Recent advances on thermosensitive hydrogels-mediated precision therapy

Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites,increased therapeutic efficacy,and reduced adverse effects.Over the past few years,sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential.These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature.Inspired by their unique properties,thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine.In this review,the state-of-theart developments in thermosensitive hydrogels for precision therapy are investigated,which covers from the thermo-gelling mechanisms and main components to biomedical applications,including wound healing,anti-tumor activity,osteogenesis,and periodontal,sinonasal and ophthalmic diseases.The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.

Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.

Synergistic chemotherapy/PTT/oxygen enrichment by multifunctional liposomal polydopamine nanoparticles for rheumatoid arthritis treatment

Amultifunctional liposomal polydopamine nanoparticle(MPM@Lipo)was designed in this study,to combine chemotherapy,photothermal therapy(PTT)and oxygen enrichment to clear hyperproliferating inflammatory cells and improve the hypoxic microenvironment for rheumatoid arthritis(RA)treatment.MPM@Lipo significantly scavenged intracellular reactive oxygen species and relieved joint hypoxia,thus contributing to the repolarization of M1 macrophages into M2 phenotype.Furthermore,MPM@Lipo could accumulate at inflammatory joints,inhibit the production of inflammatory factors,and protect cartilage in vivo,effectively alleviating RA progression in a rat adjuvant-induced arthritis model.Moreover,upon laser irradiation,MPM@Lipo can elevate the temperature to not only significantly obliterate excessively proliferating inflammatory cells but also accelerate the production of methotrexate and oxygen,resulting in excellent RA treatment effects.Overall,the use of synergistic chemotherapy/PTT/oxygen enrichment therapy to treat RA is a powerful potential strategy.

Thermosensitive and Wound-Healing Gelatin-Alginate Biopolymer Hydrogels Modified with Humic Acids

The main goal of the article is the creation and study of thermosensitive and wound-healing gelatin-alginate bio-polymer hydrogels modified with humic acids.Their rheological properties,swelling and contraction behavior were experimentally investigated,elucidated using Fourier transform infrared spectroscopy and used to achieve the physiological melting point,which is necessary for successful drug delivery.It has been shown that in the gelatin-alginate-humic acid biopolymer hydrogels systems,it is possible to obtain a gel-sol transition temperature close to the physiological temperature of 37°C,which is important for drug delivery in the treatment of wounds.By changing the type and concentration of humic acids in the gelatin-alginate hydrogel,it turned out to be achiev-able to regulate the softening time of the gel on the human body in the range from 6 to 20 min,which provides the possibility of controlled prolonged delivery of drugs.Based on the study of the influence of calcium ions on the properties of humic acids and ion exchange,as well as the interaction of humic acids,sodium alginate and gelatin with the formation of tighter gel networks,approaches to regulate the rate of softening of hydrogels at physiological temperature and their swelling,which simulates the absorption of exudate,were proposed and implemented.In addition,low shrinkage of the hydrogel surface due to cross-linking of gelatin-alginate networks when modified with humic acids was experimentally confirmed,which is important for avoiding problems of wound contracture and contour deformations when using dressings for wound healing.Thus,the developed opti-mized innovative biopolymer hydrogels synergistically combine the outstanding properties of natural molecular polymers and humic acids and are promising for the creation of effective medicines for wound healing.

Isolation and Progeny Transmission of Non-Temperature-Sensitive MS-H Vaccine Strains of Mycoplasma synoviae from Temperature-Sensitive MS-H-Vaccinated Laying Breeder Hens

This pilot study reports the vertical transmission and reverse thermosensitivity of the MS-H vaccine strain of Mycoplasma synoviae (MS) by RAPD in commercial breeders and their progeny. At two weeks of age, breeders were vaccinated with the ts+ MS-H strain. At 9 weeks of age, an outbreak of infectious synovitis (IS) was detected in the progeny. Tracheal swab samples were collected from breeders at 24, 39, 48, and 70 weeks of age. At 9 weeks, pullets swab from the elbow joints were collected. RAPD was performed on the isolates at 39.5°C, and the same ts- MS-H strains were identified in the breeder hens and their progeny. Tracheal swabs from breeder hens were negative to MS isolation at 37°C and 39.5°C at 24- and 39-weeks. MS isolation was recovered from tracheal swabs from 9/10 and 10/10 breeders at 48- and 70- week. At 9 weeks of age in the progeny, MS was isolated from tracheal swabs of 10/10 from non-IS pullets. MS was isolated from 9/10 joints samples. The isolates from breeder hens and their progeny showed non-significant differences in five antimycoplasmic MIC100 values;otherwise, enrofloxacin presented a significant difference in MIC100 value (p < 0.05). This investigation demonstrated the reversal of the thermosensitivity, pathogenicity, and vertical transmission of the MS-H strain. Consequently, it is crucial to contemplate the danger of reversing pathogenicity and transmission to progeny when applying the MS-H vaccine strain.

