Strong and Elastic Hydrogels from Dual-Crosslinked Composites Composed of Glycol Chitosan and Amino-Functionalized Bioactive Glass Nanoparticles.

Mesoporous bioactive glass (BG) nanoparticles (NPs) with a high specific surface area were prepared. The surfaces of BG NPs were further modified using an amino-containing compound or synthesized precursors to produce three kinds of amino-functionalized bioactive glass (ABG) NPs via devised synthetic routes. The achieved ABG NPs possessed various spacer lengths with free amino groups anchored at the end of the spacer. These ABG NPs were then combined with glycol chitosan (GCH) to construct single- or dual-crosslinked ABG/GCH composite hydrogels using genipin (GN) alone as a single crosslinker or a combination of GN and poly(ethylene glycol) diglycidyl ether (PEGDE) as dual crosslinkers. The spacer length of ABG NPs was found to impose significant effects on the strength and elasticity of GN-crosslinked ABG/GCH hydrogels. After being dually crosslinked with GN and PEGDE, the elastic modulus of some dual-crosslinked ABG/GCH hydrogels reached around 6.9 kPa or higher with their yielding strains larger than 60%, indicative of their strong and elastic features. The optimally achieved ABG/GCH hydrogels were injectable with tunable gelation time, and also able to support the growth of seeded MC3T3-E1 cells and specific matrix deposition. These results suggest that the dual-crosslinked ABG/GCH hydrogels have the potential for some applications in tissue engineering.

Strong and Elastic Chitosan/Silk Fibroin Hydrogels Incorporated with Growth-Factor-Loaded Microspheres for Cartilage Tissue Engineering.

An emulsification method was developed for fabricating core-shell microspheres with a thick shell layer. Kartogenin (KGN) and platelet-derived growth factor BB (PDGF-BB) were respectively loaded into the core portion and the shell layer of the microspheres with high loading efficiency. The optimally built microspheres were combined with chitosan (CH) and silk fibroin (SF) to construct a new type of composite hydrogel with enhanced strength and elasticity, using genipin or/and tyrosinase as crosslinkers for the intended use in cartilage tissue engineering. The composite hydrogels were found to be thermo-responsive at physiological temperature and pH with well-defined injectability. Rheological measurements revealed that they had an elastic modulus higher than 6 kPa with a high ratio of elastic modulus to viscous modulus, indicative of their mechanically strong features. Compressive measurements demonstrated that they possessed well-defined elasticity. In addition, some gels had the ability to administer the temporal separation release of PDGF-BB and KGN in an approximately linear manner for several weeks. The released PDGF-BB was found to be bioactive based on its effects on Balb/c 3T3 cells. The composite gels supported the growth of seeded chondrocytes while preserving their phenotype. The results suggest that these composite gels have the potential for endogenous cartilage repair.

Wideband chaotic tri-mode microlasers with optical feedback.

A tri-mode micro-square laser under optical feedback is proposed and demonstrated to generate chaos with the broadband flat microwave spectrum. By adjusting lasing mode intensities, frequency intervals, and optical feedback strength, we can enhance the chaotic bandwidth significantly. The existence of two mode-beating peaks makes the flat bandwidth much larger than the relaxation oscillation frequency. Effective bandwidth of 35.3 GHz is experimentally achieved with the flatness of 8.3 dB from the chaotic output spectrum of the tri-mode mode laser under optical feedback.

Activating Titanium Metal with H2 Plasma for the Hydrogen Evolution Reaction.

Developing a high-performance nonprecious metal electrocatalyst for water splitting is a strong demand for the large-scale application of electrochemical H2 production. In this work, we design a facile and scalable strategy to activate titanium metal for the hydrogen evolution reaction (HER) in alkaline media through incorporating hydrogen into the α-Ti crystal lattice by H2 plasma bombardment. Benefiting from the accelerated charge transfer and enlarged electrochemical surface area after H2 plasma treatment, the H-incorporated Ti shows remarkably enhanced HER activity with a much lower overpotential at -10 mA cm-2 by 276 mV when compared to the pristine Ti. It is revealed that the retention of the incorporated H(D) atoms in the Ti crystal lattice during HER accounts for the durable feature of the catalyst. Density functional theory calculations demonstrate the effectiveness of hydrogen incorporation in tuning the adsorption energy of reaction species via charge redistribution. Our work offers a novel route to activate titanium or other metals by H incorporation through a controllable H2 plasma treatment to tune the electronic structure for water splitting reactions.

