Search Results (35)

Background: Overexpression of immune cell populations leads to self-amplifying cytokine loops, contributing to chronic inflammation in both allograft rejection and autoimmune conditions. Tacrolimus (TAC), despite being a potent immunosuppressant, has limitations; its systemic adverse effects include nephrotoxicity, neurotoxicity, and high variability in tissue exposure in patients. Currently available therapeutic options are limited by the lack of targeted and localized drug delivery systems, resulting in ineffective control over drug-release behavior. Moreover, TAC being highly lipophilic poses challenges for formulation development. To address these gaps, this study focuses on developing a thermoresponsive hydrogel platform comprising distinct nanocarriers for localized delivery of TAC. The nanocarriers include nanoemulsion (NE) and micelles as TAC carriers, and their particle sizes are specifically engineered at the nanoscale for differential release behavior and to support immune cell targeting (macrophages and T-cells). Incorporation into a thermoresponsive hydrogel matrix enables it to act as a local depot at the injection site and deliver TAC with a slow, extended-release profile. Methods: TAC was loaded into a coconut-rich lipid-phase-based NE via high-pressure microfluidization. Simultaneously, TAC-loaded micelles were optimized using a full-factorial design of experiments (DoE) and manufactured via the thin-film hydration method. Both nanocarriers were evaluated for long-term colloidal stability assessments. Hydrogels were produced maintaining aseptic conditions for sterile batch production. Rheological characterization was performed to assess sol-gel transition, thermoreversibility, and injectability, and in vitro release studies were conducted to evaluate TAC diffusion from the developed nanoformulations. Results: Developed nanocarriers resulted in distinct particle sizes in NE (80–85 nm) and micelles (15–17 nm) with successful TAC loading maintaining long-term colloidal stability. The developed TAC-loaded dual-nanocarrier hydrogel (Dual-HG) showed thermoresponsive behavior and gelation at 37 °C, forming as a local depot. In vitro release studies showed slow and extended tacrolimus release from hydrogels and demonstrated particle size-dependent release behavior between the NE and micelle. Conclusions: Therefore, our study highlights a novel dual nanocarrier hydrogel platform combining TAC-NE and TAC-micelle for localized delivery. The findings support that nanocarriers can be engineered to modulate drug diffusion behavior. Notably, the dual nanocarrier within a thermoresponsive hydrogel platform can be used to deliver one or multiple drugs locally, minimizing systemic exposure when sustained local immunosuppression is required. The 25 mL scale sterile batch production of hydrogels emphasizes their suitability for future translational applications. Full article

Kappa-carrageenan (κ-CRG) forms thermo-reversible physical hydrogels via a coil–helix transition and helix bundling, but its sulfate-driven electrostatic repulsion limits mechanical robustness and control over aqueous disintegration. Here, we show that plant-derived polyphenols reprogram κ-CRG gel through sulfate-directed binding in a structure-dependent manner. Tannic acid (TA) selectively engages κ-CRG sulfate groups, yielding transparent gels and a >5-fold increase in storage modulus, whereas the same TA triggers turbidity and precipitation in sulfate-free agarose, supporting sulfate-mediated specificity. Using monomeric pyrogallol as a galloyl analogue, we demonstrate that monovalent interactions partially reinforce κ-CRG but lack cooperative stabilization. Intervention timing further separates mechanism. Pyrogallol produces pathway-dependent mechanics and gelation temperature, while TA is stage-insensitive, consistent with multivalent network annealing. In simulated gastric/intestinal fluids, pyrogallol/κ-CRG gels retain morphology longer, whereas TA/κ-CRG ones disintegrate rapidly yet exhibit strong adhesion to rough substrates and human skin. These findings provide a fully food-grade route to tune κ-CRG mechanics, thermal behavior, adhesion and programmed disintegration. Full article

