Bone tissue regeneration is a complex physiological process dependent on the spatiotemporal coordination of immune cells and stem cells. Conventional research primarily elucidates the mechanism through which materials facilitate bone formation by initially modulating macrophages and subsequently encouraging the osteogenic differentiation of stem cells, while largely overlooking the proactive regulatory influence of stem cells on immune cells. Consequently, investigating the capacity of materials to concurrently attract stem cells and modulate innate immune infiltration, while establishing a tissue microenvironment response mechanism, holds substantial importance for the development of next-generation tissue regeneration materials. This study introduces a sea urchin-inspired immune instructional ionic flux (SUIF) platform, characterized by a radial mesoporous structure that employs B─O bond dissociation/dissolution rates and Sr2 + slow-release mechanisms to create a "fast-slow biphasic" ionic flow release, thereby establishing a dynamic alkaline ionic flow microenvironment. Within this microenvironment, 5B5Sr-SUIF recruits MSCs and stimulates MSCs to enhance the expression of miR-466m-5p, thereby obstructing the nuclear translocation of NF-κB in macrophages. This facilitates immunological regulatory communication between mesenchymal stem cells and macrophages, offering novel material design principles and molecular mechanism support for the exact regeneration of complicated bone deformities.

Pathological microenvironments linked to aging, trauma, malignancies, and metabolic disorders significantly hinder bone fractures and frequently result in fracture nonunion, posing substantial worldwide clinical difficulties. Widely prevalent therapies encounter difficulties in addressing diverse anatomical defects and variable illness conditions due to their inflexible designs and limitations in empirical optimization. Efficient strategies are critical to restore mechanics, improve pathological microenvironments, enhance neovascularization, and adapt to anatomical defects and clinical conditions. Deep learning networks (DLN) excel at analyzing extensive nonlinear relationships, enabling predictions of biomaterial‑biological interactions, hence accelerating biomaterial development. This study presents a synergistic DLN and 4D printing approach to fabricate a microenvironment-adaptive bioactive scaffold (MABS) for enhanced osteogenesis and angiogenesis. The scaffold integrates bioactive glass and a shape-memory PgP matrix, with a multilayer perceptron (MLP) neural network optimizing its design via nonlinear parameter-performance analysis. In vivo investigations revealed that the DLN-optimized scaffold enhanced shape-morphing adaptability and promoted the formation of dense bone tissue and vascular networks. This paradigm shift-employing DLN to integrate 4D printing dynamics, degradation kinetics, and multi-scale biological responses-transforms bone implants from static entities to dynamically adaptive systems, offering a scalable, intelligent framework for precise bone repair that rectifies the deficiencies of current strategies.

Chronic wound healing is often compromised by bacterial infection, and wound pH changes strongly correlate with infection. Therefore, the development of wound dressings capable of real-time pH monitoring, antimicrobial activity, and tissue repair is crucial for the effective management of infected chronic wounds. This study reports a novel multifunctional composite hydrogel (GM-C-mBG@P) synthesized by incorporating microwave-synthesized carbon quantum dots (CQDs) and polydopamine-modified mesoporous bioactive glass nanoparticles (mBG@P) into modified gelatin methacryloyl (GelMA). The incorporated polydopamine (PDA) confers excellent photothermal properties to the hydrogel, enabling effective antimicrobial activity. Under 360 nm UV excitation, the fluorescence intensity of CQDs in GM-C-mBG@P exhibits a strong linear correlation with pH, enabling real-time wound pH monitoring. Furthermore, mBG@P can gradually dissolve calcium, silicon, boron, and other functional ions to enhance the bioactivity and functionality of the hydrogel and accelerate wound healing. These findings suggest that the GM-C-mBG@P hydrogel has the potential to serve as a promising wound dressing for the treatment of infected chronic wounds.

