Sol-gel Phase Transition Temperature Research Articles

Polyurea-urethane Temperature-responsive Hydrogels for Sustained Delivery of Anti-VEGF Therapeutics.

Temperature-responsive hydrogels, or thermogels, have emerged as a leading platform for sustained delivery of both small molecule drugs and macromolecular biologic therapeutics. Although thermogel properties can be modulated by varying the polymer's hydrophilic-hydrophobic balance, molecular weight and degree of branching, varying the supramolecular donor-acceptor interactions on the polymer remains surprisingly overlooked. Herein, to study the influence of enhanced hydrogen bonding on thermogelation, we synthesized a family of amphiphilic polymers containing urea and urethane linkages using quinuclidine as an organocatalyst. Our findings showed that the presence of strongly hydrogen bonding urea linkages significantly enhanced polymer hydration in water, in turn affecting hierarchical polymer self-assembly and macroscopic gel properties such as sol-gel phase transition temperature and gel stiffness. Additionally, analysis of the sustained release profiles of Aflibercept, an FDA-approved protein biologic for anti-angiogenic treatment, showed that urea bonds on the thermogel were able to significantly alter the drug release mechanism and kinetics compared to usage of polyurethane gels of similar composition and molecular weight. Our findings demonstrate the unrealized possibility of modulating gel properties and outcomes of sustained drug delivery through judicious variation of hydrogen bonding motifs on the polymer structure.

Development and Evaluation of Puerarin Loaded-Albumin Nanoparticles Thermoresponsive in situ Gel for Ophthalmic Delivery.

PurposePuerarin (PUR) is a major bioactive ingredient extracted from the root of Pueraria lobata (Willd.) Ohwi, which is known as Gegen in traditional Chinese medicine. Conventional PUR ophthalmic dosage forms such as solutions and suspensions have many drawbacks, including-rapid precorneal elimination of the drug mainly due to lacrimal duct drainage. The purpose of this study is to develop a thermal responsive in situ gel system containing PUR-loaded human albumin nanoparticles (PUR-HSA-NPs ISG).MethodsThe system has the required sol-gel phase transition temperature, and therefore can be used for local ocular administration to treat glaucoma. The formulation was evaluated for its sol-gel transition temperature, viscosity and in vitro release. In vivo eye irritation was evaluated in rabbits. In this study, the animal model of glaucoma was used to evaluate the pharmacodynamics of PUR-HSA-NPs ISG in vivo.ResultsMorphologically, the PUR-HSA-NPs ISG exhibited a normal spherical shape with no aggregation or degradation. It had a mean size of 64.8 nm, and the drug-loading and encapsulation efficiency were 7.1%±0.3% and 80.7%±7.4%, respectively. The gelation temperature of the prepared PUR-HSA-NPs ISG thermogelling solutions was 37°C. Meanwhile, the PUR-HSA-NPs ISG showed thixotropic behavior with the downward curve exhibiting lower shear stress values as compared to corresponding points on the upward curve. The pharmacological results showed a continuous reduction of the IOP value for a long time and that the value remained in a lower-level range compared to that in the PUR eye drop group. According to the pharmacodynamic results, the Bcl-2/Bax ratio of the PUR-HSA-NPs ISG group was closest to 1 (0.8798, 24 h), with obvious reduction of tissue cell apoptosis.ConclusionThrough this study, it was found that PUR-HSA-NPs ISG is an ideal ocular drug delivery system. It is hoped that this product could be further promoted for clinical applications in the future.

Localized delivery of curcumin by thermosensitive hydrogels for promoting wound healing.