Inspired by their biocompatibility and thermoreversible gelation—transitioning from room temperature liquids to body temperature gels—Pluronic hydrogels were employed in this study to optimize intracanal penetration and ensure medicament stability. We developed a silver nanoparticle (AgNP)-loaded Pluronic gel (AgNPs-P-gel) as a biocompatible, easily removable intracanal medicament. Following PRILE 2021 guidelines, AgNPs-P-gels (F127/F68) were evaluated for gelation, AgNP release, and antibacterial activity against Enterococcus faecalis and Streptococcus mutans via minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and growth curves. Biofilms in bovine teeth were quantified using CFUs and scanning electron microscope (SEM) imaging. Biocompatibility was tested in L-929 fibroblasts using MTT assays and RT-qPCR for pro-inflammatory cytokines (IL-6, TNF-α, IL-1β). Removal efficacy from bovine canals was microscopically scored. The optimized formulation (20% F127, 7.5% F68) gelled at 34 °C with sustained release over 168 h. AgNPs-P-gel showed strong antibacterial activity (MIC: 25–50 µg/mL). In ex vivo models, 100 µg/mL AgNPs-P-gel (AgNPs-100-P-gel) reduced bacterial counts comparably to calcium hydroxide and chlorhexidine, but with lower cytotoxicity. Although inducing cytokine expression similar to conventional medicaments, AgNPs-P-gel demonstrated significantly superior removability. Thermoreversible AgNPs-P-gel offers sustained antimicrobial action, favorable biocompatibility, and superior removability, potentially improving endodontic disinfection predictability as a calcium hydroxide alternative. Full article

Oleuropein, the principal secoiridoid phenolic compound of olive leaves (Olea europaea L.), is recognized for its broad-spectrum antimicrobial, antibiofilm, antioxidant, and tissue-regenerative properties. However, its effective local therapeutic application remains challenging due to rapid clearance from the site of administration and limited residence time. In this study, an oleuropein-rich aqueous olive leaf extract was incorporated into a thermoresponsive sol–gel delivery system designed for localized application. The formulation was engineered to remain in a low-viscosity sol state at room temperature and to undergo a temperature-triggered sol-to-gel transition near physiological temperature (~33 °C), enabling in situ gel formation. Oleuropein content was quantified using a validated HPLC method, and the formulation was characterized with respect to physicochemical parameters, thermoreversible gelation behavior, particle size distribution, mechanical properties, and spreadability. Biological performance was evaluated through in vitro cytocompatibility (MTT assay), fibroblast migration (scratch assay), and collagen deposition (Sirius Red staining) in L929 fibroblasts, as well as antibiofilm activity against representative Gram-positive and Gram-negative bacterial strains. The developed sol–gel system demonstrated stable physicochemical characteristics, rapid and reversible thermogelation, suitable mechanical and spreading properties, concentration-dependent inhibition of biofilm formation, and acceptable cytocompatibility within the tested concentration range. Notably, the formulation supported fibroblast viability and collagen-associated responses at optimized concentrations. Overall, the results indicate that the proposed thermoresponsive sol–gel formulation represents a promising strategy for the localized delivery of oleuropein-rich olive leaf extract, combining physicochemical stability with dual wound-healing and antibiofilm functionality. Full article

This review presents a comprehensive analysis of modern thermosensitive polymer systems for in situ systems (ISSs) which are used for targeted drug delivery in situ. The main classes of polymers used to create “smart” hydrogels that undergo a “sol–gel” phase transition in response to a temperature stimulus in the physiological range are considered. Key representatives of thermosensitive matrices are described in detail: synthetic block copolymers (poloxamers, block copolymers of polylactic-co-polyglycolic acid with polyethyleneglycol, etc.) and natural, modified natural, and semi-synthetic polymers (chitosan, including in combination with β-glycerophosphate, xyloglucan, etc.). This paper systematizes the advantages and disadvantages of various thermosensitive systems and highlights the key risks in their pharmaceutical development, including the influence of the nature and concentration of the active pharmaceutical ingredients and excipients on the rheological properties and phase transition temperature. Particular attention is paid to the difference between thermoreversible and irreversible gel-forming systems. Modern in vitro, ex vivo, and in vivo methods for evaluating critical quality parameters of thermosensitive systems, such as gelation temperature and time, gel strength, mucoadhesive properties, and release kinetics, are discussed. The need to develop standardized and biologically relevant methods to improve the reproducibility and success of preclinical studies is emphasized. The review is intended to help researchers to make informed choices about polymer matrices and optimize compositions for successful pharmaceutical development. Full article

