The acidic tumor microenvironment (TME) promotes immune escape by suppressing T-cell function, creating a major barrier to immunotherapy. Here, acidic pH-mediated impairment of T cell responses via the proton-sensing receptor GPCR68 is identified, whereas mild extracellular alkalinization counteracts this pathway to restore T cell effector function. GPCR68 acts as a negative regulator of T cell–driven anti-tumor immunity, as evidenced by the enhanced cytokine production (IFN-γ, TNF-α) and suppressed tumor growth in T cell–specific GPCR68 knockout mice (GPCR68fl/flCD4Cre). Thus, a borate-optimized local tumor therapy (BOLT) strategy is engineered to target GPCR68, based on alkali-metal-ion-modulated borate bioactive glass, which is integrated, spatiotemporally multiple responsive, and locally injectable. BOLT combats tumors dually by potentiating T cell immunity and inducing tumor ferroptosis. It alleviates acid suppression of T cells via GPCR68 inhibition and PI3K/AKT/mTOR signal activation, while promoting ferroptosis through the upregulation of Duox1/ROS and suppresseion of NRF2/SLC7A11/GPX4 axis. Therapeutically, BOLT synergizes with anti-CTLA4 blockade to overcome immunotherapy suppression and markedly enhances tumor immunity. These findings establish GPCR68 as a critical pH-sensing regulator of T-cell function and a therapeutic target for pH-based immunomodulation, and propose BOLT as a translational strategy for “alkaline intervention therapy” to potentiate immunotherapy.

Bone tissue engineering materials are crucial for bone repair, but existing repair materials still face many challenges, including poor biocompatibility and bioactivity, slow self-repair processes, limited adaptability, inability to promote angiogenesis and so on. To address these issues, the development of third-generation bone repair materials, which are being designed to stimulate specific cellular responses at the molecular level, such as borate and borosilicate bioactive glasses (BBGs/BSBGs) that activate cells and genes, offers new potential for promoting bone tissue self-renewing. Their unique characteristic lies in a flow of life-giving energy, releasing beneficial ions such as boron, calcium and silicon to stimulate cell proliferation and differentiation, accelerating the regeneration of bones. Through this dynamic repair mechanism, these VitaFlux glasses operate like a "living system" within the body, not only speeding up the healing of damaged tissues but also interacting seamlessly with surrounding tissues during the repair process. In this review, we provide a comprehensive analysis of the current understanding of the osteogenesis mechanisms of BBGs/BSBGs, emphasizing their interactions with cells, including ion release and exchange, protein adsorption, and cell adhesion. We also examine key osteogenic signaling pathways related to the alkaline and ionic microenvironments of BBGs/BSBGs, such as the cell cycle, Wnt, MAPK, and BMP signaling pathways, along with macrophage polarization and angiogenesis. Additionally, strategies and future prospects for advancing BBGs/BSBGs research are discussed. Special attention is given to the NaBC1 and GPCR-mediated signaling pathways, which require further investigation.

Osteosarcoma (OS), with a high tendency for recurrence and metastasis, is associated with severe impairment of bone regeneration. The inherent temperature-sensitive property of tumors positions magnetic hyperthermia (MH) as an increasingly significant area in non-pharmacological cancer treatments. However, the temperature threshold for tumor ablation often causes tissue damage and bone homeostasis imbalance. Therefore, development of moderate MH for OS, capable of achieving tumor ablation while concurrently restoring bone homeostasis, offers significant potential for addressing this challenge. This study integrates magnetothermal nanoparticles with defined temperature thresholds and borosilicate bioactive glass (BSG) to create an injectable magnetothermal bioactive system that allows for regulation of MH temperature. The ionic and alkaline microenvironment from BSG degradation primarily impairs the malignant behavior of OS cells by activating the TNF signaling pathway. This sickening effect diminishes the hyperthermia tolerance of OS cells, thereby boosting apoptosis of OS cells, even in the presence of the limited anti-tumor effects of moderate MH. Furthermore, the combination of moderate MH and BSG also promotes optimal bone formation by stimulating human bone marrow mesenchymal stem cells (hBMSCs) via calcium and JAK-STAT3 signaling pathways. Collectively, this flourishes the therapeutic approaches and theories for the prevention and management of clinically refractory bone tumors.

