Tough Magnetic Chitosan Hydrogel Nanocomposites for Remotely Stimulated Drug Release.

As one of important biomaterials for localized drug delivery system, chitosan hydrogel still suffer several challenges, including poor mechanical properties, passive drug release behavior and lack of remote stimuli response. To address these challenges, a facile in situ hybridization method was reported for fabricate tough magnetic chitosan hydrogel (MCH), which remotely switched drug release from passive release to pulsatile release under a low frequency alternating magnetic field (LAMF). The in situ hybridization method avoided the aggregation of magnetic nanoparticles (MNPs) in hydrogel, which simultaneously brings 416% and 265% increase in strength and elastic modulus, respectively. The mechanical property enhancement was contributed by the physical crosslinking of in situ synthesized MNPs. When a LAMF with 15 min ON-15 min OFF cycles was applied to MCH, the fraction release showed zigzag shape and pulsatile release behavior with quick response. The cumulative release and fraction release of drug from MCH were improved by 67.2% and 31.9%, respectively. MTT results and cell morphology indicated that the MCH have excellent biocompatibility and no acute adverse effect on MG-63 cells. The developed tough MCH system holds great potential for applications in smart drug release system with noninvasive characteristics and magnetic field stimulated drug release behavior.

Osseointegration of bioactive microarc oxidized amorphous phase/TiO2 nanocrystals composited coatings on titanium after implantation into rabbit tibia.

The amorphous phase/TiO2 nanocrystals (APTN) composited coatings were prepared on Ti implants for biomedical applications. The Ti implants without and with the APTN composited coatings both do not cause any adverse effects after implantation into the rabbit tibia. The osseointegration of Ti implants after covering the APTN coatings is improved pronouncedly, greatly increasing the interface bonding strength between the implants and newly formed bones. In addition, it is interesting that the newly formed bone tissues appear in the micro-pores of the APTN coatings, promoting the interface bonding between the implants and new bones by the mechanical interlock. Moreover, the Ti implant with the APTN coatings formed at higher applied voltage exhibit higher shear strength and displacement during the pushing out experiment probably due to its better osseointegration.

Surface configuration of microarc oxidized Ti with regionally loaded chitosan hydrogel containing ciprofloxacin for improving biological performance.

The bacterial colonization and poor osseointegration of Ti implants significantly compromise their applications in load-bearing bone repair and replacement. To endorse the Ti with both excellent bioactivity and antibacterial ability, we developed a microarc oxidation coating that was modified uniformly by hydroxyapatite (HA) nanodots arrays and loaded regionally with chitosan hydrogel containing ciprofloxacin. The bonding between the HA nanodots covered coating and the chitosan hydrogel is further enhanced via silanization and chemical grafting of glutaraldehyde. Benefiting from the regionally loaded structure of the chitosan hydrogel, the chitosan hydrogel unloaded area can promote the cell adhesion and proliferation with excellent bioactivity, though relatively low OD value of cck8 has been observed at the beginning of the cell culturing. Whereas, the OD value of cck8 rises with the prolongation of the cell culturing time due to the degradation of the regionally loaded chitosan hydrogel. With the help of the laden ciprofloxacin in chitosan hydrogels, the sample effectively sterilizes the bacterial with a bacteriostatic ring. Therefore, regional loading of chitosan hydrogel containing ciprofloxacin on the modified microarc oxidation coating is a good approach to endorse Ti with both excellent bioactivity and antibacterial ability.

Facilitating Uniform Large-Scale MoS2, WS2 Monolayers, and Their Heterostructures through van der Waals Epitaxy.