Gelatin is a commonly used protein-based hydrogel. However, the thermo-reversible nature of gelatin makes it unstable at physiological and higher temperatures. Therefore, this study adopted phosphates and glutaminase transaminase (TG) to modify gelation and studied the effects of combining sodium hexametaphosphate (SHP) and TG on the structure and gel properties of TG-crosslinked gelatin. This study focused on the effects of different SHP concentrations (0, 0.4, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8 mmol/L) on the water distribution, textural properties, rheological properties, and microstructure of the TG-crosslinked gelatin gels. Results showed that the free water content in the TG-crosslinked gelatin gel declined with the increasing SHP addition when the concentration of SHP was kept below 2.0 mmol/L. The gel of TG-crosslinked gelatin at the SHP concentration of 1.6 mmol/L exhibited the highest hardness (304.258 g), chewiness (366.916 g) and η₅₀. All the TG-crosslinked gelatin gels with SHP modification were non-Newtonian pseudoplastic fluids. The G′ and G″ of TG-crosslinked gelatin increased before the SHP concentration reached 1.6 mmol/L, and the TG-crosslinked gelatin with 1.6 mmol/L SHP exhibited the largest G″ and G′. The fluorescence intensity of TG-crosslinked gelatin with SHP concentration above 1.6 mmol/L decreased with the increasing SHP concentration. SHP modified the secondary structure of TG-crosslinked gelatin gels. The gel of TG-crosslinked gelatin with the SHP concentration of 1.6 mmol/L exhibited a porous, smooth, and dense network structure. This research provides references for modifying gelatin and the application of gels in the encapsulation of bioactive ingredients and probiotics. Full article

Oleogels (organogels) are systems resembling a solid substance based on the gelation of organic solvents (oil or non-polar liquid) through components of low molecular weight or oil-soluble polymers. Such compounds are organogelators that produce a thermoreversible three-dimensional gel network that captures liquid organic solvents. Oleogels based on natural oils are attracting more attention due to their numerous advantages, such as their unsaturated fatty acid contents, ease of preparation, and safety of use. As a result of the research, two oleogels were developed, into which freeze-dried alginate carriers with a probiotic, L. casei, were incorporated. Two techniques were used to produce probiotic-loaded capsules—extrusion and emulsification. Alginate beads obtained by the extrusion process have a size of approximately 1.2 mm, while much smaller microspheres were obtained using the emulsification technique, ranging in size from 8 to 17 µm. The trehalose was added as a cryoprotectant to improve the survival rate of probiotics in freeze-dried alginate carriers. The encapsulation efficiency for both of the methods applied, the emulsification and the extrusion technique, was high, with levels of 90% and 87%, respectively. The obtained results showed that the production method of probiotic-loaded microspheres influence the bacterial viability. The better strain survival in the developed systems was achieved in the case of microspheres produced by the emulsification (reduction in bacterial cell viability in the range of 1.98–3.97 log in silica oleogel and 2.15–3.81 log in sucragel oleogel after 7 and 30 days of storage) than by the extrusion technique (after a week and a month of oleogel storage, the decrease in cell viability was 2.52–4.52 log in silica oleogel and 2.48–4.44 log in sucragel oleogel). Full article

Supramolecular gels were developed by taking advantage of an assembly of small dipeptides containing pyrrolo-pyrazole scaffolds. The dipeptides were prepared through a robust and ecofriendly synthetic approach from the commercially available starting materials of diazoalkanes and maleimides. By playing with the functionalization of the scaffold, the choice of the natural amino acid, and the stereochemistry, we were able to obtain phase-selective gels. In particular, one peptidomimetic showed gelation ability and thermoreversibility in aromatic solvents at very low concentrations. Rheology tests showed a typical viscoelastic solid profile, indicating the formation of strong gels that were stable under high mechanical deformation. NMR studies were performed, allowing us to determine the conformational and stereochemical features at the base of the supramolecular interactions. Full article