Osteosarcoma (OS) blooms significant clinical challenges due to risks of metastasis, recurrence and disruption of bone homeostasis (BH). This study tactically offers a multifunctional time-sequential scaffold comprising of borosilicate bioactive glass (BSG) core, Fe3O4 magnetothermal nanoparticles (FMNPs) intermediate layer, and doxorubicin-infused pH-responsive hydrogel (PRH) outer layer. BSG degradation can generate ionic and alkaline microenvironment (IAM/BSG) to fasten PRH gel state to prevent doxorubicin leakage. FMNPs-induced hyperthermia can elicit PRH gel-sol transitions under alternating magnetic field (AMF) after engagement with tumor microenvironment (TME), improving PRH infiltration into remote tumor sites. Whereas the acidic TME then cleaves Schiff base bonds generated by carboxymethyl chitosan and oxidized dextran in PRH to release doxorubicin sustainably and selectively. IAM/BSG can also reduce OS cell viability, while hyperthermia can further impair tumor cells as needed, synergistically enhancing doxorubicin release's tumor eradication effect even at lower dosages, potentially reducing chemotherapy's systemic toxicity. Subsequently, the IAM/BSG polarizes macrophages to the M2 phenotype, creating an immunoregulatory milieu promoting osteogenesis of BMSCs for optimal bone regeneration after tumor ablation. Summarily, BSG integrating with hyperthermia to manipulate pH-responsive release of chemotherapeutic agent for targeted cancer eradication and unbalanced BH reconstruction, harmonizes the challenge of efficient OS treatment with bone regeneration time-sequentially.

Bone infection is a catastrophe in clinical orthopedics. Despite being the standard therapy for osteomyelitis, antibiotic-loaded polymethyl methacrylate (PMMA) cement has low efficiency against bacteria in biofilms. Furthermore, high-dose antibiotic-loaded implants carry risks of bacterial resistance, tissue toxicity, and impairment of local tissue healing. By incorporating borosilicate bioactive glass (BSG) into low-dose gentamicin sulfate (GS)-loaded PMMA cement, an intelligent strategy that synergistically eradicates bacteria and sequentially promotes osseointegration, was devised. Results showed that BSG did not compromises the handling properties of the cement, but actually endowed it with an ionic and alkaline microenvironment, thereby damaging the integrity of bacterial cell walls and membranes, inhibiting ATP synthesis by disrupting the respiratory chain in cell membranes and glycogen metabolism, and elevating reactive oxygen species (ROS) levels by weakening antioxidant components (peroxisomes and carotenoids). These antibacterial characteristics of BSG synergistically reinforced the effectiveness of GS, which was far below the actual clinical dosage, achieving efficient bacterial killing and biofilm clearance by binding to the 30S subunit of ribosomes. Furthermore, the released GS and the ionic and alkaline microenvironment from the implants fostered the osteogenic activity of hBMSCs in vitro and coordinately enhanced osseointegration in vivo. Collectively, this study underscores that BSG incorporation offers a promising strategy for reducing antibiotic dosage while simultaneously enhancing the antibacterial activity and osteogenesis of implants. This approach holds potential for resolving the conflict between bacterial resistance and bone infection.

Osteoarthritis (OA), as a degenerative disease, often necessitates intra-articular administration to alleviate pain. Synovial inflammation represents an important pathological factor in the development of OA. ZIF-8 (a type of Zeolitic imidazolate frameworks), a newly developed drug carrier, has garnered significant attention due to its high drug loading capacity and favorable biocompatibility. However, pH-sensitive burst drug release in inflammatory environments hampered its clinical application. To overcome this limitation, we have engineered a novel lychee-like double-layered bioactive nanocapsule, with ZIF-8 serving as the core and a bioactive amorphous sol as the outer shell, facilitated by Zn ion and Si-O coordination. The amorphous sol not only inhibits the rapid degradation of ZIF-8 in inflammatory conditions, preventing quick drug release, but also enhances the immunomodulatory capabilities of the functional carrier. Remarkably, our studies reveal that, in addition to sustained drug release, the synergistic effect of the functional carrier and anti-inflammatory drugs can regulate inflammation-induced lymphatic abnormalities. This is manifested by the suppression of macrophage secretion of excessive VEGF-C and iNOS, thereby modulating lymphatic density and restoring normal lymphatic rhythmic function. These findings indicate that such pathology-adaptive functional carriers possess superior drug release control and immunomodulatory potential compared to traditional carriers, presenting a promising innovative material for synovitis treatment.

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.