The commonly used metal bone implants fail to specifically modulate pathological microenvironments to exert therapeutic or reparative efficacy in tricky diseases such as osteosarcoma. Herein, a novel "Interfacial confined oxidation" (ICO) strategy has been proposed to construct black bioceramic coating on various metal implants for ondemand remodeling of osteosarcoma pathological microenvironment. The ICO strategy leverages the confined oxidation of liquified bioactive glass with low transition temperature to in situ construct black bioceramic coating composed of metal suboxides and bioactive oxides without high-vacuum reducing atmosphere conditions. The as-prepared black bioceramic coating could generate an alkaline microenvironment containing bioactive ions to promote bone formation. In addition, the alkalinity of the microenvironment generated by this coating can be enhanced by near-infrared light stimulation, which exhibits potent tumor inhibition through apoptosis induction and immune activation, and antibacterial activity via interfering with ATP synthesis and triggering oxidative stress. This study provides a simple and universal strategy for the construction of black bioceramic coating for therapy and regeneration, which has a prominent clinical application prospect on the modification of metal implants.

Activation of coagulation cascades, especially FX and prothrombin, prevents blood loss and reduces mortality from hemorrhagic shock. Inorganic salts are efficient but cannot stop bleeding completely in hemorrhagic events, and rebleeding carries a significant mortality risk. The coagulation mechanism of biominerals has been oversimplified in the past two decades, limiting the creation of novel hemostats. Herein, at the interface, the affinity of proteins, the protease activity, fibrinolysis, hydration shell, and dynamic microenvironment are monitored at the protein level. Proteomic analysis reveals that fibrinogen and antithrombin III's affinity for kaolin's interface causes a weak thrombus and rebleeding during hemostasis. Inspiringly, amorphous bioactive glass (BG) with a transient-dynamic ion microenvironment breaches the hydration layer barrier and selectively and slightly captures procoagulant components of kiniogen-1, plasma kallikrein, FXII, and FXI proteins on its interface, concurrently generating a continuous biocatalytic interface to rapidly activate both intrinsic and extrinsic coagulation pathways. Thus, prothrombin complexes are successfully hydrolyzed to thrombin without platelet membrane involvement, speeding production of high-strength clots. This study investigates how the interface of inorganic salts assists in coagulation cascades from a more comprehensive micro-perspective that may help elucidate the clinical application issues of kaolin-gauze and pave the way to new materials for managing hemorrhage.

针对硼硅酸盐生物活性玻璃(BBG)临床应用的瓶颈问题,对比不同硼硅比(样品 0B、样品 1.5B、样品 3B)生物活性玻璃与30%(质量分数)柠檬酸混合形成的骨水泥浸提液在体外对人骨髓间充质干细胞(hBMSCs)增殖活性与成骨分化的影响,及该骨水泥体内移植后对大鼠股骨缺损的修复效果.结果表明:骨水泥的降解速率随生物玻璃中B元素含量的增加而增快,同时其浸提液在体外对hBMSCs增殖活性与成骨分化的抑制效果更明显;然而,含最高浓度B的骨水泥(样品 3B)在体内诱导更多新骨生成,展示出更好的骨修复性能.基于 BBG 在体内外生物学效应的显著性差异,本工作为硼基生物活性材料特性的优化设计及其体外有效性评价体系的构建提出了思考和建议.