Agarose forms a homogeneous thermoreversible gel in an aqueous solvent above a critical polymer concentration. Contrary to the prevailing consensus, recent confirmations indicate that agarose gels are also stable in non-solvents like acetone and ethanol. A previous study compared gel characterisations and behaviours in water and ethanol, discussing the gelation mechanism. In the current work, the ethanol gel is exchanged with water to explore the potential reversibility of the displacement of water in agarose. Initially, the structure is characterised using ¹H NMR in DMSO-d₆ and D₂O solvents. Subsequently, a very low yield (0.04) of methyl substitution per agarobiose unit is determined. The different gels after stabilisation are characterised using rheology, and their physical properties are compared based on the solvent used. The bound water molecules, acting as plasticizers in aqueous medium, are likely removed during the exchange process with ethanol, resulting in a stronger and more fragile gel. Next, the gel obtained after the second exchange from ethanol back to water is compared with the initial gel prepared in water. This is the first time where such gel has been characterised without undergoing a phase transition when switching from a good solvent to a non-solvent, and vice versa, thereby testing the reversibility of the solvent exchange. Reversibility of this behaviour is demonstrated through swelling and rheology experiments. This study extends the application of agarose in chromatography and electrophoresis. Full article

High-performance properties of interpenetration polymer network (IPN) hydrogels, based on physically crosslinked chitosan (CS) and chemically crosslinked poly(N-isopropylacrylamide) (PNiPAM), were successfully developed. The IPN of CS/PNiPAM is proposed to overcome the limited mechanical properties of the single CS network. In this study, the viscoelastic behaviors of prepared materials in both solution and gel states were extensively examined, considering the UV exposure time and crosslinker concentration as key factors. The effect of these factors on gel formation, hydrogel structures, thermal stabilities of networks, and HeLa cell adhesion were studied sequentially. The sol–gel transition was effectively demonstrated through the scaling law, which agrees well with Winter and Chambon’s theory. By subjecting the CS hydrogel to the process operation in an ethanol solution, its properties can be significantly enhanced with increased crosslinker concentration, including the shear modulus, crosslinking degree, gel strength, and thermal stability in its swollen state. The IPN samples exhibit a smooth and dense surface with irregular pores, allowing for much water absorption. The HeLa cells were adhered to and killed using the CS surface cationic charges and then released through hydrolysis by utilizing the hydrophilic/hydrophobic switchable property or thermo-reversible gelation of the PNiPAM network. The results demonstrated that IPN is a highly attractive candidate for anti-fouling materials. Full article

A simple model is introduced to describe phase behaviours of binary mixtures of a thermoreversible gel and a low-molecular-weight liquid crystal (LC). We predict novel phase diagrams on the temperature–concentration plane, including sol–gel transition, nematic–isotropic phase transition, and phase separation. At high temperatures, the phase separation between the isotropic sol and gel phases appears. As the temperature decreases, we have the phase separation between nematic sol and isotropic gel phases, in which the nematic domains are dispersed in the isotropic gel phase. We suggest that thermoreversible gelation of reactive molecules mixed with LCs will become one of the new classes of polymer-dispersed liquid crystals. Full article

Coil–rod copolymers with a dendritic polyethylene (DPE) core and multiple helical poly(γ-benzyl-L-glutamate) (PBLG) arms (DPE-(PBLG)_n) were prepared by palladium-catalyzed copolymerization in tandem with ring-opening polymerization (ROP). Macroinitiator (DPE–(NH₂)₁₁) was firstly prepared by the group transformation of DPE–(OH)₁₁ generated from palladium-catalyzed copolymerization of ethylene and acrylate comonomer. Coil–helical DPE-(PBLG)₁₁ copolymers were prepared by ROP of γ-benzyl-L-glutamate-N-carboxyanhydride (BLG-NCA). These DPE-(PBLG)₁₁ copolymers could form thermoreversible gels in toluene solvent, and the dendritic topology of the DPE core increased the critical gelation concentrations. The self-assembled nanostructure of gels was fully characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), small-angle X-ray scattering (SAXS), and wide-angle X-ray diffraction (WAXD), and the morphology of the fibrous structure was a twisted flat ribbon through a self-assembled nanoribbon mechanism. The self-assembled fibers formed by DPE-(PBLG₄₅)₁₁ are more heterogeneous and ramified than previously observed fibers formed by PBLG homopolymer and block copolymers. Full article