Osteochondral defect repair presents a significant clinical challenge due to the immune microenvironment at the injury site, which impairs osteogenesis. In this study, a Ce/MnHAp was developed by integrating it into an HES hydrogel. This bi-layered hydrogel system comprises an upper cartilage-mimicking layer composed of pure hydrogel and a lower subchondral bone-mimicking layer containing Ce/MnHAp. The HESH hydrogel exhibits dual responsiveness to pH and NIR laser irradiation, enabling spatiotemporally controlled release of the Ce/MnHAp and bioactive ions in response to physiological stimuli during the repair process. Upon release, Ce/MnHAp modulates the local immune micro-environment by ROS, inducing M2 macrophage polarization, restoring immune homeostasis, and improving osteogenic activity. Treatment with the NIR-irradiated HESH hydrogel significantly accelerated osteochondral regeneration over 12 weeks in a rabbit osteochondral defect model. These results highlight this multifunctional hydrogel system's therapeutic potential as an effective osteochondral tissue repair strategy.

Bioprinting technology plays a crucial role for constructing tissue substitutes. However, the mismatched scaffold shapes and the poor treatment timeliness limit its clinical translational application. In situ printing technology that prints bioregenerants directly inside patient's body can meet the needs of specific tissue repair. This study develops a smartphone controlled handheld bioprinter for in situ skin wounds dressing. The mini bioprinter can be handheld and placed on any printing surface to create strips, complex patterns, and 3D structures, and can be equipped with microchannel needles to expand functionality. The size of the strips as well as the printing path can be programmed and controlled by the smartphone to ensure the precision of the printed product quality. Furthermore, the device not only allows for smooth switching between different bioinks for printing heterogeneous structure, but also allows for fast and uniform coverage of large wound surfaces. When dealing with complex wounds in vitro & vivo, the printer can effectively fill and precisely close wounds, promoting wound healing. The programmable handheld bioprinter can balance mobility and customizability in the management of skin wounds and is expected to realize its potential for emergency medical treatment in condition-constrained scenarios, such as battlefields or disaster areas.

Tumor therapy has advanced significantly in recent years, but tumor cells can still evade and survive the treatment through various mechanisms. Notably, tumor cells use autophagy to sustain viability by removing impaired mitochondria and clearing excess reactive oxygen species (ROS). In this study, the aim is to amplify intracellular oxidative stress by inhibiting mitochondrial autophagic flux. Multisynergistic environmental-response nanoparticles (ERNs) are engineered by integrating gold nanoparticles and copper peroxide with borosilicate bioactive glass. The controlled release of copper and inhibition of autophagy flux triggered an overabundance and accumulation of oxidative stress within the tumor cells. This stress triggered immunogenic tumor cell death, believed to initiate a systemic immune response. The tumor microenvironment (TME) transitioned back to a normal physiological state as tumor cells are ablated. ERNs responded to the microenvironment changes by depositing hydroxyapatite on the surface and spontaneously enhancing bone regeneration. This innovative formulation facilitates the functional transition of ERNs from "anti-tumor therapy" to "biomineralization" that kills cancers and induces new bone formation. Overall, it is shown that the ERNs effectively eradicate cancers by utilizing chemodynamic therapy, starvation therapy, and immunotherapy.

Implant -associated Staphylococcus aureus ( S. aureus ) osteomyelitis is a severe challenge in orthopedics. While antibiotic -loaded bone cement is a standardized therapeutic approach for S. aureus osteomyelitis, it falls short in eradicating Staphylococcus abscess communities (SACs) and bacteria within osteocyte-lacuna canalicular network (OLCN) and repairing bone defects. To address limitations, we developed a borosilicate bioactive glass (BSG) combined with ferroferric oxide (Fe 3 O 4 ) magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities. We conducted comprehensive assessments of the osteoinductive, immunomodulatory, antibacterial properties, and thermal response of this scaffold, with or without an alternating magnetic field (AMF). Utilizing a well -established implant -related S. aureus tibial infection rabbit model, we evaluated its antibacterial performance in vivo . RNA transcriptome sequencing demonstrated that BSG + 5%Fe 3 O 4 enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs. Notably, BSG + 5% Fe 3 O 4 upregulated gene expression of NOD -like receptor and TNF pathway in MSCs, alongside increased the expression of osteogenic factors (RUNX2, ALP and OCN) in vitro . Flow cytometry on macrophage exhibited a polarization effect towards M2, accompanied by upregulation of anti-inflammatory genes (TGF-81 and IL-1Ra) and downregulation of pro -inflammatory genes (IL -6 and IL -18) among macrophages. In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG + 5%Fe 3 O 4 + AMF at 42 days. Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42, along with new bone formation, signifying effective control of S. aureus osteomyelitis. Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.