Curcumin can promote wound healing, but its drug delivery medium needs to be improved further. A curcumin-loaded thermosensitive hydrogel was prepared, its characterization was evaluated, and its promoting effect on wound healing was observed. Curcumin-loaded thermosensitive hydrogels were prepared with different percentages of poloxamer 188 and poloxamer 407. A small tube inversion assay was used to observe the sol-gel transition temperature, and a rotational rheometer was used to detect the sol viscosity, sol-gel phase transition temperature, and phase transition time. The microstructure of the gel was observed by scanning electron microscopy, and Fourier infrared spectroscopy was used to evaluate whether curcumin was successfully loaded. Finally, its promoting effect on wound healing was observed in vivo and in vitro. Poloxamer 407 24% and poloxamer 188 1% were selected to prepare curcumin-loaded thermosensitive hydrogels. After 60±15s at 32°C, the sol-gel transition process was completed, with certain elastic behavior and solid-like rheological properties. Scanning electron microscopy showed that the pores of the curcumin-P407/P188 thermosensitive hydrogel were interconnected, with an average pore size ranging from 5 to 10μm. Hydrogels showed a higher swelling ratio. Fourier transform infrared spectroscopy showed that curcumin had been incorporated into the hydrogel. Live/dead cell assays suggested that the hydrogel was not toxic to fibroblasts. Curcumin-loaded thermosensitive hydrogels can promote an increase in S-phase fibroblasts and improve wound healing. Curcumin-loaded P407/P188 thermosensitive hydrogel improves wound healing. More in-depth research is needed in the future.

Effect of ionic liquid on sol-gel phase transition, kinetics and rheological properties of high amylose starch

The effect of 1-butyl-3-methylimidazolium chloride (BMIMCl) as a plasticizer on sol-gel phase transition, rheological, and physical properties of high amylose rice starch was studied. The inter-relationships of parameters were determined using principal component analysis. The sol-gel phase transition temperature and storage modulus of starch was varied significantly (p ≤ 0.05) in the presence of BMIMCl. The sol-gel phase transition temperature of native starch was varied between 53.99 and 39.7 °C, whereas, for starch with ionic liquid varied between 49.50 and 40.6 °C. The changes in storage modulus (G') during the sol-gel phase transition were suitable with first order kinetics. The temperature dependent rheology of starch during the sol-gel phase transition was efficiently (0.93 ≤ R2 ≤ 0.98) explained using the Arrhenius model. The thermal stability of the gel was improved in the presence of BMIMCl. The textural and electrical properties of the gel were significantly affected by the presence of BMIMCl. The inter-relationships between the parameters were developed and the initial temperature, resistance, and storage modulus showed a strong interrelation.

Preparation and characterization of 12-HSA-based organogels as injectable implants for the controlled delivery of hydrophilic and lipophilic therapeutic agents.

Organogels prepared with low molecular weight organogelators to structure liquid oils represent excellent matrices for the controlled delivery of a wide variety of drug molecules. Although studies on organogel systems are reported in the literature, relatively few investigate their potential as gels formed in situ intended for drug delivery. This study reports the development of injectable subcutaneous 12- hydroxystearic acid (12-HSA) organogels for the delivery of both lipophilic and hydrophilic drugs. The rheological characterization (flow, dynamic temperature ramp and amplitude oscillatory measurements) and physicochemical properties (syringeability, swelling and degradation studies), as well as permeability and cytotoxicity were analyzed to gain insights into the influence of the gel composition (surfactant addition, organogelator concentration) on the gelation process and organogel properties. Sol-gel phase transition temperature (Tgel) and gel-sol phase transition temperature (Tmelt) were determined by the tube-inverting method and complementary rheology studies. An increase in 12-HSA concentration led to an augmentation in gel strength and storage (G') and loss (G″) moduli values, evidencing the self-assembly of crystalline gelator structure entrapping the oil phase into a three-dimensional (3D) network. The addition of polysorbate 80 (Tween 80, T80) surfactant molecules in the system caused a weaker gel-like structure, with lower flow rate during syringeability assays, despite its lower apparent viscosity compared to those of 12-HSA organogels. In addition, the swelling studies of 12-HSA/12-HSA T80 organogels as a function of time in phosphate buffered saline (PBS) revealed that the erosion rates were modulated by the organogel compositions. The permeability of acyclovir (ACV) and clotrimazole (CTM), hydrophilic and lipophilic model drugs, respectively, loaded in 12-HSA-based organogels, was assessed in Franz diffusion cells. Organogel-loaded drugs presented lower in vitro release rates and ex vivo drug permeabilities compared to the corresponding drug solutions. Furthermore, 12-HSA T80 organogel could slow down the release of ACV by a factor of about 2.6-fold, up to 6 h, compared to CTM-loaded 12-HSA organogels. Finally, the cytotoxicity of 12-HSA-based organogels was evaluated through in vitro cell viability assays in human foreskin fibroblasts (HFF). Increased 12-HSA concentration resulted in higher cytotoxic effect, with a higher test sensitivity observed for the 3D collagen-embedded cell layer setup matrix versus 2-D cell cultures. Our results support the hypothesis that 12-HSA-based organogels are promising systems for controlled drug delivery as in situ-forming implants.

