Silicon-Based Biomaterials Modulate the Adaptive Immune Response of T Lymphocytes to Promote Osteogenesis/Angiogenesis via Epigenetic Regulation.

Silicon (Si)-based biomaterials are widely applied for bone regeneration. However, the underlying mechanisms of the materials function remain largely unknown. T lymphocyte-mediated adaptive immune response plays a vital role in the process of bone regeneration. In the current study, mesoporous silica (MS) is used as a model material of Si-based biomaterials. It shows that the supernatant of CD4+ T lymphocytes pretreated with MS extract significantly promotes the vascularized bone regeneration. The potential mechanism is closely related to the fact that MS extract can reduce the expression of regulatory factor X-1 (RFX-1) in CD4+ T lymphocytes. This may result in the overexpression of interleukin-17A (IL-17A) by boosting histone H3 acetylation and lowering DNA methylation and H3K9 trimethylation. Importantly, the in vivo experiments further reveal that MS particles significantly enhance bone regeneration with improved angiogenesis in the critical-sized calvarial defect mouse model accompanied by upregulation of IL-17A in peripheral blood and the proportion of Th17 cells. This study suggests that modulation of the adaptive immune response of T lymphocytes by silicate-based biomaterials plays an important role for bone regeneration.

High-strength, thermosensitive double network hydrogels with antibacterial functionality.

Herein, we report a method of fabricating strong and thermosensitive double network (T-DN) poly(N-isopropyl acrylamide) (PNIPAM)-based hydrogels, i.e. rigid and brittle poly(2-acrylamido-2-methylpropanesulfonic acid sodium salt) (PNaAMPS) as the first and soft and ductile poly(N-isopropyl acrylamide-co-acrylamide) (P(NIPAM-co-AAm)) as the second interpenetrating each other. In particular, NIPAM was deliberately integrated into the double network as an adjustor of elastic modulus and hydrophilicity, besides thermosensitivity. Such double network construction strategy resulted in PNaAMPS/P(NIPAM-co-AAm) T-DN hydrogels of excellent mechanical properties (0.83-1.37 MPa) and desirable temperature-dependent swellabilities. Besides, T-DN hydrogels with various NIPAM contents exhibited good biocompatibility with high cell survival rates around normal body temperatures. Furthermore, crystal violet (CV) could be readily loaded to impart antibacterial functionality to the T-DN hydrogels against E. coli. The double network construction strategy could be adapted to fabricating high-strength antibacterial hydrogels for a broad range of biomedical applications.

Luminescent net-like inorganic scaffolds with europium-doped hydroxyapatite for enhanced bone reconstruction.

Bone reconstruction is an urgent problem during clinical treatment. In the past few decades, the construction of composite scaffolds has been a hot spot in the research field of bone tissue engineering (BTE). However, the disadvantages of composite materials raise our awareness to explore the potential application of hydroxyapatite (HAp) in bone substitutes due to the closest properties of HAp to natural bone tissue. In our study, we synthesized Eu3+-doped HAp (HAp:Eu3+) ultralong nanowires, which can be transformed to hydrophilic net-like scaffolds via a thiol-ene click reaction. The property of luminescence of HAp from Eu3+ is beneficial for identifying the relative position of materials and bone marrow mesenchymal stem cells (BMSCs). HAp:Eu3+ scaffolds with excellent cell biocompatibility could promote the expression of early bone formation markers (ALP and ARS) and enhance the expression of genes and proteins associated with osteogenesis (Runx 2, OCN, and OPN). In the end, the results of the in vivo osteogenesis experiment showed that pure HAp scaffolds presented different effects of bone tissue reconstruction compared with the composite scaffolds with HAp nanorods and polymer materials. The superior osteogenic effect could be observed in net-like pure HAp scaffold groups. Furthermore, the absorption of HAp:Eu3+ scaffolds could be monitored due to the luminescence property of Eu3+. This strategy based on ultralong HAp nanowires proved to be a new method for the construction of simple reticular scaffolds for potential osteogenic applications.