The assessment of biodegradable materials, such as bioactive glass, under the existing ISO 10993 standard test methods poses a significant challenge due to potential cell viability impairment caused by the accumulation of degraded products in a static environment. Therefore, innovative methodologies are urgently needed to tailor the unique biodegradation characteristics of these materials, providing more precise and scientific insights into biosafety and efficacy verification. Motivation by its bidirectional regulation of angiogenesis and immunity, zinc (Zn) was incorporated into sol-gel-derived borosilicate bioactive glasses (SBSGs) to fabricate Zn-incorporated borosilicate bioactive glasses (SBSG-Zn) to complement the tissue repair capabilities of bioactive glasses. Both SBSG and SBSG-Zn glasses consist of nanosized particles, slit mesoporous pores, high specific surface areas, and bioreactivity. In vitro comparative analysis, conducted according to ISO 10993 standards, demonstrates that only at suitable dilution rates─such as the 8-fold dilution employed in this study─do extracts of SBSG and SBSG-Zn glasses exhibit low cytotoxicity when cultured with human umbilical vein endothelial cells (HUVECs). Notably, SBSG-Zn glasses show optimal promotion of angiogenic gene expression in HUVECs. Furthermore, within an appropriate concentration range of released ions, SBSG-Zn glass extracts not only promote cell survival but also modulate the expression of anti-inflammatory genes while simultaneously inhibiting pro-inflammatory genes concurrently. After being implanted in rat subcutaneous defect models, both SBSG and SBSG-Zn glasses demonstrated the local immunoregulation and angiogenic effects. SBSG-Zn stands out by demonstrating superior modulation of M1/M2 polarization in macrophages as validated by altered secretion of key factors in macrophages and expression of relevant growth factors in HUVECs. These findings underscore the potential for convenient manipulation of localized angiogenic and immunoregulation through the incorporation of zinc into bioactive glass, emphasizing the importance of ensuring the appropriate ion doses are applied for achieving optimal therapeutic efficiency.

Implant-associated Staphylococcus aureus (S. aureus) osteomyelitis is a severe challenge in orthopedics. While antibiotic-loaded bone cement is a standardized therapeutic approach for S. aureus osteomyelitis, it falls short in eradicating Staphylococcus abscess communities (SACs) and bacteria within osteocyte-lacuna canalicular network (OLCN) and repairing bone defects. To address limitations, we developed a borosilicate bioactive glass (BSG) combined with ferroferric oxide (Fe3O4) magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities. We conducted comprehensive assessments of the osteoinductive, immunomodulatory, antibacterial properties, and thermal response of this scaffold, with or without an alternating magnetic field (AMF). Utilizing a well-established implant-related S. aureus tibial infection rabbit model, we evaluated its antibacterial performance in vivo. RNA transcriptome sequencing demonstrated that BSG + 5%Fe3O4 enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs. Notably, BSG + 5%Fe3O4 upregulated gene expression of NOD-like receptor and TNF pathway in MSCs, alongside increased the expression of osteogenic factors (RUNX2, ALP and OCN) in vitro. Flow cytometry on macrophage exhibited a polarization effect towards M2, accompanied by upregulation of anti-inflammatory genes (TGF-β1 and IL-1Ra) and downregulation of pro-inflammatory genes (IL-6 and IL-1β) among macrophages. In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG + 5%Fe3O4 + AMF at 42 days. Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42, along with new bone formation, signifying effective control of S. aureus osteomyelitis. Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.