Rapid Constructing a Genetic Linkage Map by AFLP Technique and Mapping a New Gene tms5

In this study, we reported the repaid construction of a molecular marker linkage map of rice (Oryza sativa L.). An F-2 population from the cross between Annong S-1 and Nanjing 11 was used to construct a genetic linkage map of rice. Total of 142 newly screened AFLP markers and 30 anchor markers (25 SSR markers and 5 RFLP markers) were mapped on the 12 chromosomes covering 1537.4 cM of rice genome. The average interval between these markers was 9.0 cM. The total work which usually was finished in more than one year was finished within only 3 months by one person. This is the first plant AFLP map developed in China. A new thermosensitive genic male sterile gene in rice, tms5, was Egged and mapped onto chromosome 2 during the development of the linkage map.

Preparation and evaluation of ophthalmic thermosensitive in situ gels of penciclovir

Aim To develop pluronic F127 （PF127） based formulations of penciclovir （PCV） aimed at enhancing its ocular bioavailability. Methods Thermosensitive in situ gels of penciclovir were prepared through combination of HPMC K4M or carbopol 934P and pluronic F127. Optimized formulations were examined through measuring gelation temperature, rheology speciality, drug release behavior, pharmacokinetics and ocular irritation. Results The gelation temperature was reduced by adding HPMC K4M or carbopol 934P, and the viscosity was enhanced slightly. Either HPMC K4M or carbopol 934P delayed the release of PCV from in situ gel. PCV was released by non-Fickian diffusion. The study of ocular irritation for different PCV formulations did not show any irritation or damage for the cornea. PCV bioavailability from combination of carbopol 934P and pluronic F127 gels was higher than that obtained from any other gels. Conclusion Pluronic F127 formulations of PCV can be used as liquid for administration by instilling into the eye. Facilitated by the appropriate eye temperature, the formulations were transformed to gel phase. On the basis of in vitro and in vivo results, PCV formulations containing HPMC K4M or carbopol 934P and low concentration of pluronic F127 （12%） showed potential for use as a drug delivery system with improved ocular bioavailability.

Cloning of the APRT Gene from Rice and Analysis of Its Association with TGMS

Adenine phosphoribosyltransferase (APRT) is the major enzyme that converts adenine into adenosine-3'-phosphate (AMP). APRT-deficient mutant caused by APRT gene mutation results in the male sterility in Arabidopsis thaliana L. In order to confirm the existence of rice APRT gene and to investigate its association with thermo-sensitive genic male sterile (TGMS) phenotype of rice, a APRT gene was identified from BLAST search of the rice genome database using APRT gene sequences from other plant species as probes. Further, the gene was cloned from rice and named APRT(GenBank accession number AY238894) using the combination of bioinformatic and experimental approaches. The rice APRT was located in the 56 000 bp to 63 000 bp region of a rice bacterial artificial chromosome (BAC) clone (AL606604) on chromosome 4 and was deduced by software from the positive DNA clone. Its cDNA was amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) using primers designed according to the sequence of the putative gene. The full-length cDNA was obtained by rapid amplification of cDNA ends (RACE) procedure and was sequenced. Open reading frame (ORF) analysis indicated that the rice APRT gene encodes a peptide of 212 amino acid residues, including seven exons and six introns. Using reverse position specific BLAST (RPS-BLAST), the APRT domain was identified in the polypeptide. The homology comparison demonstrated that the polypeptide exhibits 54.9%, 54.9%, 49.6% and 59.5% identity with that from Hordeum vulgare, Ttriticum aestivum, and A. thaliana (APRT types 1 and 2), respectively. Comparing the sequence of APRT gene from TGMS mutant lines 'Annong S-1' (Oryza sativa subsp. indica) with that from its corresponding wild type 'Annong F' (Oryza sativa. subsp. indica), we found that there are five single nucleotid polymorphism (SNP) sites in the gene of 'Annong S-1', which locate mainly in the second intron. However, the result of cDNA sequencing showed that these SNP sites do not damage the successful splicing of intron 2. Qualitative RT-PCR and Northern blot indicated that the gene tran-scription in the 'Annong S-1' young panicles that were verified to be the thermo-sensitive organ at the early stage of pollen fertility alternation is down-regulated by high temperature stress (28 V), which is the critical temperature causing 'Annong S-1' fertility conversion. These results revealed that the change of expression pattern of APRT in young particles of 'Annong S-1' in high temperature conditions is perhaps related to the TGMS of 'Annong S-1'.