Colorectal Tumor Microenvironment-Activated Bio-Decomposable and Metabolizable Cu2 O@CaCO3 Nanocomposites for Synergistic Oncotherapy.

Rational design of tumor microenvironment (TME)-activated nanocomposites provides an innovative strategy to construct responsive oncotherapy. In colorectal cancer (CRC), the specific physiological features are the overexpressed endogenous H2 S and slightly acidic microenvironment. Here, a core-shell Cu2 O@CaCO3 nanostructure for CRC "turn-on" therapy is reported. With CaCO3 responsive to pH decomposition and Cu2 O responsive to H2 S sulfuration, Cu2 O@CaCO3 can be triggered "on" into the therapeutic mode by the colorectal TME. When the CaCO3 shell decomposes and releases calcium in acidic colorectal TME, the loss of protection from the CaCO3 shell exposes the Cu2 O core to be sulfuretted by H2 S to form metabolizable Cu31 S16 nanocrystals that gain remarkably strong near-infrared absorption. After modifying hyaluronic acid, Cu2 O@CaCO3 can achieve synergistic CRC-targeted and TME-triggered photothermal/photodynamic/chemodynamic/calcium-overload-mediated therapy. Moreover, it is found that the generation of hyperthermia and oxidative stress from Cu2 O@CaCO3 nanocomposites can efficiently reprogram the macrophages from the M2 phenotype to the M1 phenotype and initiate a vaccine-like immune effect after primary tumor removal, which further induces an immune-favorable TME and intense immune responses for anti-CD47 antibody to simultaneously inhibit CRC distant metastasis and recurrence by immunotherapy.

Cu2 MoS4 /Au Heterostructures with Enhanced Catalase-Like Activity and Photoconversion Efficiency for Primary/Metastatic Tumors Eradication by Phototherapy-Induced Immunotherapy.

Photoimmunotherapy can not only effectively ablate the primary tumor but also trigger strong antitumor immune responses against metastatic tumors by inducing immunogenic cell death. Herein, Cu2 MoS4 (CMS)/Au heterostructures are constructed by depositing plasmonic Au nanoparticles onto CMS nanosheets, which exhibit enhanced absorption in near-infrared (NIR) region due to the newly formed mid-gap state across the Fermi level based on the hybridization between Au 5d orbitals and S 3p orbitals, thus resulting in more excellent photothermal therapy and photodynamic therapy (PDT) effect than single CMS upon NIR laser irradiation. The CMS and CMS/Au can also serve as catalase to effectively relieve tumor hypoxia, which can enhance the therapeutic effect of O2 -dependent PDT. Notably, the NIR laser-irradiated CMS/Au can elicit strong immune responses via promoting dendritic cells maturation, cytokine secretion, and activating antitumor effector T-cell responses for both primary and metastatic tumors eradication. Moreover, CMS/Au exhibits outstanding photoacoustic and computed tomography imaging performance owing to its excellent photothermal conversion and X-ray attenuation ability. Overall, the work provides an imaging-guided and phototherapy-induced immunotherapy based on constructing CMS/Au heterostructures for effectively tumor ablation and cancer metastasis inhibition.

A Multifunctional Cascade Bioreactor Based on Hollow-Structured Cu2 MoS4 for Synergetic Cancer Chemo-Dynamic Therapy/Starvation Therapy/Phototherapy/Immunotherapy with Remarkably Enhanced Efficacy.

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu2 MoS4 (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo-dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu1+/2+ , Mo4+/6+ ) exhibit Fenton-like, glutathione (GSH) peroxidase-like and catalase-like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton-like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase-like CMS could react with endogenous H2 O2 to generate O2 for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H2 O2 . The regenerated H2 O2 can devote to Fenton-like reaction for realizing GOx-catalysis-enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor-killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O2 - ) generation performance. More importantly, the PEGylated CMS@GOx-based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.

BMP-2-Loaded HAp:Ln3+ (Ln = Yb, Er, Gd) Nanorods with Dual-Mode Imaging for Efficient MC3t3-E1 Cell Differentiation Regulation.