The fabrication process for the uniform large-scale MoS2, WS2 transition-metal dichalcogenides (TMDCs) monolayers, and their heterostructures has been developed by van der Waals epitaxy (VdWE) through the reaction of MoCl5 or WCl6 precursors and the reactive gas H2S to form MoS2 or WS2 monolayers, respectively. The heterostructures of MoS2/WS2 or WS2/MoS2 can be easily achieved by changing the precursor from WCl6 to MoCl5 once the WS2 monolayer has been fabricated or switching the precursor from MoCl5 to WCl6 after the MoS2 monolayer has been deposited on the substrate. These VdWE-grown MoS2, WS2 monolayers, and their heterostructures have been successfully deposited on Si wafers with 300 nm SiO2 coating (300 nm SiO2/Si), quartz glass, fused silica, and sapphire substrates using the protocol that we have developed. We have characterized these TMDCs materials with a range of tools/techniques including scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), micro-Raman analysis, photoluminescence (PL), atomic force microscopy (AFM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), and selected-area electron diffraction (SAED). The band alignment and large-scale uniformity of MoS2/WS2 heterostructures have also been evaluated with PL spectroscopy. This process and resulting large-scale MoS2, WS2 monolayers, and their heterostructures have demonstrated promising solutions for the applications in next-generation nanoelectronics, nanophotonics, and quantum technology.

Sugar-Derived Isotropic Nanoscale Polycrystalline Graphite Capable of Considerable Plastic Deformation.

Obtaining large plastic deformation in polycrystalline van der Waals (vdW) materials is challenging. Achieving such deformation is especially difficult in graphite because it is highly anisotropic. The development of sugar-derived isotropic nanostructured polycrystalline graphite (SINPG) is discussed herein. The structure of this material preserves the high in-plane rigidity and out-of-plane flexibility of graphene layers and enables prominent plasticity by activating the rotation of nanoscale (5-10 nm) grains. Thus, micrometer-sized SINPG samples demonstrate enhanced compressive strengths of up to 3.0 GPa and plastic strains of 30-50%. These findings suggest a new pathway for enabling plastic deformation in otherwise brittle vdW materials. This new class of nanostructured carbon materials is suitable for use in a broad range of fields, from semiconductor to aerospace applications.

Rapid structural regulation, apatite-inducing mechanism and in vivo investigation of microwave-assisted hydrothermally treated titania coating.

Owing to the poor bioactivity of microarc oxidation (MAO) coating and the rapid activation ability of the microwave hydrothermal (MH) technique, MH treatment was applied to optimize the in vivo interface status between MAO-treated titanium and bone. In this study, consequently, new outermost layers were prepared using hydroxyapatite (HA) nanorods, HA submicron pillars or sodium titanate nanosheets. The results revealed that the NaOH concentration significantly influenced the surface structure and phase constitution of the MAO samples. Moreover, on enhancing the NaOH concentration, the number of HA phases was decreased. Further, the influence of the NaOH concentration on the interfacial bonding strength was insignificant for concentrations ≤0.5 mol L-1. Transmission electron microscopy (TEM) analysis showed that the induction of apatite was accompanied by the dissolution of the HA crystals and there was excellent crystallographic matching with the HA crystals. The in vitro and in vivo analyses revealed that the MH-treated MAO sample with the HA nanorods possessed superior apatite-formation ability and osseointegration, including a small amount of soft tissue and optimal bone-implant interfacial bonding force, thus signifying strong potential for the optimization of the bone-implant interfacial status.

Comparative investigations of in vitro and in vivo bioactivity of titanium vs. Ti-24Nb-4Zr-8Sn alloy before and after sandblasting and acid etching.

To avoid the failure of clinical surgery due to "stress shielding" and the loosening of an implant, a new type of alloy, Ti-24Nb-4Zr-8Sn (TNZS), with a low Young's modulus acted as a new implant material in this work. Meanwhile, the surface characteristics, MC3T3-E1 cell behavior and in vivo osseointegration of the titanium and TNZS before and after sandblasting and acid etching were studied comparatively. TNZS and Ti had the same microstructure based on the transmission electron microscopy results. Meanwhile, the TNZS alloy had a lower Young's modulus and surface nanohardness compared with pure titanium. However, the corrosion resistance of Ti was better than that of the TNZS sample in simulated body fluid solution. In addition, the TNZS alloy after sandblasting and acid etching (SLATNZS) had excellent cell adhesion, proliferation, differentiation, ALP activity and in vivo osseointegration ability such as there being almost no soft tissue as compared with other implants. Based on the current results, the new type of Ti-24Nb-4Zr-8Sn alloy showed good potential and promising application prospects in its biochemical aspects.

Tanshinone IIA promotes osteogenic differentiation of human periodontal ligament stem cells via ERK1/2-dependent Runx2 induction.