Optical frequency comb and picosecond pulse generation based on a directly modulated microcavity laser.

Optical frequency comb (OFC) and picosecond pulse generation are demonstrated experimentally based on a directly modulated AlGaInAs/InP square microcavity laser. With the merit of a high electro-optics modulation response of the microcavity laser, power-efficient OFCs with good flatness are produced. Ten 8-GHz-spaced optical tones with power fluctuation less than 3 dB are obtained based on the laser modulated by a sinusoidal signal. Moreover, the comb line number is enhanced to 20 by eliminating the nonlinear dynamics through optical injection locking. Owing to the high coherence of the OFC originating from the directly modulated microcavity laser, a 6.8 ps transform-limited pulse is obtained through dispersion compensation. The optical pulse is further compressed to 1.3 ps through the self-phase modulation effect in high nonlinear fiber.

Liver kinase B1 inhibits smooth muscle calcification via high mobility group box 1.

Vascular calcification is a common pathological feature of atherosclerosis, chronic kidney disease, vascular injury, and aging. Liver kinase B1 (LKB1) plays pivotal roles in cellular processes such as apoptosis, metabolism, and cell cycle regulation. In addition, growing evidence has indicated that LKB1 functions as a tumor suppressor gene. However, its role in vascular calcification has not been reported. LKB1flox/flox mice were hybridized with SM22-CreERT2 transgenic mice and adult mice received tamoxifen to obtain smooth muscle-specific LKB1-knockout (LKB1SMKO) mice. LKB1 expression was decreased under calcifying conditions, and LKB1 overexpression had a protective effect on vascular calcification. However, high mobility group box 1 (HMGB1) overexpression partially counteracted the promotion of vascular calcification induced by LKB1 overexpression. Mechanically, LKB1 could bind to HMGB1 to promote HMGB1 degradation. Furthermore, LKB1SMKO mice showed intensified vascular calcification, which was alleviated by treatment with the HMGB1 inhibitor glycyrrhizic acid. Based on our results, LKB1 may inhibit vascular calcification via inhibiting HMGB1 expression.

Dual Network Hydrogels Incorporated with Bone Morphogenic Protein-7-Loaded Hyaluronic Acid Complex Nanoparticles for Inducing Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells.

Alginate-poloxamer (ALG-POL) copolymer with optimal POL content was synthesized, and it was combined with silk fibroin (SF) for building ALG-POL/SF dual network hydrogels. Hyaluronic acid(HA)/chitosan-poly(dioxanone)(CH-PDO) complex nanoparticles (NPs) with optimized composition and high encapsulation efficiency were employed as a vehicle for loading bone morphogenic protein-7 (BMP-7). BMP-7-loaded HA/CH-PDO NPs were incorporated into ALG-POL/SF hydrogel for constructing composite gels to achieve controlled release of BMP-7. These gels showed thermosensitive sol-gel transitions near physiological temperature and pH; and they were tested to be elastic, tough and strong. Some gels exhibited abilities to administer the BMP-7 release in nearly linear manners for a few weeks. Synovium-derived mesenchymal stem cells (SMSCs) were seeded into optimally fabricated gels for assessing their chondrogenic differentiation potency. Real-time PCR analyses showed that the blank ALG-POL/SF gels were not able to induce the chondrogenic differentiation of SMSCs, whereas SMSCs were detected to significantly express cartilage-related genes once they were seeded in the BMP-7-loaded ALG-POL/SF gel for two weeks. The synthesis of cartilaginous matrix components further confirmed that SMSCs seeded in the BMP-7-loaded ALG-POL/SF gel differentiated toward chondrogenesis. Results suggest that BMP-7-loaded ALG-POL/SF composite gels can function as a promising biomaterial for cartilage tissue engineering applications.

