Thermoresponsive Hydrogel Research Articles

Modular Synthetic Platform to Tailor Therapeutic-Specific Delivery in Injectable Hydrogels.

Injectable thermoresponsive hydrogels (thermogels), valued for their conformability and minimal invasiveness, are increasingly used as in situ forming implants for drug delivery and as regenerative scaffolds. These gels exhibit sol-to-gel phase transitions at body temperature. As localized depots and scaffolds, these gels determine the chemical and mechanical environments and could dramatically influence the release kinetics of drugs or the fate of cells. Current synthetic approaches for thermogels, however, often limit the ability to fully exploit interactions between the thermogel matrix and the encapsulated agent. In this study, we introduce a modular synthetic platform for creating a library of functionalized polyurethane thermogels that enables customization of gelation properties and intermolecular interactions. These thermogels can exhibit a wide range of stiffness, offer complementary ionic interactions, and enhance hydrophobic interactions and hydrogen bonding. By leveraging these tunable interactions between the thermogelling scaffold, functional groups, and encapsulated agents, we achieved sustained and controlled release, from days to over 6 months, for both low and high molecular weight drug analogs. Release profiles varied from monophasic to biphasic and triphasic depending on the compatibility between the thermogel properties and the encapsulated agents. The design rules identified here support the development of drug-specific formulations, facilitating precise, sustained, and modulated release tailored to therapeutic needs. Beyond providing an adaptable strategy for customizable injectable drug depots, this synthetic strategy lays the groundwork for future iterations of multi stimuli-responsive thermogels with enhanced bioactivity, advancing the potential for customizable, biointeractive therapeutic systems.

Laboratory synthesis and preparation of thermo-responsive polymeric micelle and hydrogel for resveratrol delivery and release

Laboratory synthesis and preparation of thermo-responsive polymeric micelle and hydrogel for resveratrol delivery and release

Formulation of Emulgels Containing Clotrimazole for the Treatment of Vaginal Candidiasis.

Vaginal candidiasis poses significant health concerns that affect approximately 75% of women globally and often leads to discomfort and a decrease in quality of life. Traditional treatments, despite their effectiveness, may cause discomfort and adverse effects, such as vaginal discharge, bleeding, and dryness, promoting the exploration of alternative formulations. In this study, we aimed to develop a novel therapeutic approach for the treatment of vaginal candidiasis utilizing oleic acid containing emulgels made from thermoresponsive poloxamer-based hydrogels. These emulgels were designed to provide a sustained release of clotrimazole, an antifungal agent. Incorporating oleic acid enhanced the drug's solubility and contributed to vaginal health. The formulations were characterized by their rheological properties, in vitro release, mucoadhesion, and spreadability. We conducted rheological measurements on the hydrogels that served as the base for the emulgels, as well as on the emulgels themselves. The emulgels exhibited continuous rheological behavior with changing temperatures, making them suitable for storage at room temperature. With an increasing HPMC content, we achieved enhanced mucoadhesion, which is beneficial for formulations used in body cavities. Moreover, in vitro release studies revealed sustained drug release profiles, which can be adjusted by varying the ratios of poloxamers and HPMC. These findings suggest that the developed emulgels offer a promising therapeutic option for vaginal candidiasis, addressing both the symptoms and the treatment of discomfort.

Numerical modeling of heterogeneous stimuli-responsive hydrogels

In this paper, we introduce a computational technique for modeling heterogeneous thermoresponsive hydrogels. The model resolves local fluid-solid interactions in hydrogel pores during the deswelling process. The model is a Lagrangian particle-based technique, which benefits from computational grids that represent polymer beads inside hydrogel scaffolds. The results show that the mechanical properties of hydrogels during deswelling, e.g., shrinkage ratio and elastic modulus, have a direct effect on the development of the front of expelled fluid. It is also observed that in certain parameter regimes the hydrogel may generate inertial fluid jets at the early stages of deswelling. Finally, simple heterogeneous designs are developed using Menger sponge-inspired shapes to investigate the effect of design heterogeneity on promoting directional release. Published by the American Physical Society 2024

Photochemical Patterning and Characterization of Mechanical Properties on Soft Materials

AbstractAlthough different chemistries for the spatio‐temporal localization of molecules and gradients of chemical signals within soft materials are now available, the achievement of spatio‐temporal patterns of mechanical properties in such materials and their characterization remain considerable challenges. This study presents the syntheses of two novel photo‐sensitive and thermoresponsive hydrogel systems, a photo‐stiffening and a photo‐softening hydrogel. Their potential for fabricating soft materials with patterned mechanical properties is then demonstrated by fabricating an actuator whose higher‐order bending properties can be switched on with light, and by encoding mechanical properties for digital information encryption and storage. Microindentation and a custom‐made data analysis software are essential for the characterization of all the materials. From a general perspective, this work opens a route to the fabrication of soft materials with patterned mechanical properties, addressing an important emerging challenge in soft materials science with applications in soft robotics and information encryption and storage.