Stretchable and Self-Healable Conductive Hydrogels for Wearable Multimodal Touch Sensors with Thermoresponsive Behavior.

Multifunctional hydrogels with properties including transparency, flexibility, self-healing, and high electrical conductivity have attracted great attention for their potential application to soft electronic devices. The presence of an ionic species can make hydrogels conductive in nature. However, the conductivity of hydrogels is often influenced by temperature, due to the change of the internal nano/microscopic structure when temperature reaches the sol-gel phase transition temperature. In this regard, by introducing a novel surface-capacitive sensor device based on polymers with lower critical solution temperature (LCST) behavior, near-perfect stimulus discriminability of touch and temperature may be realized. Here, we demonstrate a multimodal sensor that can monitor the location of touch points and temperature simultaneously, using poly(N-isopropylacrylamide) (PNIPAAm) in hybrid poly(vinyl alcohol) (PVA) and sodium tetraborate decahydrate cross-linked hydrogels doped with poly(sodium acrylate) (SA) [w/w/w = 5:2.7:1-3]. This multimodal sensor exhibits a response time of 0.3 s and a temperature coefficient of resistance of -0.58% K-1 from 20 to 40 °C. In addition, the LCST behavior of PNIPAAm-incorporated PVA/SA gels is investigated. Incorporation of LCST polymers into high-end hydrogel systems may contribute to the development of temperature-dependent soft electronics that can be applied in smart windows.

Synthesis of malonamide pseudopeptidic compounds using a pseudo five-component reaction and evaluation of their gelation properties

A new class of malonamide pseudopeptidic compounds (MPPCS) was prepared via an isocyanide-based pseudo five-component reaction. Amino acid esters, which were used in this reaction, were phenylalanine ethyl ester and glycine ethyl ester. MPPCS that were obtained from l-phenylalanine ethyl ester and glycine ethyl ester gave stable gels in the mixture of dimethyl sulfoxide (DMSO)/water as solvent while MPPCs derived from d-phenylalanine did not give gel. Also, when MPPCS of d- and l-form (1:1) were mixed, they could not create a gel in low and even high concentrations. The sol-gel phase transition temperature of the gels showed that they have agreeable thermal stability. Rheological results showed high mechanical strength for some of gels. Fourier transform infrared (FT-IR) spectra indicated that three types of driving forces have the key role in this self-assembly include hydrogen bondings, van der Waals, and π-π interactions. Moreover, morphology of the xerogel was clarified using the scanning electron microscope (SEM) image.

Molecular level investigation on the interaction of pluronic F127 and human intestinal bile salts using excited state prototropism of 1-naphthol

Pluronic F127 (PF127), a surfactant polymer is used as a drug delivery system and has been introduced recently in the food research to delay lipid digestion process. In this context study the interaction of this polymer with human intestinal bile salts assumes important. The studies involving interaction of PF127 with human intestinal bile salts sodium taurocholic acid (NaTC) and sodium cholate acid (NaC) by using differential scanning calorimetry (DSC) and 1-naphthol as a fluorescent molecular probe show that the bile salts induce decrease of sol–gel phase transition temperature of the PF127 to lower temperature, from ~21°C to ~18°C. Variation of neutral form fluorescence intensity of 1-naphthol with bile salts in water confirmed efficient micellar aggregation with critical micellar concentration (CMC) values of 12.6mM for NaTC and 12.7mM for NaC. Fluorescence parameters like fluorescence intensity and fluorescence lifetime of the two excited state prototropic forms {neutral form emission (λem=370nm), anion form emission (λem=470nm)} of 1-naphthol suggested that the NaTC (below critical micellar concentration 12mM) and NaC (above critical micellar concentration 12mM) induce appreciable dehydration of the hydrophilic corona as well as core region PF127 hydrogel. The micropolarity of the hydrogel microenvironment decreases with increase in concentration of both the bile salts.