Rheological behavior of ZnO suspension with thermosensitive poly(N-isopropylacrylamide) for colloidal processing of ceramics

Novel colloidal processing using thermosensitive poly（N-isopropylacrylamide） （PNIPAM） as a coagulating agent has beendeveloped to prepare complex-shaped ceramic components. In this work, the properties of PNIPAM aqueous solutions and therheological behavior of ZnO suspensions with PNIPAM were investigated. The results show that the PNIPAM solutions exhibitobvious thermosensitivity and its transition temperature is around 32℃. When the temperature is above 40℃ （Tc, the criticaltransition temperature of thermosensitive suspension）, the 50% ZnO （volume fraction） suspension with 8 mg/mL PNIPAM has asharp increase in viscosity and reaches up to 11.49 Pa·s at 50℃, displaying strong elasticity. The main reasons are the increase ofeffective volume fraction attributed to precipitation of PNIPAM segments and the flocculation between ZnO powder particles. Inaddition, the maximum solid loading （volume fraction） at 20 ℃ is higher than that at 40℃, which proves that the phase transition ofPNIPAM can induce the flocculation of suspension.

Molecular regulation and genetic control of rice thermal response

Global warming threatens food security.Rice(Oryza sativa L.),a vital food crop,is vulnerable to heat stress,especially at the reproductive stage.Here we summarize putative mechanisms of high-temperature perception(via RNA secondary structure,the phyB gene,and phase separation)and response(membrane fluidity,heat shock factors,heat shock proteins,and ROS(reactive oxygen species)scavenging)in plants.We describe how rice responds to heat stress at different cell-component levels(membrane,endoplasmic reticulum,chloroplasts,and mitochondria)and functional levels(denatured protein elimination,ROS scavenging,stabilization of DNA and RNA,translation,and metabolic flux changes).We list temperature-sensitive genetic male sterility loci available for use in rice hybrid breeding and explain the regulatory mechanisms associated with some of them.Breeding thermotolerant rice species without yield penalties via natural alleles mining and transgenic editing should be the focus of future work.

Current developments in drug delivery with thermosensitive liposomes

Thermosensitive liposomes(TSLs) have been an important research area in the field of tumor targeted chemotherapy. Since the first TSLs appeared that using 1,2-dipalmitoyl-snglyce-ro-3-phosphocholine(DPPC) as the primary liposomal lipid, many studies have been done using this type of liposome from basic and practical aspects. While TSLs composed of DPPC enhance the cargo release near the phase transition temperature, it has been shown that many factors affect their temperature sensitivity. Thus numerous attempts have been undertaken to develop new TSLs for improving their thermal response performance. The main objective of this review is to introduce the development and recent update of innovative TSLs formulations, including combination of radiofrequency ablation(RFA), highintensity focused ultrasound(HIFU), magnetic resonance imaging(MRI) and alternating magnetic field(AMF). In addition, various factors affecting the design of TSLs, such as lipid composition, surfactant, size and serum components are also discussed.

Recent Advances on Early-Stage Fire-Warning Systems: Mechanism, Performance, and Perspective

Early-stage fire-warning systems(EFWSs)have attracted significant attention owing to their superiority in detecting fire situations occurring in the pre-combustion process.Substantial progress on EFWSs has been achieved recently,and they have presented a considerable possibility for more evacuation time to control constant unintentional fire hazards in our daily life.This review mainly makes a comprehensive summary of the current EFWSs,including the working mechanisms and their performance.According to the different working mechanisms,fire alarms can be classified into graphene oxide-based fire alarms,semiconductor-based fire alarms,thermoelectric-based fire alarms,and fire alarms on other working mechanisms.Finally,the challenge and prospect for EFWSs are briefly provided by comparing the art of state of fire alarms.This work can propose a more comprehensive understanding of EFWSs and a guideline for the cutting-edge development direction of EFWSs for readers.