Toward a Plasmon-Based Biosensor throughout a Thermoresponsive Hydrogel.

This study investigates the potential of thermoresponsive hydrogels as innovative substrates for future in vitro diagnostic (IVD) applications using AVAC technology, developed and patented by the Mecwins biomedical company. In order to convert the hydrogel in a substrate compatible with AVAC technology, the following prerequisites were established: (1) the hydrogel layer needs to be permeable to gold nanoparticles (AuNPs), and (2) the optical properties of the hydrogel should not interfere with the detection of AuNPs with AVAC technology. These two key aspects are evaluated in this work. A silicon substrate (Sil) was coated with a layer of a thermosensitive hydrogel (TSH) based on poly(N-isopropylacrylamide-co-N,N'-methylene bis(acrylamide) (PNIPAAm-co-MBA). The TSH offers the advantage of easy modulation of its porosity through cross-linker adjustments, crucial for the plasmonic nanoparticle (NP) permeation. The platforms, denominated as (Sil)-g-(PNIPAAm-co-MBA), were fabricated by changing the cross-linker concentrations and exploring three deposition methods: drop casting (DC), spin coating (SC), and 3D printing (3D); the DC approach resulted in a very homogeneous and thin hydrogel layer, very suitable for the final application. Furthermore, after physical-chemical characterization, the TSH demonstrated its functionality in regulating nanoparticle absorption, and AVAC technology's capability to precisely identify such NPs through the hydrogel matrix was validated. The proposed hydrogel platform fulfills the initial requirements, opening the possibility for employing these hydrogels as dynamic substrates in sandwich immunoassay devices. The next step in the development of the hydrogel substrate would be its functionalization with biorecognition groups to allow for biomarker detection. By leveraging their enhanced capture efficiency and the ability to manipulate particle flow thermally, we anticipate a significant advancement in diagnostic methodologies, combining the spatial benefits of three-dimensional hydrogel structures with the precision of AVAC's digital detection.

Thermo-responsive hydrogel loading hypericin induces pro-inflammatory response against trichinella spiralis infection via toll-like receptor 3 activation

Thermo-responsive hydrogel loading hypericin induces pro-inflammatory response against trichinella spiralis infection via toll-like receptor 3 activation

Temperature-Responsive Injectable Composite Hydrogels Based on Poly(N-Isopropylacrylamide), Chitosan, and Hemp-Derived Cellulose Nanocrystals.

Injectable and temperature-responsive Poly(N-Isopropylacrylamide) (PNIPAAm)/Chitosan composite hydrogels reinforced with cellulose nanocrystals (CNCs) were successfully fabricated via photopolymerization. 0.1-3% (w/v) of cellulose nanocrystals were incorporated into the PNIPAAm/chitosan matrix to form thermo-responsive injectable composite hydrogels. FT-IR spectra confirmed the successful formation of these hydrogels, highlighting the characteristic peaks PNIPAAm, chitosan and CNCs. The inclusion of CNCs led to a reduced pore size as compared to the control hydrogels. The mechanical properties of the hydrogel were characterized under various temperature conditions. Rheology tests showed that storage modulus (G') increased significantly above 30 °C, indicating gel-like behavior. Thermogravimetric analysis showed thermal stability up to 300 °C. The volume phase transition temperatures (VPTT) of the hydrogels were found to be in the range of 34-38 °C, close to physiological body temperature. The equilibrium swelling ratio (ESR) of the CNC-containing hydrogels was higher than that of the control. In vitro studies with Human Dermal Fibroblast adult (HDFa) cells showed the hydrogels to be non-toxic, suggesting their potential for biomedical applications.

Bioinspired Hydro- and Hydrothermally Responsive Tubular Soft Actuators.

Soft actuators made of thermoresponsive polymers have great potential for intelligent robotics and biomedical devices due to their reversible deformation capability in response to temperature fluctuations. However, they are constrained by a predefined phase transition temperature, limited directional deformation, and nonbiocompatible formulations, thereby restricting their practical utility. Herein a new biomimicry approach is presented to overcome these limitations by developing hydro- and hydrothermally responsive soft actuators made of biocompatible and pliable materials i.e. cotton yarn and polyurethane. We mimic the tubular shape of elephant trunks with their unique muscle orientation by embedding a helical cotton yarn within a hydrophilic polyurethane tube, followed by targeted surface patterning. Unlike the narrow-range shape morphing across the phase transition temperature boundary of typical thermoresponsive hydrogel actuators, we harness hydrothermal stiffness variations in polyurethane to obtain consistent morphing capabilities over a much wider temperature range. The developed actuators can perform versatile activities such as linear, bending, curvilinear, and rotating movements, overcoming the unidirectional motion limitations of conventional soft actuators. The cell viability assay on the building block materials also confirms the high biocompatibility of the actuators. The reported facile fabrication strategy provides new insights for designing complex yet free-standing soft actuators from readily available supple materials.