Fabrication of smart biointerfaces in nanochannels with a thiolated temperature-responsive polymer

Event Abstract Back to Event Fabrication of smart biointerfaces in nanochannels with a thiolated temperature-responsive polymer Yan Xu1, Misato Shinomiya1, 2 and Atsushi Harada2 1 Osaka Prefecture University, Nanoscience and Nanotechnology Research Center, Japan 2 Osaka Prefecture University, Department of Applied Chemistry, Graduated School of Engineering, Japan Introduction: Recently, nanofluidic devices have attracted much attention in the fields of chemistry, biology, and medicine. For example, nanofluidic devices are very promising in the development of early diagnostic tools for diseases because nanochannels in the nanofluidic devices allow confining biomolecules such as proteins, DNAs at the single molecular level[1]. However, these applications rely on the precise control of fluids in nanochannels, which is still a challenge in nanofluidics due to the extreme difficulty to construct fluid control units in nanochannels. Therefore, we proposed a concept of smart nanofluidic control (SNC). In SNC, the ‘open’ and ‘closed’ states of nanochannels are smartly controlled by the change of the external stimuli such as temperature, pH, light, through self-assembled stimuli-responsive interfaces which are locally constructed in nanochannels (Figure 1). Towards the realization of SNC, we have first achieved the fabrication of gold nanopatterns in glass nanochannels[2]-[4]. The gold nanopatterns in nanochannels provide robust surfaces to form self-assembled monolayers (SAM) when reacting with thiolated molecules. In this study, we focused on temperature-responsive SNC. A thiolated temperature-responsive polymer, poly(N-isopropylacrylamide) (referred to as PNIPAAm-SH, Figure 2), was specially designed and synthesized to fabricate smart biointerfaces in nanochannels for SNC. Materials and Methods: The SNC chips (Figure 3) were fabricated on fused-silica glass substrates using the methods previously reported by us[2]-[4]. PNIPAAm-SH was synthesized by a reversible addition fragmentation chain transfer (RAFT) polymerization. While SAMs of PNIPAAm-SH prepared on the gold-deposited glass substrates were used to characterized the bulk interfacial properties, SAMs of PNIPAAm-SH formed on the gold pattern surfaces in nanochannels were used to evaluate their capability to control fluids in nanochannels using an experimental setup previously reported by us[5]. Results and Discussion: The well-controlled structures of synthesized PNIPAAm-SH were identified by H1 NMR. Independent on polymerization time, PNIPAAm-SH with small molecular weight lower than 10,000 and narrow polydispersity lower than 1.2 were obtained, which is considered to be appropriate to inject into nanochannels. The SAMs formed on the gold surface using PNIPAAm-SH of different concentration were elementally confirmed by XPS and exhibited smooth morphology having extremely small roughness lower than that of glass substrate. Further, the synthesized PNIPAAm-SH exhibited sharp sol-gel phase transition at 30.8 °C in solution, suggesting that it would possess a quick temperature responsiveness in nanochannel, which is very ideal for SNC. Finally, nanofluidic experiments conducted below and above the sol-gel phase transition temperature revealed that the smart biointerfaces consisting of SAMs of PNIPAAm-SH on the gold pattern surfaces in the nanochannels allowed the smart control of fluids in the nanochannels. Conclusion: By fabricating a smart PNIPAAm-SH biointerfaces in nanochannels, SNC was achieved for the first time. This work was partially supported by JSPS KAKENHI Grant Numbers 26706010,26630403, and MEXT KAKENHI Grant Number 26107714, and the Asahi Glass Foundation.