In vitro Evaluation of Lysozyme-loaded Microspheres in Thermosensitive Methylcellulose-based Hydrogel

Long-terrn injectable microspheres have some inherent disadvantages such as migration of microspheres from the originalsite an.d the burst effect. In order to avoid these problems, microsphere-loaded thermosensitive, hydrogel system was designed and expected to achieve a zero-order release Of biomolecular drugs in relativehigh initial drug loadings. Lysozyme, an antibacterial protein usually used to reduce prosthetic valve endocarditis,was selected as the model drug. Poly （DL-lactide-co-glycolide） （PLGA） microspheres, prepared by solvent evaporation method, were employee to encapsulate lysozyme and dispersed into thermosensitive pre-gel solution containing methylcellulose （MC）, polyethylene glycol （PEG）, sodium citrate （SC）, and sodium alginate （SA）. The mixture could act asadrug reservoir by.performing sol-gel transition rapidly if the temperature was raised from roomtemperature to 37℃. The in vitro release results showed that the burst effect was avoided due to strengthening ofdiffusion resistance in the gel. The formulation was able.to deliver lysozy.me for over.30 daysin a nearly zero-order release profile with a rate of 32.8μg.d^-1 which exhibits its remarkable potential for effective aoolication in long-term drug delivery.

Synthesis and Characterization of Novel Temperature and pH Responsive Hydroxylpropyl Cellulose-based Graft Copolymers

In this study, double-hydrophilic hydroxylpropyl cellulose （HPC） based copolymers with poly（N- isopropylacrylamide） （PNIPAM） and poly（acrylic acid） （PAA） as graft chains were synthesized and characterized. The release behavior of drug-loaded micelles was studied. The results show that the hydrophilicity of copolymers improves as the pH increases, whereas the hydrophobicity of copolymers enhances as the temperature increases, and all the phase behaviors are reversible. The diameter of micelles decreases and then increases with pH increase. It shows different micellizing behavior under acidic and basic conditions according to the temperature increase. In vitro release experiments, which used theophylline as a model drug, show that the micelles enhance pH sensitivity in the release process.

Dynamics and coherence resonance in a thermosensitive neuron driven by photocurrent

A feasible neuron model can be effective to estimate the mode transition in neural activities in a complex electromagnetic environment.When neurons are exposed to electromagnetic field,the continuous magnetization and polarization can generate nonlinear effect on the exchange and propagation of ions in the cell,and then the firing patterns can be regulated completely.The conductivity of ion channels can be affected by the temperature and the channel current is adjusted for regulating the excitability of neurons.In this paper,a phototube and a thermistor are used to the functions of neural circuit.The phototube is used to capture external illumination for energy injection,and a continuous signal source is obtained.The thermistor is used to percept the changes of temperature,and the channel current is changed to adjust the excitability of neuron.This functional neural circuit can encode the external heat(temperature)and illumination excitation,and the dynamics of neural activities is investigated in detail.The photocurrent generated in the phototube can be used as a signal source for the neural circuit,and the thermistor is used to estimate the conduction dependence on the temperature for neurons under heat effect.Bifurcation analysis and Hamilton energy are calculated to explore the mode selection.It is found that complete dynamical properties of biological neurons can be reproduced in spiking,bursting,and chaotic firing when the phototube is activated as voltage source.The functional neural circuit mainly presents spiking states when the photocurrent is handled as a stable current source.Gaussian white noise is imposed to detect the occurrence of coherence resonance.This neural circuit can provide possible guidance for investigating dynamics of neural networks and potential application in designing sensitive sensors.

Low-temperature Preparation of Photocatalytic TiO_2 Thin Films on Polymer Substrates by Direct Deposition from Anatase Sol

Anatase TiO2 sol was synthesized under mild conditions （75℃ and ambient pressure） by hydrolysis of titaniumn-butoxide in abundant acidic aqueous solution and subsequent reflux to enhance crystallization. At room temperature and in ambient atmosphere, crystalline TiO2 thin films were deposited on polymethylmethacrylate （PMMA）, SiO2-coated PMMA and SiO2-coated silicone rubber substrates from the as-prepared TiO2 sol by a dip-coating process. SiO2 layers prior to TiO2 thin films on polymer substrates could not only protect the substrates from the photocatalytic decomposition of the TiO2 thin films but also enhance the adhesion of the TiO2 thin films to the substrates. Field-emission type scanning electron microscope （FE-SEM） investigations revealed that the average particle sizes of the nanoparticles composing the TiO2 thin films were about 35-47 nm. The TiO2 thin films exhibited high photocatalytic activities in the degradation of reactive brilliant red dye X-3B in aqueous solution under aerated conditions. The preparation process of photocatalytic TiO2 thin films on the polymer substrates was quite simple and a low temperature route.

