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.

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.

The preparation of Thermosensitive in Situ Gel of Iodine

objective:To Investigate the preparation,dissolution and release in vitro of thermosensitive in situ gel of iodine.Methods:Using orthogonal test method for screening the best prescription;Using the formula of gel accumulative dissolution percentage=(W1-Wt)/(W1-W0)to calculate the dissolution rate of Q by membrane-free;Calculating the accumulative release rate by the standard curve.As time increases,the dissolution rate and the release rate of the gel increased significantly.Conclusion:Thermosensitive in situ gel of iodine has good sustained release effect.

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.

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.

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.

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.

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.

Synthesis and Swelling Properties of Thermosensitive Hydrogels based on Terpolymerization

Novel thermosensitive hydrogels based on polymerization of N-isopropyl acrylamide, Sodium acrylate, and diacetone acrylamide were synthesized. The swelling ratio and dynamic swelling were investigated. The results indicated that the hydrogels exhibited high water uptake and themosensitivity. The swelling properties and volume phase transition temperature could be adjusted by contents of the comonomers in the gels.

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.

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.

Preparation of Thermosensitive Microcapsules Containing Water Soluble Powder by Melting Dispersion Cooling Method

It was tried to prepare the thermosensitive microcapsules containing the water soluble solid powder by the melting dispersion cooling method and to establish the optimum preparation conditions. As a model water soluble solid powder, sodium hydrogen carbonate was adopted in order to generate carbon dioxide gas and as a thermosensitive shell material, olefin resin with the melting point of ca. 40°C was used. In the experiment, the concentration of olefin resin in the shell material solution was mainly changed together with the concentrations of the oil soluble surfactant species and the α-tocopherol as a modifier of shell. Addition of α-tocopherol into the shell material solution could prevent the core from breaking away during the microencapsulation process and result in the higher microencapsulation efficiency, because the dispersion stability of solid powder in the shell material solution could be increased due to the increase in affinity between the shell material solution and solid powder. Also, the microencapsulation efficiency increased with the concentration of olefin resin, became maximum at 50 wt% and then, decreased. The microcapsules were found to begin melting at 36°C and to generate carbon dioxide gas.

Synthesis and characterization of new biodegradable thermosensitive polyphosphazenes with lactic acid ester and methoxyethoxyethoxy side groups

Two novel biodegradable thermosensitive polyphosphazenes with lactic acid ester and methoxyethoxyethoxy side groups were synthesized via the macromolecular substitution reactions of poly(dichlorophosphazene) with the sodium salt of lactic acid ester and sodium methoxyethoxyethoxide.Their structures were confirmed by ^(31)p NMR,~1H NMR,^(13)C NMR,IR,DSC,and elemental analysis.The lower critical solution temperature(LCST) behavior in water and in vitro degradation property of the polymers was investigated.The...

Effects of Chitin Nanocrystal on Solution Behavior and Gelation of Chitosan/β-Glycerophosphate Thermosensitive Hydrogel

The chitosan/β-glycerophosphate( CS/β-GP),a physical hydrogel system with thermosensitive and injectable features combined with biocompatibility and biodegradability, has great potentials as matrices for drug or cell encapsulation and delivery,or as in situ gel-forming materials for tissue repair. Here,the chitin nanocrystal( Chi NC) was introduced into the aforementioned system, and its effects on solution behavior and mechanical properties was investigated. The results showed the incorporation of Chi NC complicated sol-to-gel transition process; a higher loading ratio( 20%) speeded up sol-to-gel transition rate,reduced the solto-gel transition temperature,while still maintained shear-thinning behavior or injectable feature. Moreover,the mechanical properties of gels were significantly enhanced by Chi NC, accompanied by decreased water uptake. The above mentioned behavior favored better applications as injectable tissue-repair implants.

Control of firing activities in thermosensitive neuron by activating excitatory autapse

Temperature has distinct influence on the activation of ion channels and the excitability of neurons,and careful change in temperature can induce possible mode transition in the neural activities.The formation and development of autapse connection to neuron can enhance its self-adaption to external stimulus,and thus the firing patterns in neuron can be controlled effectively.The autapse is activated to drive a thermosensitive neuron,which is developed from the FitzHugh-Nagumo neural circuit by incorporating a thermistor,and the dynamics in the neural activities is explored to find mode dependence on the temperature and autaptic current.It is found that the firing modes can be controlled by temperature,and the neuron is wakened from resting state to periodic oscillation with the increase of temperature.Furthermore,the intensity and the intrinsic time delay in the autapse are respectively adjusted to control the neural activities,and it is confirmed that appropriate setting for autaptic current can balance and enhance the temperature effect on the neural activities.