Effect of milk fat content on the viscoelasticity of mozzarella-type cheese curds

The effect of fat content in cheese curds on their rheological properties was examined using dynamic shear measurements. Surplus fat addition to milk samples caused two distinct types of changes in the temperature dependence of the viscoelastic moduli of resultant curds. The first was a significant reduction in the moduli over a wide temperature range, which is attributed to the presence of liquefied fat globules within the milk protein network. The second was the excess contribution to the low-temperature moduli owing to the reinforcing effect of solidified fat globules. An upward shift in the sol–gel phase transition temperature driven by an increased fat content was also observed.

Estimation of organogel formation and influence of solvent viscosity and molecular size on gel properties and aggregate structures

This paper proposes a simple method for predicting organogel formation, and highlights the important role played by solvent viscosity (η) and molecular size (V) in influencing the gel properties and the aggregate structures of methyl 4,6-O-(p-chlorobenzylidene)-α-D-glucopyranoside (MPBG, a model gelator) in different solvents. The research of gelation tests shows that a Teas plot derived from solubility parameters can be used to predict the behaviour of a known gelator in untested solvents. The method has successfully been tested on eight gelators reported in the literature and on untested solvents in the gelation of MPBG. The research on solvent role reveals that the aggregate morphologies of MPBG and the main factors determining the gel properties are obviously different in monohydric alcohols and aromatic hydrocarbons. According to SEM images and X-ray diffraction patterns, in monohydric alcohols with high viscosity, the self-assembly of MPBG is a diffusion-limited aggregation process resulting from solvent viscosity. Furthermore, it is found that solvent viscosity, compared with the secondary role of polar solubility parameter (δa), plays a key role in determining the morphologies of aggregates, the sol–gel phase-transition temperature (Tgel) and the gelation number (Ngel). In contrast, for aromatic hydrocarbon gels, solvent molecular size is very important in determining Tgel and Ngel although δa is the key factor.

Novel multi-stimuli responsive sodium alginate-grafted-poly(N-isopropylacrylamide) copolymers: II. Dilute solution properties

Multi-stimuli responsive biocompatible and biodegradable materials can be obtained by combining polysaccharides with the thermoresponsive polymer poly(N-isopropylacrylamide)-PNIPAM. Behaviour of dilute aqueous solution of sodium alginate (AgA) grafted with (PNIPAM) (AgA-g-PNIPAM) copolymers as function of composition, temperature and pH has been studied by viscometry coupled with particle size analysis. The effect of grafting on the solution properties has been established. The sol–gel phase transition temperature has been also determined.

Solvent-dependent photophysical and anion responsive properties of one glutamide gelator

One gelator consisting of four amide units and one chromophore was designed and synthesized. These four amide groups could induce the self-assembly of the gelator molecules in one-dimensional (1-D) direction. Two cyano and one nitro terminal groups were also appended into the chromophore as electron withdrawing groups to make the gelator’s own typical D–π–A electron structure. As a result, it was found that the color of the gel phases, the sol–gel phase transition temperature, microscopic morphologies, emission behaviour and response to anions were dependent on the solvent because of the different packing models and solvation effect in different solvents. For example, the color of the DMSO gel was orange, but ODCB gel possessed a yellow color. In addition, multicolor emission could be realized in DMSO gel systems, but ODCB gels only emitted yellow fluorescence. Moreover, the gelator was responsive to F−, H2PO4− and OAc− in DMSO, but in ODCB it selectively responded to F−.

Design and evaluation of thermoreversible in situ gelling system of forskolin for the treatment of glaucoma

The contact time of a vehicle on the cornea is of utmost importance for ophthalmic drug delivery. The poor bioavailability and therefore poor therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of a drug may be overcome by the use of the in situ gel forming systems, which upon instillation as drops into the eye, undergo a sol-gel transition in the cul-de-sac. The purpose of this work was to develop an ophthalmic delivery system of the forskolin, based on the concept of temperature activated in situ gelation. Poloxamer 407 (Pluronic F-127) is a block copolymer made of poly (oxy ethylene) and poly (oxy propylene). The sol-gel transition is induced by an increase in temperature; however, it depends on the concentration of the polymer and presence of other additives. The developed formulations were therapeutically efficacious (on albino New Zealand rabbit model); reducing intra ocular pressure (IOP) for 12 hours and showed sol-gel phase transition (gelling) temperature of 22°C and sustained drug release 72% ± 0.056% in vitro behavior over a period of 4 h.