Corneal sensitivity,ocular surface health and tear film stability after punctal plug therapy of aqueous deficient dry eye

AIM： To evaluate the effect of punctal occlusion using thermosensitive（smart plug） versus silicone plug for management of aqueous deficient dry eye on cornea sensitivity, ocular surface health and tear film stability.METHODS： A comparative prospective interventiona case study included 45 patients with bilateral severe form of aqueous deficient dry eye. In each patient, the smar plug was inserted in the lower punctum of the right eye which was considered as study group 1 and silicone plug was inserted in the lower punctum of the left eye o the same patient which was considered as study group2. All patients were subjected to careful history taking and questionnaire for subjective assessment of severity of symptoms. Corneal sensitivity, corneal fluorescein rose bengal staining, Schirmer＇s I test, tear film break up time and conjunctival impression cytology were performed pre and 1, 3 and 6mo post plug insertion.RESULTS： A statistically significant improvement in subjective and objective manifestations occurred following treatment with both types of plugs（P 〈0.01）The thermosensitive plug caused significant overal improvement, decrease in frequency of application o tear substitutes and improvement of conjunctiva impression cytology parameters in the inserted side（P 〈0.01）. Canaliculitis was reported in two eyes（4.4% following punctal occlusion using thermosensitive plug（study group 1）. Spontaneous plug loss occurred in 21eyes（46.6%） in the silicone plug group（study group 2）.CONCLUSION： Improvement of subjective and objective manifestations of aqueous deficient dry eye occurs following punctal plug occlusion. Thermosensitive plug has good patient＇s compliance with fewer complications and lower rates of loss compared to the silicone plug.

Dynamic culture of a thermosensitive collagen hydrogel as an extracellular matrix improves the construction of tissue-engineered peripheral nerve

Tissue engineering technologies offer new treatment strategies for the repair of peripheral nerve injury, hut cell loss between seeding and adhesion to the scaffold remains inevitable. A thermosensitive collagen hydrogel was used as an extracellular matrix in this study and combined with bone marrow mesenchymal stem cells to construct tissue-engineered peripheral nerve composites in vitro. Dynamic culture was performed at an oscillating frequency of 0.5 Hz and 35° swing angle above and below the horizontal plane. The results demonstrated that bone marrow mesenchymal stem cells formed membrane-like structures around the poly-L-lactic acid scaffolds and exhibited regular alignment on the composite surface. Collagen was used to fill in the pores, and seeded cells adhered onto the poly-L-lactic acid fibers. The DNA content of the bone marrow mesenchymal stem cells was higher in the composites constructed with a thermosensitive collagen hydrogel compared with that in collagen I scaffold controls. The cellular DNA content was also higher in the thermosensitive collagen hydrogel composites constructed with the thermosensitive collagen hydrogel in dynamic culture than that in static culture. These results indicate that tissue-engineered composites formed with thermosensitive collagen hydrogel in dynamic culture can maintain larger numbers of seeded cells by avoiding cell loss during the initial adhe-sion stage. Moreover, seeded cells were distributed throughout the material.

Evaluation of micelles incorporated into thermosensitive hydrogels for intratumoral delivery and controlled release of docetaxel:A dual approach for in situ treatment of tumors

The in situ gelling hybrid hydrogel system has been reported to effectively concentratechemotherapeutic drugs at the tumor site and sustain their release for a long period. DTX-micelles(docetaxel-loaded mixed micelles) are able to increase the solubility of DTX inwater, and then a high drug loading rate of hydrogels can be achieved by encapsulatingthe docetaxel-loaded mixed micelles into the hydrogels. The thermosensitive nature ofDTX-MM-hydrogels(thermosensitive hydrogels incorporated with docetaxel-loaded mixedmicelles) can accelerate the formation of a depot of this drug-loaded system at the siteof administration. Therefore, the hydrogels provide a much slower release compared withDTX-micelles and DTX-injection. An in vivo retention study has demonstrated that the DTX-MM-hydrogels can prolong the drug retention time and in viv o trials have shown that theDTX-MM-hydrogels have a higher antitumor efficacy and systemic safety. In conclusion, theDTX-MM-hydrogels prepared in this study have considerable potential as a drug deliverysystem, with higher tumor inhibition effects and are less toxic to normal tissues.

Study on Thermosensitive Micellization of Dextran-g-PNIPAAm in Aqueous Solutions

The thermosensitive micellization of dextran-g-PNIPAAm in aqueous solutions has been investigated by fluorescence spectroscopy, dynamic light scattering and transmission electron microscope. The formed polymeric micelles showed different diameters of about 20 nm or 100 nm, when the solution temperature was below or above the phase transition temperature.