Mesenchymal stem cells (MSCs) of the dental or craniofacial origin include Human periodontal ligament stem cells (hPDLSCs), which are able to readily differentiate into osteoblasts. Tanshinone IIA (TSA) is a diterpene quinone compound that is derived from Danshen (also known as Salvia miltiorrhiza) used frequently in the context of traditional Chinese medicine (TCM). This study sought to assess how TSA affects the osteogenic differentiation of hPDLSCs. We found that TSA promotes both this differentiation and hPDLSC maturation. This was dependent on TSA-mediated activation of the ERK1/2 signaling pathway, and ERK1/2 inhibition disrupted TSA-induced Runx2 expression. From these results, we conclude that TSA can induce hPDLSC osteogenesis through the ERK1/2-Runx2 axis, suggesting that TSA is a viable therapeutic option for regenerative medical approaches aimed at the treatment of periodontitis.

Rapid Fabrication, Microstructure, and in Vitro and in Vivo Investigations of a High-Performance Multilayer Coating with External, Flexible, and Silicon-Doped Hydroxyapatite Nanorods on Titanium.

A high-performance multilayer coating with external, flexible, and silicon-doped hydroxyapatite (Si-HA) nanorods was designed using bionics. Plasma electrolytic oxidation (PEO) and the microwave hydrothermal (MH) method were used to rapidly deposit this multilayer coating on a titanium (Ti) substrate, applied for 5 and 10 min, respectively. The bioactive multilayer coating was composed of four layers, and the outermost layer was an external growth layer that consisted of many Si-HA nanorods with a single-crystal structure. The Si-HA nanorods exhibited good flexibility, likely because of their complete single-crystal structures, smooth surfaces, and suitable diameters and lengths. This multilayer coating with a high surface energy was superhydrophilic and exhibited good in vitro bioactivities, such as good apatite formation ability, good cell spreading, and high osteogenic gene expression levels. After implantation in the tibia of rabbits for 16 weeks, almost no soft tissues were formed at the MH treated PEO implant-bone interface. A direct bone contact interface was formed by a bridging effect of the flexible Si-HA nanorods, which further produced a high implant-bone interface bonding strength. The current results demonstrated that the bioactive multilayer layers with the flexible Si-HA nanorods displayed a very good osseointegration ability, showing promising applications in the biomedical field.

The effect of applied voltages on the structure, apatite-inducing ability and antibacterial ability of micro arc oxidation coating formed on titanium surface.

The micro arc oxidation (MAO) coatings with different concentrations of Ca, P and Zn elements are successfully formed on the titanium substrate at the different applied voltages. After MAO treatment, the MAO coating exhibits the porous surface structure and composed of anatase and rutile TiO2 phases. Meanwhile, the average size and density of micro-pores on the MAO coatings have been modified via the adjusting the applied voltages. In addition, the contents of the incorporated elements such as Zn, Ca and P elements in the MAO coatings have been optimized. The bonding strength test results reveal that the MAO coating shows higher bonding strength, which is up to 45 ±â€¯5 MPa. Compared to the pure Ti plate, the MAO coating formed at 350 and 400 V show good apatite-inducing ability. Meanwhile, the MAO coating containing Zn, Ca and P elements have better antibacterial ability for E.coli and S.aureus. Thus, the incorporation of Zn, Ca and P elements was an effective method to improve the antibacterial ability. Moreover, the concentrations of Zn, Ca and P elements could be adjusted with the changing of the applied voltages. As a result, the enhancement of the antibacterial ability on the MAO coating surfaces was depended on the comprehensive effect of the incorporated elements and the surface property of MAO coatings.

Characteristic and in vitro bioactivity of a microarc-oxidized TiO(2)-based coating after chemical treatment.

