Distinct mechanisms of iron and zinc metal ions on osteo-immunomodulation of silicocarnotite bioceramics.

The immunomodulatory of implants have drawn more and more attention these years. However, the immunomodulatory of different elements on the same biomaterials have been rarely investigated. In this work, two widely used biosafety elements, iron and zinc added silicocarnotite (Ca5(PO4)2SiO4, CPS) were applied to explore the routine of elements on immune response. The immune reactions over time of Fe-CPS and Zn-CPS were explored at genetic level and protein level, and the effects of their immune microenvironment with different time points on osteogenesis were also investigated in depth. The results confirmed that both Fe-CPS and Zn-CPS had favorable ability to secret anti-inflammatory cytokines. The immune microenvironment of Fe-CPS and Zn-CPS also could accelerate osteogenesis and osteogenic differentiation in vitro and in vivo. In terms of mechanism, RNA-seq analysis and Western-blot experiment revealed that PI3K-Akt signaling pathway and JAK-STAT signaling pathways were activated of Fe-CPS to promote macrophage polarization from M1 to M2, and its immune microenvironment induced osteogenic differentiation through the activation of Hippo signaling pathway. In comparison, Zn-CPS inhibited polarization of M1 macrophage via the up-regulation of Rap1 signaling pathway and complement and coagulation cascade pathway, while its osteogenic differentiation related pathway of immune environment was NF-κB signaling pathway.

Sol-gel preparation of ZrO2-Li2Si2O5 ceramics and their sintering properties.

Despite zirconia (ZrO2) ceramics and lithium disilicate (Li2Si2O5) glass-ceramics have been widely applied on the market for dental restorations, composites that can combine the advantages of both are still demanded. Here we introduced a ZrO2-Li2Si2O5 ceramic with minimized glass phases that fabricated through a sol-gel method and subsequent pressureless sintering. ZrO2-Li2Si2O5 powders were obtained after the gel precursors were heat treated under 800 °C. The gel-derived powders were molded and pressureless sintered under 900-1000 °C to investigate their sintering properties. From the microstructures of the sintered samples, we knew that the densification process was dominated by the growth of Li2Si2O5 grains instead of the growth of ZrO2 grains. Increasing in Li2Si2O5 content can promote ceramic densification. Interestingly, reactions between ZrO2 and Li2Si2O5 were observed with sintering temperature higher than 916 °C, which can increase the porosity of the ceramics. Therefore, both the content of Li2Si2O5 and sintering temperature should be well adjusted to achieve samples with desired properties. Finally, ceramics with flexural strength of 226 MPa and porosity of 0.4% were achieved from powders with moderate Li2Si2O5 content after sintering at 1000 °C.

Design of a Smart Self-Healing Coating with Multiple-Responsive Superhydrophobicity and Its Application in Antibiofouling and Antibacterial Abilities.

Inspired by the restoration of the superhydrophobic surfaces after the damage in nature such as lotus leaf and clover, smart self-healing coating with controllable release of loaded healing agents is both of scientific and technological interest. Herein, a smart self-healing coating with superhydrophobicity was gained through blending UV/NIR/acid/base multiple-responsive ZnO-encapsulated mesoporous polydopamine (MPDA) microspheres (zinc oxide-encapsulated mesoporous polydopamine microspheres) with silicone latex and hydrophobic nanoparticles. The hydrophobic and micro/nanostructured ZnO-encapsulated MPDA microspheres provided UV/NIR/acid/base multiple response sources for the smart self-healing coating, combining the photocatalytic activity and acid/base solubility of ZnO nanoparticles, zwitterionic characteristic of amino-modified silicone oil (ASO), as well as the photothermal conversion abilities and charge characteristics of PDA. The ZnO nanoparticles simultaneously acted as the protective layer for the stimuli-responsive microspheres and functional filler in the coating, contributing to realize the controllable and long-period release of loaded hydrophobic ASO and the further antibacterial functionalization for the coating. The super/high hydrophobicity and antibiofouling performances of the coating could be self-healed by UV, NIR, acid, or base stimuli, attributing to the release of ASO from the microspheres. Then, large-area, rapid, and controllable healing superiority could be achieved on the coating with the combined multiple responses under different conditions. Robust environmental endurances for superhydrophobic coating were also confirmed under harsh environments by directly exposing to UV-accelerated weathering and immersing into various solutions (including strong acid/base, salt, and artificial seawater solution). This smart coating has high application prospects due to its environmentally friendly nature, excellent self-healing, and multifunctional characteristics, and the multiple-responsive ZnO-encapsulated MPDA microspheres can be used for the functionalization of other materials.