Effective bone tissue reconstitution improves the treatment success rate of dental implantation and preserves natural teeth during periodontal tissue repair. Hydroxyapatite (HAp) has received much attention in bone remodeling field because its mineralized structure is similar to that of the natural bone tissue. For this reason, it has been used as a carrier for growth factors. Although HAp possesses outstanding biomedical properties, its capacity of loading and releasing bone growth factors and promoting osteogenesis is not well understood. In this study, Ln3+ (Ln = Yb3+, Er3+, Gd3+)-doped HAp (HAp:Ln3+) nanorods were synthesized by one-step hydrothermal method. To improve its biocompatibility and surface properties, bone morphogenetic protein-2 (BMP-2) was loaded onto the surface of HAp:Ln3+ nanorods. The results showed that BMP-2 incorporation promoted bone formation and enhanced the expression of early bone-related gene and protein (RunX2, SP7, OPN). In addition, Yb3+- and Er3+-doped HAp nanorods were examined by upconversion luminescence with 980 nm near-infrared laser irradiation to monitor the delivery position of BMP-2 protein. Furthermore, due to the positive magnetism correlated with the concentration of Gd3+, HAp:Ln3+ with enhanced contrast brightening can be deemed as T1 MIR contrast agents. These findings indicate that HAp doped with rare-earth ions and loaded with BMP-2 has the potential to promote bone tissue repair and execute dual-mode imaging.

High strength and antibacterial polyelectrolyte complex CS/HS hydrogel films for wound healing.

We report a simple and facile self-assembly approach to fabricate polyelectrolyte complex (PEC) hydrogel films with positively charged chitosan (CS) and negatively charged heparin sodium (HS) by combining hydrogen bonding and electrostatic interactions. The CS/HS hydrogel films exhibited excellent tensile strength and toughness, good self-recovery ability, superior water absorbency, and pH-dependent surface charge characteristics. The gelation mechanism was investigated by zeta potential measurements. The CS/HS hydrogel films exhibited high antibacterial efficacy against E. coli at selected pHs or when coordinated with various metal ions and a significant effect on accelerating wound healing. The self-assembly approach presented in this work may serve as a generic strategy for the fabrication of novel multi-functional PEC hydrogels for broad biomedical applications.

Enhanced photoconversion performance of NdVO4/Au nanocrystals for photothermal/photoacoustic imaging guided and near infrared light-triggered anticancer phototherapy.

Although neodymium vanadate (NdVO4) has been investigated and applied in some fields owing to its intensive ultraviolet (UV) light absorption, weak absorption in visible (Vis) and near infrared (NIR) regions constrains its environmental remediation and biomedical applications. Herein, plasmonic precious metal Au as light trapping agent is deposited onto NdVO4 to form metal/semiconductor hybrid nanostructure for improving the Vis/NIR light absorption. NdVO4/Au heterojunction nanocrystals (NCs) were synthesized by NdVO4 nanorods (NRs) and plasmonic Au nanoparticles (NPs), followed by introducing polyvinylpyrrolidone (PVP) to enhance stability and biocompatibility, which exhibit elevated photocatalytic performance for organic dye degradation, photothermal conversion effect as high as 32.15% and cytotoxic reactive oxygen species (ROS) production ability. NdVO4/Au can be internalized efficiently via endocytosis and cause apparent phototoxicity on HeLa cells. In vivo experiments further show that NdVO4/Au can act as a high-efficiency NIR light-triggered anticancer agent with excellent tumor inhibition effect. In addition, based on outstanding light-to-heat conversion performance and thermal expansion effect under NIR irradiation, NdVO4/Au provides photothermal (PT) and photoacoustic (PA) dual-modal imaging platform for precise cancer diagnosis and treatment. STATEMENTS OF SIGNIFICANCE: It's the first report on integrating precious metal Au and rare earth orthovanadates semiconductor into NdVO4/Au heterojunction NCs. The as-prepared NdVO4/Au heterojunction NCs exhibits improved absorption in Vis/NIR region and increased generation efficiency of photo-induced electron/hole pairs due to the LSPR effect, which results in enhanced photothermal conversion efficiency and the production ability of cytotoxic O2- and OH in comparison with pristine NdVO4. For further clinical application, NdVO4/Au heterojunction NCs could be served as anticancer therapeutic agent for PA/PT dual-modal imaging guided and NIR-triggered photothermal/photodynamic synergistic anticancer treatment.

