors. The modulated osteoimmune environment enhanced the osteogenic differentiation of BMSCs, suggesting that collagen membranes with nanometer-sized Ca2ZnSi2O7 coating can be promising for GBR applications. These results collectively imply that barrier membranes are bioactive barriers with an osteoimmunomodulatory effect and not just physical barriers. New generation barrier membranes should be designed with a favourable osteoimmunomodulatory property.

The difficulties associated with metal implants and soft tissue integration have significantly affected the applications of metal implants in soft-tissue-related areas. Prompted by the close association between soft tissue integration and the immune response, an immunomodulation-based strategy is proposed to manipulate the immune microenvironment and improve metal implantsoft tissue integration. Considering their vital roles in soft tissue responses to metal implants, macrophages are used and the cytokines fingerprints of M1 and M2 macrophage immune microenvironments are evaluated for their potential modulatory effects on metal implant-soft tissue integration. The modulatory effects of different immune microenvironments on model soft tissue cells (human gingival epithelium cells) cultured on model metal implants (titanium alloy disks) are then described, with the underlying possible mechanism FAK-AKT-mTOR signaling unveiled. As further proof of concept, IL-4/PDA (polydopamine)-coated titanium alloy implants, aiming at modulating M2 macrophage polarization, are prepared and found to improve the in vivo metal implant-soft tissue integration. It is the authors' ambition that this immunomodulation-based strategy will change the negative perception and encourage the active development of metal materials with favorable soft tissue integration properties, thus improving the success rates of perforating metal implants and broadening their application in soft-tissue-related areas.

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In a previous study, we successfully prepared fluorinated porcine hydroxyapatite (FPHA) by immersing porcine hydroxyapatite (PHA) in an aqueous solution of 0.25 M sodium fluoride (NaF) under thermal treatment, and the resulting FPHA showed better physicochemical and biological properties than PHA. The purpose of this study was to further investigate how fluorine incorporation influenced the biocompatibility and osteogenic capacity of PHA. The concentrations of Ca, P, F, and Mg ions in PHA and FPHA extracts were detected by inductively coupled plasma optical emission spectrometry. Rat bone marrow stromal cells (rBMSCs) were treated with PHA and FPHA extracts, and the effects of these extracts on cell proliferation and osteoblastic differentiation were evaluated via Cell Counting Kit-8 assay, alkaline phosphatase assay, and real time-quantitative polymerase chain reaction. For the in vivo assessment, PHA and FPHA were implanted into subcutaneous pockets (n = 6) and rat calvarial defects (diameter = 5 mm, n = 14) for 12 weeks to determine their biocompatibility and osteogenic capacity by using micro-computed tomography (CT) and histological analysis. FPHA extracts, which release higher concentrations of F and Mg ions, better promoted the osteoblastic differentiation of rBMSCs in vitro. The result of biocompatibility evaluation confirmed that the host response and chronic inflammation cells infiltration degree around PHA and FPHA granules were similar. Micro-CT and histological analysis showed newer mineralized bone formation in rats with FPHA-treated defects than in rats with PHA-treated defects. The results of in vitro and in vivo tests consistently indicate that fluorine incorporation effectively enhanced the osteogenic capacity of PHA.

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Xenograft, namely bone-derived biological apatite (BAp), is widely recognized as a favorable biomaterial in bone tissue engineering owing to its biodegradability, biocompatibility, and osteoconductive properties. Substitutions of endogenous trace ions are thought to improve the osteogenic capacity of xenograft compared with synthetic hydroxyapatite (HAp). In order to modify the physicochemical and biological properties of apatite, different approaches to induce trace ion incorporation have been widely considered. In this study, we demonstrated that the incorporation of fluoride ions into porcine bone-derived biological apatite (pBAp) contributes to altered crystal morphology of the apatite, the sustained release of fluoride, and the in situ release of endogenous trace ions (e.g., magnesium and calcium) into the peripheral tissue microenvironment. This ionic balanced perimaterial microenvironment not only led to superior proliferation and osteogenic differentiation of rat bone mesenchymal stem cells (rBMSCs), but also accelerated new bone formation of the calvarial defect on a rat model via the activation of Wnt/β-catenin signaling. These promising observations may be attributed to the controlled release of endogenous trace ions from the xenograft to the peripheral tissue microenvironment driven by fluoride ion incorporation. Lastly, this study may provide a new insight to strengthen the osteogenicity of xenografts for clinical applications in the future.