Efficient antibacterial activity of hydroxyapatite through ROS generation motivated by trace Mn(iii) coupled H vacancies.

Hydroxyapatite (HA) has attracted wide attention for medical application due to its biocompatibility and bioactivity. However, the infection problems of HA remain among the leading reasons for implantation failure. Thus, it is urgent to endow HA biomaterials with antibacterial activity. Herein, the high antibacterial activity was achieved by introducing trace Mn3+ and H vacancy couples in HA through a facile heat-treatment strategy in air. The theoretical results indicated that Mn3+ was preferentially substituted for the Ca(2) site in the HA structure with a charge-compensating H vacancy appearing at the adjacent OH- site. The antibacterial tests showed that Mn-HA possessed antibacterial activity towards both E. coli and S. aureus with trace Mn content at the ppm level, and implied that Mn3+ and centers may play an important role in the antibacterial process. The Mn3+ and couples in Mn-HA, serving as oxidative and reductive centers respectively, could then collectively participate in the CoQ/CoQH2 redox cycling and synergistically facilitate the accumulation of CoQ˙- and ROS radicals. This enhanced ROS production was the main factor to endow Mn-HA with efficient antibacterial activity. Moreover, the in vitro bioactivity assay showed that Mn-HA materials exhibited enhanced osteogenic activity and good biocompatibility. Therefore, this work not only provides a feasible method to control the oxidation state of Mn elements in HA, but also proposes a novel trace Mn3+-doped HA for potential applications in tissue engineering.

Mild generation of surface oxygen vacancies on CeO2 for improved CO2 photoreduction activity.

The vacancy defects of semiconductor photocatalysts play key roles in enhancing their photocatalytic CO2 reduction activity. In this work, CeO2 was chosen as a model catalyst and oxygen vacancies were introduced on its surface by a facile and mild oxalic acid treatment followed by moderate heating in N2. Such a treatment resulted in a much increased ratio of Ce3+/Ce4+ in CeO2, and the oxygen vacancy-enriched CeO2 showed remarkably enhanced photocatalytic activity in CO2 reduction, with CO being the dominant reduction product, whose yield was about 8 times that on the pristine CeO2. In situ FT-IR spectra showed that the abundant oxygen vacancies substantially improved the CO2 adsorption/activation on the surface of CeO2, which facilitated the subsequent reduction of CO2. However, the carbonates strongly adsorbed on the photocatalyst surface might be the main obstacle to maintaining the high CO2 reduction activity and stability of CeO2 with O vacancies.

Mesoporous Silica Nanoparticles for Dual-Mode Chemo-Sonodynamic Therapy by Low-Energy Ultrasound.

Low-energy ultrasound (LEUS), exhibiting obvious advantages as a safe therapeutic strategy, would be promising for cancer therapy. We had synthesized a LEUS-responsive targeted drug delivery system based on functional mesoporous silica nanoparticle for cancer therapy. Paclitaxel (PTX) was loaded in mesoporous silica nanoparticles with a hydrophobic internal channel, and folic acid (FA) functionalized ß-Cyclodextrin (ß-CD) was capped on the surface of the nanoparticles (DESN), which acted as a cancer-targeting moiety and solubilizer. The existence of a hydrophobic internal channel in the DESN was beneficial to the storage of hydrophobic PTX, along with the enhancement of the cavitation effect produced by mild low-energy ultrasound (LEUS, ≤1.0 W/cm², 1 MHz). The DESN showed significantly enhanced cavitation effect, selective targeting, and achieved a rapid drug release under mild LEUS. To investigate the in vivo antitumor efficacy of the DESN upon LEUS irradiation, we established a 4T1 mammary tumor model. The DESN were confirmed to be of great biodegradability/biocompatibility. The tumor growth was significantly inhibited when the mice were treated with DESN (10 mg/kg) + LEUS with the relative tumor volume reduced to 4.72 ± 0.70 compared with the control group (V/V0 = 17.12 ± 2.75). The DESN with LEUS represented excellent inhibiting effect on tumor cell in vivo. This work demonstrated that DESN mediating dual mode chemo-sonodynamic therapy could be triggered by extracorporeal remote control, may suggest a promising clinical application in cancer therapy.

A redox cycling-amplified electrochemical immunosensor for α-fetoprotein sensitive detection via polydopamine nanolabels.