Self-assembled CeVO4/Ag nanohybrid as photoconversion agents with enhanced solar-driven photocatalysis and NIR-responsive photothermal/photodynamic synergistic therapy performance.

The plasmonic cerium vanadate (CeVO4) semiconductor and plasmonic silver (Ag) metal exhibit a localized surface plasmon resonance (LSPR) effect in the visible (Vis)-light region; however, weak absorption in the near-infrared (NIR) region restricts their environmental remediation and biomedical application. Herein, CeVO4/Ag nanohybrids with self-assembled heterostructure and improved Vis/NIR light absorption were synthesized from CeVO4 nanosheets and AgNO3 solution, which could serve as potential solar-driven catalytic agents and near-infrared (NIR) light responsive anticancer agents. Oleic acid-stabilized CeVO4 nanosheets were modified with the HS-PEG1000-OH by the thiol-ene click reaction and presented self-assembly morphology in aqueous solution due to hydrophobic-hydrophobic interactions. Sulfhydryl (-SH) groups provided stable sites for Ag+ ions on the surface of CeVO4, and Ag+ ions could be directly reduced by Ce3+ ions to form CeVO4/Ag heterojunction nanocrystals (NCs). Due to the higher absorption in the Vis/NIR light region than CeVO4 nanosheets, CeVO4/Ag NCs led to the improved solar light responsive photocatalytic degradation of organic dyes. Upon the exposure of these NCs to an 808 nm laser, CeVO4/Ag NCs show high photothermal conversion efficiency, ROS generation ability and photoacoustic (PA) signal for implementing PA imaging-guided photothermal/photodynamic synergistic cancer therapy with better tumor inhibition effect.

Strong, tough and mechanically self-recoverable poly(vinyl alcohol)/alginate dual-physical double-network hydrogels with large cross-link density contrast.

Strong and tough poly(vinyl alcohol) (PVA)/alginate hydrogen-bonded-ionic dual-physical double-network (DN) hydrogels have been successfully prepared by a facile route of a freeze-thaw (25-25-25 °C) cycle followed by concentrated (1.0 mol L-1 of) aqueous-Ca2+ immersion of PVA/Na alginate (SA) mixed aqueous solutions. It was found that, at mole ratios of the PVA- to SA repeat units of 20/1 to 80/1, the DN gels likely evolved a semi-interpenetrating polymer network (IPN) morphology of rigid alginate networks dispersed in while interlocking with ductile PVA network to accomplish DN synergy that gave their high strength and toughness, where the high alginate rigidity originated probably from its dense cross-link induced syneresis and dispersion along crosslink-defective voids to result in little internal stress concentration. Tentatively mechanistically, as the 20/1-80/1 DN gels were stretched steadily, their mechanical response was gradually differentiated into distinct synergistic states: the sparsely hydrogen-bonded PVA served as a ductile matrix to bear small fractions of the established stresses at its large elongations; whereas the densely ionically (i.e. Ca2+) cross-linked alginate functioned as a rigid skeleton to sustain the remaining larger stresses upon its smaller local strains. Promisingly, this ductile-rigid matrix-skeleton synergistic mechanism of semi-IPN morphology may be universally extended to all A/B DN hydrogels of large A-B rigidity (or cross-link density) contrast, whether the cross-link nature of network(s) A or B is covalent, ionic, hydrogen bonded or van der Waals interacted. The strong and tough DN gels also displayed satisfactory self-recovery of viscoelastic behaviour, in that their Young's modulus and dissipated energy in the uniaxial tensile mode and dynamic storage and loss moduli in the oscillatory shear mode all recovered significantly from non-linear viscoelastic regimes despite different degrees of failure to revert to (quasi)linear viscoelasticity.