Microarc oxidation (MAO) was used to prepare a TiO(2)-based coating containing Ca and P on titanium alloy. An alkali treatment was developed to modify the surface of the MAO coating to improve the apatite-forming ability of the coating. The chemically treated MAO coating exhibits a modified layer, with the main constituents being O, Ti, Ca and Na, showing anatase. The modified MAO coating shows a rough and porous morphology containing numerous nanoflakes of approximately 100nm thickness. During the alkali treatment process, P on the surface of the MAO coating shows a main dynamic process of dissolution; however, Ca exhibits a re-deposition process as well as dissolution. The formation of the modified layer could be explained by this mechanism: negatively charged HTiO(3)(-) ions are formed on the MAO coating due to the attack of OH(-) ions on the TiO(2) phase. The HTiO(3)(-) ions could incorporate sodium from the alkali solution and calcium from the alkali solution and MAO coating. The apatite-forming ability of the MAO coating is improved remarkably by the simple chemical treatment, since the surface of the alkali-treated MAO coating could provide abundant Ti-OH groups probably formed by ionic exchanges between (Ca2+, Na+) ions of the alkali-treated MAO coating and H3O+ ions of a simulated body fluid (SBF). Moreover, Ca released from the alkali-treated MAO coating increases the degree of supersaturation of SBF, promoting the formation of apatite. The apatite induced by the alkali-treated MAO coating possesses carbonated structure and pore networks on the nanometer scale.

UV-crosslinkable and thermo-responsive chitosan hybrid hydrogel for NIR-triggered localized on-demand drug delivery.

Innovative drug delivery technologies based on smart hydrogels for localized on-demand drug delivery had aroused great interest. To acquire smart UV-crosslinkable chitosan hydrogel for NIR-triggered localized on-demanded drug release, a novel UV-crosslinkable and thermo-responsive chitosan was first designed and synthesized by grafting with poly N-isopropylacrylamide, acetylation of methacryloyl groups and embedding with photothermal carbon. The UV-crosslinkable unit (methacryloyl groups) endowed chitosan with gelation via UV irradiation. The thermo-responsive unit (poly N-isopropylacrylamide) endowed chitosan hydrogel with temperature-triggered volume shrinkage and reversible swelling/de-swelling behavior. The chitosan hybrid hydrogel embedded with photothermal carbon exhibited distinct NIR-triggered volume shrinkage (∼42% shrinkage) in response to temperature elevation as induced by NIR laser irradiation. As a demonstration, doxorubicin release rate was accelerated and approximately 40 times higher than that from non-irradiated hydrogels. The UV-crosslinkable and thermal-responsive hybrid hydrogel served as in situ forming hydrogel-based drug depot is developed for NIR-triggered localized on-demand release.

Microarc oxidation coating covered Ti implants with micro-scale gouges formed by a multi-step treatment for improving osseointegration.

The sub-microporous microarc oxidation (MAO) coating covered Ti implant with micro-scale gouges has been fabricated via a multi-step MAO process to overcome the compromised bone-implant integration. The as-prepared implant has been further mediated by post-heat treatment to compare the effects of -OH functional group and the nano-scale orange peel-like morphology on osseointegration. The bone regeneration, bone-implant contact interface, and biomechanical push-out force of the modified Ti implant have been discussed thoroughly in this work. The greatly improved push-out force for the MAO coated Ti implants with micro-scale gouges could be attributed to the excellent mechanical interlocking effect between implants and biologically meshed bone tissues. Attributed to the -OH functional group which promotes synostosis between the biologically meshed bone and the gouge surface of implant, the multi-step MAO process could be an effective strategy to improve the osseointegration of Ti implant.

Visual in vivo degradation of injectable hydrogel by real-time and non-invasive tracking using carbon nanodots as fluorescent indicator.

Visual in vivo degradation of hydrogel by fluorescence-related tracking and monitoring is crucial for quantitatively depicting the degradation profile of hydrogel in a real-time and non-invasive manner. However, the commonly used fluorescent imaging usually encounters limitations, such as intrinsic photobleaching of organic fluorophores and uncertain perturbation of degradation induced by the change in molecular structure of hydrogel. To address these problems, we employed photoluminescent carbon nanodots (CNDs) with low photobleaching, red emission and good biocompatibility as fluorescent indicator for real-time and non-invasive visual in vitro/in vivo degradation of injectable hydrogels that are mixed with CNDs. The in vitro/in vivo toxicity results suggested that CNDs were nontoxic. The embedded CNDs in hydrogels did not diffuse outside in the absence of hydrogel degradation. We had acquired similar degradation kinetics (PBS-Enzyme) between gravimetric and visual determination, and established mathematical equation to quantitatively depict in vitro degradation profile of hydrogels for the predication of in vivo hydrogel degradation. Based on the in vitro data, we developed a visual platform that could quantitatively depict in vivo degradation behavior of new injectable biomaterials by real-time and non-invasive fluorescence tracking. This fluorescence-related visual imaging methodology could be applied to subcutaneous degradation of injectable hydrogel with down to 7 mm depth in small animal trials so far. This fluorescence-related visual imaging methodology holds great potentials for rational design and convenient in vivo screening of biocompatible and biodegradable injectable hydrogels in tissue engineering.