Porphyrin Gels Reinforced by Sol−Gel Reaction via the Organogel Phase

Porphyrins bearing four urea-linked dodecyl groups (3a) or four urea-linked triethoxysilylpropyl groups (3TEOS) at their peripheral positions were synthesized. 3a tends to assemble into a sheetlike two-dimensional structure due to the predominant hydrogen-bonding interaction among the urea groups and acts as a moderate gelator of organic solvents. On the other hand, its Cu(II) compelx (3a.Cu) tends to assemble into a fibrous one-dimensional structure due to the predominant porphyrin-porphyrin pi-pi stacking interaction and acts as an excellent gelator of many organic solvents. 3TEOS and 3TEOS.Cu, which also act as gelators, afforded similar superstructures as those of 3a and 3a.Cu, respectively, and as evidenced by SEM and TEM observations and XRD measurements, the original superstructures could be precisely immobilized by in situ sol-gel polycondensation of the triethoxysilyl groups. The TEM images of 3a gels and 3TEOS gels after sol-gel polycondensation showed a fine striped structure, the periodical distance of which was either 2 or 4 nm. X-ray crystallographic analysis of a single crystal obtained from a reference porphyrin bearing four urea-linked butyl groups revealed that there are two different porphyrin-stacked columns in the crystal and both the 2 nm distance and the 4 nm distance can appear, depending on the observation tilting angle. The hybrid gel prepared from 3TEOS.Cu by sol-gel polycondensation showed unique physicochemical properties such as a high sol-gel phase-transition temperature (>160 degrees C), sufficient elasticity, high mechanical strength, etc. Thus, the present study has established new concepts for molecular design of porphyrin-based gelators on the basis of cooperative and/or competitive actions of hydrogen-bonding and pi-pi stacking interactions and for immobilization of their superstructures leading to development of new functional organic/inorganic hybrid materials.

Quasi-solid-state dye sensitized solar cells with 1,3:2,4-di-O-benzylidene-d-sorbitol derivatives as low molecular weight organic gelators

1,3:2,4-Di-O-benzylidene-D-sorbitol (DBS) and its derivatives are efficient gelators to solidify organic solvents over a wide range of polarity. In this paper we demonstrate the usefulness of certain DBS derivatives as efficient gelators to form thermoreversible gels in electrolyte solutions which are of particular interest for solar cell applications. The adjustable, high sol–gel phase transition temperature of 1,3:2,4-di-O-dimethylbenzylidene-D-sorbitol (DMDBS) with a 3-methoxypropionitrile-based electrolyte made this particular organic gelator very attractive in dye sensitized solar cells. For example, with an amphiphilic ruthenium dye and a quasi-solid-state gel electrolyte system based on 1,3:2,4-di-O-dimethylbenzylidene-D-sorbitol/3-methoxypropionitrile, a stable overall solar energy conversion efficiency of 6.1% was achieved at AM 1.5 sunlight illumination (99.8 mW cm−2).

New sugar-based gelators with an amino group, the gelation ability of which is remarkably reinforced by the hydrogen bond and the metal coordination

Three sugar-integrated gelators bearing a p-aminophenyl group which are expected to exert a hydrogen-bonding effect and a metal coordination effect on the gelation ability were synthesised. -D-Galactose-based 2b was only soluble or precipitated and -D-glucose-based 4b gelated only two of 15 solvents tested herein whereas -D-glucose-based 1b acted as an excellent gelator which could gelate 8 solvents. The sol–gel phase-transition temperature (Tgel) values for 1b were higher by 41–78 °C than those for -D-glucose-based 1a bearing a p-nitrophenyl group. The spectral studies indicated that this gel reinforcement is due to the hydrogen-bonding interaction including the amino group. The Tgel values for the ethanol gel of 1b were markedly improved by the addition of AgNO3, CoCl2 or CdCl2. The detailed examination of a 1b + CoCl2 gel system in ethanol showed that the gel is stabilised by the cross-link of 1b molecules by the Co(II)–amino group interaction. This is the first and a convenient method for the metal reinforcement of organic gels.