A sandwich-type electrochemical immunosensor for sensitive detection of a tumor marker, α-fetoprotein (AFP), was fabricated by employing polydopamine-detection antibody nanoparticles (PDANPs-Ab2) as selective redox cycling-based signal amplifiers on an electrodeposited nano-gold electrode. In this research, PDANPs prepared through oxidative polymerization of dopamine were found to amplify the oxidation charge transfer of the electrochemical mediator (1,1'-ferrocene dimethanol, FDM), which was supported by cyclic voltammetry (CV) and X-ray photoelectron spectroscopy (XPS) investigation. Therefore, PDANPs were utilized as label materials of electrochemical immunosensors to enhance sensitivity for the first time. Meanwhile, the nano-gold electrode was used as a platform to accelerate electron transfer and immobilize capture antibody (Ab1). The electrochemical performance of the AFP immunosensor was investigated in PBS containing FDM with CV. Under optimal conditions, the constructed AFP immunosensor exhibited a wide linear range from 1 pg mL-1 to 50 ng mL-1 and a low detection limit of 0.3 pg mL-1, as well as excellent stability, reproducibility and selectivity. Measurements of AFP in human serum gave excellent correlation with the clinical standard Chemiluminescence Microparticle Immuno Assay (CMIA). These results indicated that the developed immunosensor may have promising application in the clinical diagnosis of AFP and other tumor markers.

Efficient Active Oxygen Free Radical Generated in Tumor Cell by Loading-(HCONH2)·H2O2 Delivery Nanosystem with Soft-X-ray Radiotherapy.

Tumor hypoxia is known to result in radiotherapy resistance and traditional radiotherapy using super-hard X-ray irradiation can cause considerable damage to normal tissue. Therefore, formamide peroxide (FPO) with high reactive oxygen content was employed to enhance the oxygen concentration in tumor cells and increase the radio-sensitivity of low-energy soft-X-ray. To improve stability of FPO, FPO is encapsulated into polyacrylic acid (PAA)-coated hollow mesoporous silica nanoparticles (FPO@HMSNs-PAA). On account of the pH-responsiveness of PAA, FPO@HMSNs-PAA will release more FPO in simulated acidic tumor microenvironment (pH 6.50) and subcellular endosomes (pH 5.0) than in simulated normal tissue media (pH 7.40). When exposed to soft-X-ray irradiation, the released FPO decomposes into oxygen and the generated oxygen further formed many reactive oxygen species (ROS), leading to significant tumor cell death. The ROS-mediated cytotoxicity of FPO@HMSNs-PAA was confirmed by ROS-induced green fluorescence in tumor cells. The presented FPO delivery system with soft-X-ray irradiation paves a way for developing the next opportunities of radiotherapy toward efficient tumor prognosis.

The Effect and Osteoblast Signaling Response of Trace Silicon Doping Hydroxyapatite.

It is commonly accepted that silicon-doped hydroxyapatite (HAp) can achieve good repair effects for both spinal fusion and bone defect filling. However, the underlying mechanism by which silicon aids such beneficial effects is still not fully understood. Herein, we report on silicon-doped hydroxyapatites with excellent biocompatibility to osteoblast cells and suggest the signaling pathway involved. Non-doped HAp and trace Si-doped HAp (Si/HAp) with Si concentration close to and higher than natural bones were synthesized (i.e., 32, 260, and 2000 ppm Si). The composition, crystal lattice vibration pattern, and morphology of these samples are characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR), and SEM, respectively. Positive biological activities of these Si-doped HAp materials were demonstrated through a cytotoxicity study and with the MTT and alkaline phosphatase (ALP) activity assays. The Si-doped samples were not toxic to MC3T3-E1 cells. Indeed, osteoblast proliferation measurement illustrated that 2000 ppm Si-doped HAp increased osteoblast proliferation by about 1.6 times compared to non-doped HAp. The ALP assay also proves that the trace Si doping has the function to enhance cell proliferation and differentiation. The ALP assay showed that Si doping also enhanced cell differentiation. QRT-PCR results revealed that Si-doped HAp enhanced osteogenic differentiation of osteoblast cells by upregulating genes such as MAPK3, Fzd1, Wnt1, Lrp6, and BMP2. In conclusion, Si-doped HAp promotes osteoblast proliferation and differentiation by activating the Wnt/ß-catenin and MAPK signaling pathways. This work could provide useful information of the beneficial effects of silicon in human bones and provide clues as to the molecular mechanism of the promotive effect of Si-doped HAp biomaterials.

Functional hydroxyapatite bioceramics with excellent osteoconductivity and stern-interface induced antibacterial ability.