Ultrahigh-yield synthesis of N-doped carbon nanodots that down-regulate ROS in zebrafish.

Oxidative damage induced by accumulation of excessive reactive oxygen species (ROS) could result in increased chronic inflammation and thus ageing and age-related diseases. Carbonaceous nanodrugs hold great promise for ameliorating age-related diseases, and it is necessary to develop ultrahigh-yield synthesis of such nanodrugs. To improve the synthetic yield (less than 50%) of carbon nanodots (CNDs), the general choice is to screen precursors. However, no reliable concept for improving the yield has been explored over the past few decades. We are the first to propose the concept of using carbon-carbon double bonds to boost the synthetic yield and demonstrate record breaking ultrahigh-yield (85.9%) synthesis of N-doped CNDs. When the C[double bond, length as m-dash]C content increased from 14 to 56 mmol, the synthetic yield exhibited a 3.3-fold increase. Nitrogen elements are doped as pyridinic-like N and NH2, where conjugated π-systems as electron donors and pyridinic-like structures would benefit the potential down-regulated effect for ROS. N-doped CNDs exhibit an outstanding protective effect against oxidative stress via inhibiting exogenous and endogenous ROS generation, where the ROS in zebrafish are significantly reduced by 68%. Hence the concept of carbon-carbon double bond-boosted ultrahigh-yield synthesis of N-doped CNDs provides a promising strategy to be employed for carbonaceous nanodrugs aiming at preventing and curing ageing and age-related diseases.

High-yield synthesis of strong photoluminescent N-doped carbon nanodots derived from hydrosoluble chitosan for mercury ion sensing via smartphone APP.

Photoluminescent carbon nanodots (CNDs) have offered considerable potential to be used in biomedical and environmental fields including live cell imaging and heavy metal ion detection due to their superior quantum emission efficiencies, ability to be functionalized using a variety of chemistries and apparent absence of toxicity. However, to date, synthetic yield of CNDs derived from biomass via hydrothermal carbonization is quite low. We report here the synthesis of nitrogen-doped carbon nanodots (N-doped CNDs) derived from hydrosoluble chitosan via hydrothermal carbonization. The synthetic yield could reach 38.4% which is 2.2-320 times increase compared with that from other biomass reported so far. These N-doped CNDs exhibited a high quantum yield (31.8%) as a consequence of nitrogen incorporation coincident with multiple types of functional groups (C=O, O-H, COOH, and NH2). We further demonstrate applications of N-doped CNDs as probes for live cell multicolor imaging and heavy metal ion detection. The N-doped CNDs offered potential as mercury ion sensors with detection limit of 80nM. A smartphone application (APP) based on N-doped CNDs was developed for the first time providing a portable and low cost detection platform for detection of Hg(2+) and alert of heavy metal ions contamination.

Synergistic effects of surface chemistry and topologic structure from modified microarc oxidation coatings on Ti implants for improving osseointegration.

Microarc oxidation (MAO) coating containing Ca, P, Si, and Na elements on a titanium (Ti) implant has been steam-hydrothermally treated and further mediated by post-heat treatment to overcome the compromised bone-implant integration. The bone regeneration, bone-implant contact, and biomechanical push-out force of the modified Ti implants are discussed thoroughly in this work. The best in vivo performances for the steam-hydrothermally treated one is attributed to the synergistic effects of surface chemistry and topologic structure. Through post-heat treatment, we can decouple the effects of surface chemistry and the nanoscale topologic structure easily. Attributed to the excellent in vivo performance of the surface-modified Ti implant, the steam-hydrothermal treatment could be a promising strategy to improve the osseointegration of the MAO coating covered Ti implant.