PMMA bone cement has been clinically used for decades in vertebroplasty due to its high mechanical strength and satisfactory injectability. However, the interface between bone and PMMA is fragile and more prone to refracture in situ because PMMA lacks a proper biological response from the host bone with minimal bone integration and dense fibrous tissue formation. Here, we modified PMMA by incoporating borosilicate glass (BSG) with a dual glass network of [BO3] and [SiO4], which spontaneously modulates immunity and osteogenesis. In particular, the BSG modified PMMA bone cement (abbreviated as BSG/PMMA cement) provided an alkaline microenvironment that spontaneously balanced the activities between osteoclasts and osteoblasts. Furthermore, the trace elements released from the BSGs enhanced the osteogenesis to strengthen the interface between the host bone and the implant. This study shows the first clinical case after implantation of BSG/PMMA for three months using the dual-energy CT, which found apatite nucleation around PMMA instead of fibrous tissues, indicating the biological interface was formed. Therefore, BSG/PMMA is promising as a biomaterial in vertebroplasty, overcoming the drawback of PMMA by improving the biological response from the host bone.

Injectable bone biomaterials like bone cement should be designed and fabricated with certain biological criteria, which include: 1) recruitment and polarization of the macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype, 2) enhance vascularization, and 3) activate osteogenic differentiation of bone marrow-derived stem cells to promote bone healing. So far, no injectable biomaterials could spontaneously regulate the entire bone healing process that involves inflammation, angiogenesis, and osteogenesis. Therefore, in this study, we designed bone cement comprised of strontium and copper-incorporated borosilicate glass (Sr/Cu-BSG) in the liquid phase of chitosan to modulate bone healing. In vitro studies showed that the controlled release of Sr and Cu ions up-regulated anti-inflammatory genes(IL-1Ra and TGF-β1) while down-regulating pro-inflammatory genes(IL-1β and IL-6) in macrophages at 3 days. Sr and Cu ions also increased the expressions of angiogenic genes (VEGF and bFGF) in HUVECs at 5 days and osteogenic genes (Runx-2, OCN, and OPN) in hBMSCs at 7, 14, and 21 days. 5Sr3Cu-BSG bone cement exhibited the best anti-inflammatory, angiogenic, and osteogenic properties among the bone cement groups with different Sr and Cu ratios. Short-term and long-term implantation of Sr/Cu-BSGs in femoral condylar bone defects of rats and rabbits confirmed the in vitro results, where the degradation rate of Sr/Cu-BSG matched the bone healing rate. Similar to in vitro, the 5Sr3Cu-BSG group also showed the highest bone formation in vivo. Excellent physical and chemical properties, along with its bone repairing ability, make the Sr/Cu-BSG bone cement a good candidate biomaterial for treating bone defects.

Calcium phosphate cements (CPC) are widely anticipated to be an optimum bone repair substitute due to its satisfied biocompatibility and degradability, suitable to be used in minimally invasive treatment of bone defects. However the clinical application of CPC is still not satisfied by its poor cohesiveness and mechanical properties, in particular its osteoinductivity. Hyaluronic acid reinforced calcium phosphate cements (HA/CPC) showed extroadinary potential not only enhancing the compressive strength of the cements but also significantly increasing its osteoinductivity. In our study, the compressive strength of HA/CPC increased significantly when the cement was added 1% hyaluronic acid (denoted as 1-HA/CPC). In the meantime, hyaluronic acid obviously promoted ALP activity, osteogenic related protein and mRNA expression of hBMSCs (human bone marrow mesenchymal stem cells) in vitro, cement group of HA/CPC with 4% hyaluronic acid adding (denoted as 4-HA/CPC) showed optimal enhancement in hBMSCs differentiation. After being implanted in rat tibial defects, 4-HA/CPC group exhibited better bone repair ability and bone growth promoting factors, comparing to pure CPC and 1-HA/CPC groups. The underlying biological mechanism of this stimulation for HA/CPC may be on account of higher osteogenic promoting factors secretion and osteogenic genes expression with hyaluronic acid incorporation. These results indicate that hyaluronic acid is a highly anticipated additive to improve physicochemical properties and osteoinductivity performance of CPCs for minimally invasive healing of bone defects.