The biocompatibility and antibacterial properties of hydroxyapatite (HAp) bioceramics are crucial in medical applications. However, it is still a challenge to control HAp with antibacterial ability while maintaining other biological properties in the development of bioactive bone implants. Herein, we report functional silver ion substituted HAp bioceramics with excellent osteoconductivity and efficient antibacterial activity and propose a stern-interface induced antibacterial mechanism of such bioactive ceramics. In this antibacterial process, the concentration of Ag(+) at the stern-interface of Ag/HAp bioceramics is nearly 5 times higher than that in the bulk solution due to the trace dopant Ag(+) enrichment in the stern layer of the electric double layer at the negatively charged surface of Ag/HAp bioceramics. Trace Ag-doping in HAp induces a positive shift of zeta potential and increase of hydrophilicity, which may help inhibit bacterial proliferation. The positive osteoblast adhesion, proliferation and differentiation of ultra-trace doped Ag/HAp are also demonstrated through actin cytoskeleton staining, MTT and alkaline phosphatase (ALP) activity assays. This work may enlighten us on the artificial design of novel smart anti-infective bone grafts using ultra-trace functional elements and also suggest its potential applications in orthopedic surgery and bone osseointegration.

Efficient free radical generation against cancer cells by low-dose X-ray irradiation with a functional SPC delivery nanosystem.

Tumor hypoxia is a negative prognostic factor in cancer radiotherapy, due in part to its role in causing resistance to radiotherapy. It has attracted extensive critical attention to radiation sensitizers by using active oxygen to improve radiotherapy outcome. Active oxygen delivery functional materials are promising candidates to transport active oxygen to tumor cells. Herein, we report an oxygen delivery functional material by using hollow mesoporous silica nanoparticles (HMSNs) as carriers, synthesizing sodium percarbonate (SPC) in the channels and cavity of HMSNs (SPC@HMSNs) and coating polyacrylic acid (PAA) on the functional materials (SPC@HMSNs-PAA). SPC@HMSNs-PAA could release more SPC in a simulated tumor acidic microenvironment (pH ∼ 6.5), which can provide oxygen to improve radiotherapy outcome even under low energy X-ray irradiation. The events induce obvious overproduction of reactive oxygen radicals to kill cancer cells with a significant effect. Meanwhile, no obvious cytotoxicity was observed when SPC@HMSNs-PAA applied alone. The radiosensitization of SPC@HMSNs-PAA on cancer cells, even exposure to low-energy X-ray irradiation, may suggest promising application in radiotherapy.

Lysosome-controlled efficient ROS overproduction against cancer cells with a high pH-responsive catalytic nanosystem.

Excess reactive oxygen species (ROS) have been proved to damage cancer cells efficiently. ROS overproduction is thus greatly desirable for cancer therapy. To date, ROS production is generally uncontrollable and outside cells, which always bring severe side-effects in the vasculature. Since most ROS share a very short half-life and primarily react close to their site of formation, it would be more efficient if excess ROS are controllably produced inside cancer cells. Herein, we report an efficient lysosome-controlled ROS overproduction via a pH-responsive catalytic nanosystem (FeOx-MSNs), which catalyze the decomposition of H2O2 to produce considerable ROS selectively inside the acidic lysosomes (pH 5.0) of cancer cells. After a further incorporation of ROS-sensitive TMB into the nanosystem (FeOx-MSNs-TMB), both a distinct cell labeling and an efficient death of breast carcinoma cells are obtained. This lysosome-controlled efficient ROS overproduction suggests promising applications in cancer treatments.

Selective intracellular free radical generation against cancer cells by bioactivation of low-dose artesunate with a functionalized mesoporous silica nanosystem.

Excessive free radicals are noxious for living organisms and lead to cell death. Destruction of malignant cells by reactive free radicals has been widely used in cancer treatment. A key consideration is how to allow targeted free radical attack on cancer cells and avoid unwanted side-effects. Herein, we develop an efficient intracellular free radical generation strategy against cancer cells by delivering active ingredients into cancer cells, where free radicals are selectively generated by a lysosomal bioactivation process. Artesunate (ART), which is non-toxic to normal cells, was chosen as the free radical source and transported into cells with a hollow mesoporous silica-based delivery system (ART@HMS). To selectively activate the ART@HMS inside cancer cells, a high-bioactive Fe/O cluster-mesoporous silica nanosystem (Fe/O-MSN) was elaborately prepared. Under the bioactivation of the lysosome, the low-dose ART@HMS together with biocompatible Fe/O-MSN induced significant intracellular generation of toxic free radicals and efficient death of cancer cells. This selective intracellular free radical generation strategy is encouraging for its development into an effective low-cost cancer therapy.