Hydrosoluble, UV-crosslinkable and injectable chitosan for patterned cell-laden microgel and rapid transdermal curing hydrogel in vivo.

Natural and biodegradable chitosan with unique amino groups has found widespread applications in tissue engineering and drug delivery. However, its applications have been limited by the poor solubility of native chitosan in neutral pH solution, which subsequently fails to achieve cell-laden hydrogel at physiological pH. To address this, we incorporated UV crosslinking ability in chitosan, allowing fabrication of patterned cell-laden and rapid transdermal curing hydrogel in vivo. The hydrosoluble, UV crosslinkable and injectable N-methacryloyl chitosan (N-MAC) was synthesized via single-step chemoselective N-acylation reaction, which simultaneously endowed chitosan with well solubility in neutral pH solution, UV crosslinkable ability and injectability. The solubility of N-MAC in neutral pH solution increased 2.21-fold with substitution degree increasing from 10.9% to 28.4%. The N-MAC allowed fabrication of cell-laden microgels with on-demand patterns via photolithography, and the cell viability in N-MAC hydrogel maintained 96.3 ± 1.3% N-MAC allowed rapid transdermal curing hydrogel in vivo within 60s through minimally invasive clinical surgery. Histological analysis revealed that low-dose UV irradiation hardly induced skin injury and acute inflammatory response disappeared after 7 days. N-MAC would allow rapid, robust and cost-effective fabrication of patterned cell-laden polysaccharide microgels with unique amino groups serving as building blocks for tissue engineering and rapid transdermal curing hydrogel in vivo for localized and sustained protein delivery.

The effect of NaOH concentration on the steam-hydrothermally treated bioactive microarc oxidation coatings containing Ca, P, Si and Na on pure Ti surface.

The microarc oxidation (MAO) coating covered pure Ti plates are steam-hydrothermally treated in autoclaves containing NaOH solutions with different concentrations of 0, 0.001, 0.01, 0.1 and 1mol·L(-1). Due to the composition of Ti, O, Ca, P, Si and Na elements in the MAO coating, anatase and hydroxyapatite (HA) crystals are generated from the previously amorphous MAO coating after the steam-hydrothermal treatment. Meanwhile, it is noticed that the amount of HA crystals increases but showing a decline trend in aspect ratio in morphologies with the increasing of NaOH concentration. Interestingly, the steam-hydrothermally treated MAO coatings exhibit better bonding strength with Ti substrate (up to 43.8±1.1MPa) than that of the untreated one (20.1±3.1MPa). In addition, benefiting from the corrosive attack of the dissolved NaOH in water vapor on the MAO coating, Ti-OH is also formed on the steam-hydrothermally treated MAO coating surface, which can trigger apatite nucleation. Thus, the steam-hydrothermally treated MAO coatings exhibit good apatite-inducing ability.

Structure, MC3T3-E1 cell response, and osseointegration of macroporous titanium implants covered by a bioactive microarc oxidation coating with microporous structure.

Macroporous Ti with macropores of 50-400 µm size is prepared by sintering Ti microbeads with different diameters of 100, 200, 400, and 600 µm. Bioactive microarc oxidation (MAO) coatings with micropores of 2-5 µm size are prepared on the macroporous Ti. The MAO coatings are composed of a few TiO2 nanocrystals and lots of amorphous phases with Si, Ca, Ti, Na, and O elements. Compared to compact Ti, the MC3T3-E1 cell attachment is prolonged on macroporous Ti without and with MAO coatings; however, the cell proliferation number increases. These results are contributed to the effects of the space structure of macroporous Ti and the surface chemical feature and element dissolution of the MAO coatings during the cell culture. Macroporous Ti both without and with MAO coatings does not cause any adverse effects in vivo. The new bone grows well into the macropores and micropores of macroporous Ti with MAO coatings, showing good mechanical properties in vivo compared to Ti, MAO-treated Ti, and macroporous Ti because of its excellent osseointegration. Moreover, the MAO coatings not only show a high interface bonding strength with new bones but also connect well with macroporous Ti. Furthermore, the pushing out force for macroporous Ti with MAO coatings increases significantly with increasing microbead diameter.