Controlled Delivery of Insulin-like Growth Factor-1 from Bioactive Glass-Incorporated Alginate-Poloxamer/Silk Fibroin Hydrogels.

Thermosensitive alginate-poloxamer (ALG-POL) copolymer with an optimal POL content was synthesized, and it was used to combine with silk fibroin (SF) for building ALG-POL/SF hydrogels with dual network structure. Mesoporous bioactive glass (BG) nanoparticles (NPs) with a high level of mesoporosity and large pore size were prepared and they were employed as a vehicle for loading insulin-like growth factor-1 (IGF-1). IGF-1-loaded BG NPs were embedded into ALG-POL/SF hydrogels to achieve the controlled delivery of IGF-1. The resulting IGF-1-loaded BG/ALG-POL/SF gels were found to be injectable with their sol-gel transition near physiological temperature and pH. Rheological measurements showed that BG/ALG-POL/SF gels had their elastic modulus higher than 5kPa with large ratio of elastic modulus to viscous modulus, indicative of their mechanically strong features. The dry BG/ALG-POL/SF gels were seen to be highly porous with well-interconnected pore characteristics. The gels loaded with varied amounts of IGF-1 showed abilities to administer IGF-1 release in approximately linear manners for a few weeks while effectively preserving the bioactivity of encapsulated IGF-1. Results suggest that such constructed BG/ALG-POL/SF gels can function as a promising injectable biomaterial for bone tissue engineering applications.

Wideband multiwavelength Brillouin fiber laser based on dual-mode AlGaInAs/InP microcavity lasers.

A multiwavelength Brillouin fiber laser (BFL) is demonstrated using a 1.55-µm AlGaInAs/InP microcavity laser as a seed source. The combination of a nonlinear fiber cavity and a feedback loop leads to multiwavelength generation with a channel spacing of double-Brillouin-frequency assisted by cavity-enhanced four-wave mixing. The amplified output of a dual-mode lasing square microcavity laser with a wavelength interval of 1.5 nm is applied as the pump source for the broadband multiwavelength generation. A wideband multiwavelength BFL covering from 1490 nm to 1590 nm is successfully generated at an optimized pump power of 25 dBm and a feedback power of -17.2dBm. The power stability of 0.82 dB over a 60 min duration of the multiwavelength BFL can satisfy the demands for the optical fiber sensing and microwave photonic systems.

Quantitative measurement of hydrogen isotopes in titanium using laser-induced breakdown spectroscopy.

Laser-induced breakdown spectroscopy (LIBS) has been considered a promising technology for nuclear safeguard inspection, especially for isotope content ratio determination, since it can be easily designed for portable, fast, and in situ measurement. However, it was a challenge to determine hydrogen isotopes in metal samples due to the unfavorable spectral interference, the poor calibration of the hydrogen content, and the small difference between the atomic emission intensity of hydrogen isotopes at around 656.28 nm. This paper presents the determination of hydrogen isotope contents ratio using LIBS under partially baseline-resolved conditions. The results show that by introducing a proper buffer atmosphere for the LIBS measurement, the resolution of the hydrogen and deuterium emissions could be improved, but still not enabled, by a baseline resolution with a moderate resolution spectrometer. However, with the method of integral intensity correction, the accurate quantitative measurement of hydrogen and deuterium contents in a metal matrix could be achieved. This work provided the possibilities for the further development of LIBS in hydrogen isotopes in in situ measurement for nuclear safeguards.

Lethal giant larvae 1 inhibits smooth muscle calcification via high mobility group box 1.