Diabetic wound healing remains a critical challenge due to its special hyperglycemic environment and disorder in wound healing process. The hyperglycemic microenvironment of diabetic wounds causes inhibitive angiogenesis and overproduction of reactive oxygen species (ROS), which leads to oxidative stress damage to biological macromolecules and cells, and hindrance of wound healing. Herein, an injectable thermo-sensitive methyl cellulose hydrogel with capacities of improving angiogenesis, scavenging ROS and antibiosis is developed to overcome the obstacles of diabetic wound healing. Through loading antioxidative cerium-doped bioactive glass nanoparticles (CeBG), the hydrogel demonstrates efficient ROS scavenging to protect cells from oxidative stress harm, as well as stimulation of dermal fibroblast proliferation and migration. Moreover, addition of quaternary chitosan (QCS) endows the hydrogel with antibacterial ability against E. coli and S. aureus. The hydrogel effectively accelerates diabetic wound healing in a mice model, and more importantly, the wound area presents improved angiogenesis, diminished inflammation and decreased ROS level. These data demonstrate that the hydrogel is a promising biomaterial for the clinical treatment of diabetic wounds, as well as facilitating the therapy of oxidative stress related diseases.

Effective treatment of osteomyelitis remains to be clinical challenge due to the recurrent and persistent nature of the disease. Studies have shown that borate glasses can serve as implants for local drug delivery in treating osteomyelitis, as well as aid in regenerating bone defects in vivo. However, both the kinetics of drug release from borate glass-based implants and the underlying molecular mechanism for promoting bone regeneration remain unclear. Here, delivery implants with varying amounts of antibiotics were fabricated by encapsulating gentamicin sulfate (GS) into a chitosan glue and applying it to borosilicate glass (BSG). Upon immersion in phosphate buffered saline (PBS), delivery implants degraded and converted into hydroxyapatite (HA). All delivery implants released GS sustainably over a period of around 25 days in both PBS and K2HPO4 solutions and displayed efficacious inhibition of E. coli and S. aureus in vitro. GS release occurred through diffusion for inhibition whereby Fickian diffusion was revealed to be the predominant release kinetic. Ions (B, Ca, P and Si) released from BSG supported the proliferation, differentiation, osteogenic gene expression and protein secretion of human bone marrow mesenchymal stem cells (hBMSCs) in vitro. When implanted in a rabbit tibial osteomyelitis model, osteomyelitis in the experimental group with delivery implants was effectively cured. Meanwhile, delivery implants have significant osteogenesis-promoting effects after implantation time of 12-weeks in vivo. Implantation of BSG-based drug delivery implants developed in this study may provide a promising method for treating osteomyelitis as well as for facilitating efficient bone regeneration.

Chronic hypoxia and ischemia make diabetic wounds non-healing. Cellular functions of diabetic chronic wounds are inhibited under a pathological environment. Therefore, this work develops a composite hydrogel system to promote diabetic wound healing. The composite hydrogel system consists of ε-poly-lysine (EPL), calcium peroxide (CP), and borosilicate glass (BG). The hydrogel supplies continuous dissolved oxygen molecules to the wound that can penetrate the skin tissue to restore normal cellular function and promote vascular regeneration. Biofunctional ions released from BGs can recruit more macrophages through neovascularization and modulate macrophage phenotypic transformation. Combining oxygen-mediated vascular regeneration and ion-mediated inflammatory regulation significantly accelerated diabetic wound healing. These findings indicate that this composite hydrogel system holds promise as a novel tissue engineering material.

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.

Metal-organic frameworks (MOFs) have a high specific surface area, adjustable pores and can be used to obtain functional porous materials with diverse and well-ordered structures through coordination and self-assembly, which has intrigued wide interest in a broad range of disciplines. In the arena of biomedical engineering, the functionalized modification of MOFs has produced drug carriers with excellent dispersion and functionalities such as target delivery and response release, with promising applications in bio-detection, disease therapy, tissue healing, and other areas. This review summarizes the present state of research on the functionalization of MOFs by physical binding or chemical cross-linking of small molecules, polymers, biomacromolecules, and hydrogels and evaluates the role and approach of MOFs functionalization in boosting the reactivity of materials. On this basis, research on the application of functionalized MOFs composites in biomedical engineering fields such as drug delivery, tissue repair, disease treatment, bio-detection and imaging is surveyed, and the development trend and application prospects of functionalized MOFs as an important new class of biomedical materials in the biomedical field are anticipated, which may provide some inspiration and reference for further development of MOF for bio-medical applications.