Effect of astrocyte on synchronization of thermosensitive neuron–astrocyte minimum system

Astrocytes have a regulatory function on the central nervous system(CNS), especially in the temperature-sensitive hippocampal region. In order to explore the thermosensitive dynamic mechanism of astrocytes in the CNS, we establish a neuron-astrocyte minimum system to analyze the synchronization change characteristics based on the Hodgkin-Huxley model, in which a pyramidal cell and an interneuron are connected by an astrocyte. The temperature range is set as 0-40 ℃ to juggle between theoretical calculation and the reality of a brain environment. It is shown that the synchronization of thermosensitive neurons exhibits nonlinear behavior with changes in astrocyte parameters. At a temperature range of0 ℃-18 ℃, the effects of the astrocyte can provide a tremendous influence on neurons in synchronization. We find the existence of a value for inositol triphosphate(IP_(3)) production rate and feedback intensities of astrocytes to neurons, which can ensure the weak synchronization of two neurons. In addition, it is revealed that the regulation of astrocytes to pyramidal cells is more sensitive than that to interneurons. Finally, it is shown that the synchronization and phase transition of neurons depend on the change in Ca^(2+) concentration at the temperature of weak synchronization. The results in this paper provide some enlightenment on the mechanism of cognitive dysfunction and neurological disorders with astrocytes.

Fabrication and Characterization of Chitosan Based Injectable Thermosensitive Hydrogels Containing Silica/Calcium Phosphate Nanocomposite Particles

In this study, the effect of silica/calcium phosphate (SiCaP) nanocomposite particles on the properties of a novel chitosan-based thermosensitive hydrogel system was examined. SiCaP nanocomposite powder was fabricated using a sol-gel method and then used to fabricate nanocomposite hydrogels (Ch- β/7.5SiCaP and Ch-β/15SiCaP) including chitosan and β-glycerophosphate (Ch-β) as a matrix. Results revealed that compared to the Ch-β hydrogel without SiCaP, the presence of SiCaP particles in nanocomposite hydrogels maintained pH stability during the sol-gel transition, accelerated the gelation and improved the stiffness of nanocomposite hydrogels. Gelation time at 37℃ was reduced approximately 75% and stiffness was increased approximately 115%. Both of these changes are attributed to chemical and physical interactions of the SiCaP bioactive particles with chitosan. Furthermore, compared to the Ch-β hydrogel, the presence of SiCaP in the Ch-β/7.5SiCaP nanocomposite hydrogel did not affect biocompatibility negatively, but improved osteoblastic cell differentiation. Our studies suggest that these nanocomposite hydrogels may offer an innovative approach to bone regeneration strategies.

Thermosensitive Liquid Crystal Polymer Color Image Display

A color image formation method is p re sented with thermosensitive liquid crystal polymers. The liquid crystal polymers are capable of reversibly assuming optical states of transparent and scattering lights, and allow picture-element display areas in two colors at least to be co mposed on a surface. The picture elements within color areas are selected if they correspond to the color which is the spectral transmission center. A heat is applied such that the maximum haze degree of the selected picture elements is greater than that of picture elements corresponding to any of the other colo rs.

Identification and fine mapping of rtms1-D,a gene responsible for reverse thermosensitive genic male sterility from Diannong S-1X

Thermosensitive genic male sterility(TGMS)has been widely used in two-line hybrid rice breeding.Due to hybrid seed production being highly affected by changeable environments,its application scope is limited to some extent.Thus,it is of great importance to identify potential TGMS genes in specific rice varieties.Here,Diannong S-1 xuan(DNS-1 X),a reverse TGMS(RTGMS)japonica male sterile line,was identified from Diannong S-1.Genetic analysis showed that male sterility was tightly controlled by a single recessive gene,which was supported by the phenotype of the F;and F;populations derived from the cross between DNS-1 X and Yunjing 26(YJ26).Combining simple sequence repeat(SSR)markers and bulked segregation analysis(BSA),we identified a 215 kb region on chromosome 10 as a candidate reverse TGMS region,which was designated as rtmsl-D.It was narrower than the previously reported RTGMS genes rtmsl and tms6(t).The fertility conversion detected in the natural environment showed that DNS-1 X was sterile below 28-30℃;otherwise,it was fertile.Histological analysis further indicated that the pollen abortion was occurred in the young microspore stage.This study will provide new resources for two-line hybrid rice and pave the way for molecular breeding of RTGMS lines.