Vascular calcification is a pathological process closely related to atherosclerosis, diabetic vascular diseases, vascular injury, hypertension, chronic kidney disease and aging. Lethal giant larvae 1 (LGL1) is known as a key regulator of cell polarity and plays an important role in tumorigenesis. However, whether LGL1 regulates vascular calcification remains unclear. In this study, we generated smooth muscle-specific LGL1 knockout (LGL1SMKO) mice by cross-breeding LGL1flox/flox mice with α-SMA-Cre mice. LGL1 level was significantly decreased during calcifying conditions. Overexpression of LGL1 restrained high phosphate-induced calcification in vascular smooth muscle cells (VSMCs). Mechanically, LGL1 could bind with high mobility group box 1 (HMGB1) and promote its degradation via the lysosomal pathway, thereby inhibiting calcification. Smooth muscle-specific deletion of LGL1 increased HMGB1 level and aggravated vitamin D3-induced vascular calcification, which was attenuated by an HMGB1 inhibitor. LGL1 may inhibit vascular calcification by preventing osteogenic differentiation via promoting HMGB1 degradation.

Adipose HuR protects against diet-induced obesity and insulin resistance.

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. Obesity, as a worldwide healthcare problem, has attracted more and more attention. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL). HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.

Sequential Delivery of Dual Growth Factors from Injectable Chitosan-Based Composite Hydrogels.

Local administration of platelet-derived growth factor-BB (PGDF-BB) and bone morphogenetic protein-2 (BMP-2) in a sequential release manner could substantially promote bone healing. To achieve this goal, a delivery system that could sustain the release of PGDF-BB and BMP-2 by way of temporal separation was developed. One type of PGDF-BB-encapsulated alginate microsphere and another type of BMP-2-encapsulated microsphere with a core-shell structure were respectively produced using emulsification methods. These two types of microspheres were then embedded into chitosan/glycerophosphate hydrogel for constructing composite gels. Some of them were found to be injectable at ambient temperature and had thermo-sensitive features near physiological temperature and pH. The optimally formulated composite gels showed the ability to control the release of PGDF-BB and BMP-2 in a sequential fashion in which PDGF-BB was released earlier than BMP-2. In vitro release patterns indicated that the release rates could be significantly regulated by varying the embedded amount of the factor-encapsulated microspheres, which can in turn mediate the temporal separation release interval between PGDF-BB and BMP-2. The released PDGF-BB and BMP-2 were detected to be bioactive based on their respective effects on Balb/c 3T3 and C2C12 cells. These results suggest that the presently developed composite gels have the potential for bone repair by synergistically utilizing the early chemotactic effect of PDGF-BB and the subsequent osteogenic and angiogenic functions of PDGF-BB and BMP-2.

Chitosan-Based Hydrogels Embedded with Hyaluronic Acid Complex Nanoparticles for Controlled Delivery of Bone Morphogenetic Protein-2.

Chitosan(CH)-poly(dioxanone) (CH-PDO) copolymers containing varied amounts of PDO and having free amino groups at their CH backbone were synthesized using a group protection method. The selected CH-PDO with soluble characteristics in aqueous media was used together with hyaluronic acid (HA) to prepare HA/CH-PDO polyelectrolyte complex nanoparticles (NPs) via an ionotropic gelation technique, and such a type of HA/CH-PDO NPs was employed as a carrier for delivering bone morphogenetic protein-2 (BMP-2). The optimal BMP-2-encapsulated HA/CH-PDO NPs with high encapsulation efficiency were embedded into CH/glycerophosphate composite solutions to form different hydrogels in order to achieve long-term BMP-2 release. The formulated gels were found to be injectable at room temperature and had its thermosensitive phase transition near physiological temperature and pH. They also showed abilities to administer the release of BMP-2 in approximately linear manners for a few weeks while effectively preserving the bioactivity of the encapsulated BMP-2. In view of their fully biocompatible and biodegradable components, the presently developed gel systems have promising potential for translation to the clinic use in bone repair and regeneration where the sustained and controlled stimuli from active signaling molecules and the stable biomechanical framework for housing the recruited cells are often concurrently needed.