Structure and reversibility of cross-link junctions play pivotal roles in determining the nature of thermoreversible gelation and dynamic mechanical properties of the produced polymer networks. We attempt to theoretically explore new types of sol–gel transitions with mechanical sharpness by allowing cross-links to grow without upper bound. We consider thermoreversible gelation of the primary molecules R{A${}_f$} carrying the number f of low molecular weight functional groups (gelators) A. Gelators A are assumed to form supramolecular assemblies. Some examples are: telechelic polymers ($f=2$) carrying $\pi$–$\pi$ stacking benzene derivatives at their both ends, and trifunctional star molecules ($f=3$) bearing multiple hydrogen-bonding gelators. The sol–gel transition of the primary molecules becomes sharper with the cooperativity parameter of the stepwise linear growth of the cross-links. There is a polymerization transition (crossover without singularity) of the junctions in the postgel region after the gel point is passed. If the gelator A tends to form supramolecular rings competitively with linear chains, there is another phase transition in the deep postgel region where the average molecular weight of the rings becomes infinite (Bose–Einstein condensation of rings). As a typical example of binary cross-links where gelators A and B form mixed junctions, we specifically consider metal-coordinated binding of ligands A by metal ions B. Two types of multi-nuclear supramolecular complexes are studied: (i) linear stacking (ladder) of the sandwich A${}_2$B units, and (ii) linear train of egg-box A${}_4$B units. To find the strategy towards experimental realization of supramolecular cross-links, the average molecular weight, the gel fraction, the average length of the cross-link junctions are numerically calculated for all of these models as functions of the functionality f, the concentration of the solute molecules, and the temperature. Potential candidates for the realization of these new types of thermoreversible gelation are discussed. Full article

The present study aimed to prepare, characterize, and evaluate a thermo-responsive sol–gel for intranasal delivery of lamotrigine (LTG), which was designed for sustained drug delivery to treat epilepsy. LTG sol–gel was prepared using the cold method by changing the concentrations of poloxamer 407 and poloxamer 188, which were used as thermo-reversible polymers. The optimized formulations of sol–gel were analyzed for clarity, pH, viscosity, gelation temperature, gelation time, spreadability, drug content, in vitro drug release studies, ex vivo permeation studies, and in vivo toxicological studies. FTIR, XRD, and DSC were performed to determine the thermal stability of the drug and polymers. The prepared formulations had a clear appearance in sol form; they were liquid at room temperature and became gel at temperatures between 31 °C and 36 °C. The pH was within the range of the nasal pH, between 6.2 and 6.4. The drug content was found to be between 92% and 94%. In vitro drug release studies indicated that the formulations released up to 92% of the drug within 24 h. The FTIR, DSC, and XRD analyses showed no interaction between the drug and the polymer. A short-term stability study indicated that the formulation was stable at room temperature and at 4–8 °C. There was a slight increase in viscosity at room temperature, which may be due to the evaporation of the vehicle. A histological study indicated that there were no signs of toxicity seen in vital organs, such as the brain, kidney, liver, heart, and spleen. It can be concluded from the above results that the prepared intranasal sol–gel for the delivery of LTG is safe for direct nose-to-brain delivery to overcome the first-pass effect and thus enhance bioavailability. It can be considered an effective alternative to conventional drug delivery for the treatment of epilepsy. Full article

The aim of this study was to assess the gelling potential of chiral oxalamide derivatives in vegetable oils. Special emphasis was given to the potential applications of the examined oil gels as sustained delivery systems and as fat substitutes in food products. The applicability of oil gelators is envisaged in food, cosmetics, and the pharmaceutical industry. The regulations requiring the elimination of saturated fats and rising concerns among consumers health motivated us to investigate small organic molecules capable of efficiently transforming from liquid oil to a gel state. The oxalamide organogelators showed remarkable gelation efficiency in vegetable oils, thermal and mechanical stability, self-healing properties, and a long period of stability. The physical properties of the gels were analysed by TEM microscopy, DSC calorimetry, and oscillatory rheology. The controlled release properties of acetylsalicylic acid, ibuprofen, and hydrocortisone were analysed by the LC–MS method. The influence of the oil type (sunflower, soybean, and olive oil) on gelation efficiency of diverse oxalamide derivatives was examined by oscillatory rheology. The oxalamide gelators showed thermoreversible and thixotropic properties in vegetable oils with a minimum gelation concentration of just 0.025 wt%. The substitution of palm fats with gelled sunflower oil applied in cocoa and milk spreads at gelator concentrations lower than 0.2 wt% have shown promising viscoelastic properties compared to that of the original food products. Full article