Smooth muscle-specific LKB1 deletion exaggerates angiotensin II-induced abdominal aortic aneurysm in mice.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. However, the role of LKB1 in the development of AAA has not been explored. In this study, mice with knockout of smooth muscle-specific LKB1 (LKB1SMKO) were generated by cross-breeding LKB1flox/flox mice with SM22-CreERT2 transgenic mice and induced in adult mice by tamoxifen treatment. LKB1 deficiency increased the expression of matrix metalloproteinase 2 (MMP-2), which was inhibited by LKB1 overexpression. Mechanistically, LKB1 could bind to the MMP-2 transcription factor, specificity protein 1 (Sp1), thereby reducing the binding of Sp1 to the MMP-2 promoter to inhibit MMP-2 expression. LKB1 expression was significantly reduced in abdominal aortas of the mouse AAA model. Moreover, smooth muscle-specific LKB1 deletion exaggerated angiotensin II-induced AAA formation accompanied by increased AAA incidence and aortic expansion. Finally, LKB1 level was significantly lower and MMP-2 level higher in human AAA samples than adjacent nonaneurysmal aortic sections. Thus, these results suggest that LKB1 may play a protective role in AAA formation by inhibiting MMP-2 expression and could be a potential therapeutic target for AAA disease.

Chitosan-Polylactide/Hyaluronic Acid Complex Microspheres as Carriers for Controlled Release of Bioactive Transforming Growth Factor-ß1.

Chitosan(CH)-polylactide(PLA) copolymers containing varied PLA percentages were synthesized using a group-protection method and one of them with solubility in water-based solvents was used to prepare CH-PLA/hyaluronic acid (HA) complex microspheres for the delivery of transforming growth factor-ß1 (TGF-ß1). An emulsification processing method was developed for producing TGF-ß1-loaded CH-PLA/HA microspheres using sodium tripolyphosphate (TPP) as ionic crosslinker and the size of the microspheres was devised to the micron level in order to achieve high encapsulating efficiency. The encapsulating efficiency, swelling property and release administration of the microspheres could be synergistically regulated by PLA component, the applied TPP dose and the incorporated HA amount. In comparison to CH/HA microspheres, the CH-PLA/HA microspheres had greatly reduced TGF-ß1 release rates and were able to administrate the TGF-ß1 release at controlled rates over a significant longer period of time. The released TGF-ß1 was detected to be bioactive when compared to the free TGF-ß1. These results suggest that the presently developed CH-PLA/HA complex microspheres have promising potential in delivering TGF-ß1 for cartilage repair applications where the applied TGF-ß1 amount in the early stage needs to be low whilst the sustained TGF-ß1 release at an appropriate dose in the later stage has to be maintained.

Low-phase-noise microwave generation using dual-mode microsquare laser phase locking by modulated sidebands.

An effective method for millimeter-wave (mmW) carrier generation from a dual-transverse-mode microsquare laser is experimentally demonstrated. By directly modulating the dual-mode microsquare laser at 6.7 GHz, multiple sidebands are generated due to enhanced modulation nonlinearity, and the lasing modes with an interval of 40 GHz are phase-locked. MmW carriers up to 47 GHz, corresponding to seven times that of the modulation frequency, are achieved with a linewidth below 10 Hz. The single-sideband phase noises of the signals keep the same level after transmission over 2.5 km of optical fiber.

Stability and anti-tumor effect of oncolytic herpes simplex virus type 2.

Oncolytic virotherapy is a new therapeutic strategy based on the inherent cytotoxicity of viruses and their ability to replicate and spread in tumors in a selective manner. We constructed a new type of oncolytic herpes simplex virus type 2 (oHSV-2, named OH2) to treat human cancers, but a systematic evaluation of the stability and oncolytic ability of this virus is lacking. In this study, we evaluated its physical stability, gene modification stability and biological characteristics stability, including its anti-tumor activity in an animal model. The physical characteristics as well as genetic deletions and insertions in OH2 were stable, and the anti-tumor activity remained stable even after passage of the virus for more than 20 generations. In conclusion, OH2 is a virus that has stable structural and biological traits. Furthermore, OH2 is a potent oncolytic agent against tumor cells.