Multifunctional poloxamer-based thermo-responsive hydrogel loaded with human lactoferricin niosomes: In vitro study on anti-bacterial activity, accelerate wound healing, and anti-inflammation

Chronic wound infections are attributed to delayed tissue repair, which remains a major clinical challenge in long-term health care. Particularly, infections with antibiotic resistance have more serious effects on health, often resulting in unsuccessful treatments. Thus, antimicrobial peptide (AMP)-based therapy holds promise as a potential therapeutic approach to overcoming drug resistance. Conventional wound dressing is a passive strategy for wound care that is not capable of eradicating pathogens and promoting tissue repair. In this study, we aim to construct an advanced wound dressing; a thermo-responsive hydrogel incorporated with lactoferricin (Lfcin) niosome (Lfcin-Nio/hydrogel) for bacterial pathogen treatment. The Lfcin-loaded niosome (Lfcin-Nio) has a particle size of 396.91 ± 20.96 nm, 0.38 ± 0.01 of PdI, −10.5 ± 0.3 mV of ζ potential, and 72.30 ± 7.05 % Lfcin entrapment efficiency. Lfcin-Nio exhibited broad antibacterial activity on both drug-susceptible and drug-resistant strains, and also on bacteria residing in the biofilm matrix. The Lfcin-Nio/hydrogel was fabricated from 0.5 % w/v poloxamer 188–20 % w/v poloxamer 407, and supplemented with Lfcin-Nio and epidermal growth factor (EGF). The physical properties of Lfcin-Nio/hydrogels showed elasticity, swelling ability, and strong injectability with responsiveness to 33–37 °C temperatures. The biological properties of Lfcin-Nio/hydrogels exhibited a bactericidal effect against drug-resistant strains of S. aureus and P. aeruginosa, and showed less toxicity to the human skin fibroblast. It also promoted the healing of scratches by 55 % within 6 h, compared to the wound closure rate of 20 % in the cell control. The inflammatory response of the Lfcin-Nio/hydrogel-treated cells was reduced via suppression of IL-1β and COX-2 mRNA expressions. From this study, Lfcin-Nio/hydrogels can be suggested as a modern wound dressing that possesses multifunctional and beneficial properties for the management of chronic wound infections.

Rapid Photoinduced Self-Healing, Controllable Drug Release, Skin Adhesion Ability, and Mechanical Stability of Hydrogels Incorporating Linker-Modified Gold Nanoparticles and Nanogels.

Appropriately modified thermoresponsive hydrogels, such as poly(N-isopropylacrylamide) hydrogels, bring an opportunity for a variety of biomedical applications. Incorporating compounds with different properties into poly(N-isopropylacrylamide) hydrogels offers opportunities to enhance their mechanical, self-healing ability, adhesiveness, thermal responsiveness, and drug release capabilities. In this study, we investigated the influence of Au-sulfur interactions on the properties of the poly(N-isopropylacrylamide) hydrogels after introducing N,N'-bis(acryloyl)cystine (a newly synthesized cross-linker), modified gold nanoparticles, and a p(NIPAm-BISS) nanogel into the hydrogel matrix. Our findings demonstrated that poly(N-isopropylacrylamide) hydrogels with these compounds exhibited higher mechanical strength (65% tensile stress and 25% elongation), faster thermal responsiveness, controllable self-healing [85% recovery after 2 min, using a NIR laser (800 nm, 0.75 W)], skin adhesiveness, and enhanced drug release (0.08 mg·mL-1, a 93% improvement). These results may contribute to advancements in the design of temperature-responsive hydrogels tailored for specific biomedical needs, such as targeted drug delivery with the use of a NIR laser and tissue engineering.

Phase-changing NIPAM-AM/ATO hydrogels for thermochromic smart windows with highly adaptive solar modulation

Improving the solar regulation and reducing the response temperature of thermochromic smart windows are pivotal importance for energy-saving buildings. However, these two strategies are challenging to be integrated into one window. Herein, a novel composite hydrogel based on N-isopropylacrylamide (NIPAM) doped with antimony-doped tin oxide (ATO) nanoparticles and acrylamide (AM) was developed for producing a high-performance smart window, which successfully achieved enhanced solar energy regulation and reduced response temperature. This smart window was fabricated by combining a reversible thermoresponsive hydrogel (TAH) that acted as a thermochromic material with a ATO multilayer film that performed as a transparent heater. The as-prepared smart window could modulate solar light over a range from ultraviolet (UV) to infrared (IR) radiation and achieved active responses to high-temperature weather. The smart window showed high luminous transmittance (Tlum, 82.92 %) together with an excellent solar modulation performance (ΔTlum = 73.31 %, ΔTIR = 38.26 %, and ΔTsol = 60.74 %), and a lower critical solution temperature of 32 °C. Even after 120 high- and low-temperature cyclic durability tests, the smart windows still exhibited a high solar modulation capability. In outdoor demonstrations, the as-prepared smart window exhibited a promising temperature regulation ability under strong solar irradiation. Therefore, the present universal modification framework provided some insights for the future design of energy-saving windows.

Multi-physics numerical simulation study on thermo-sensitive gel delivery for a local post-tumor surgery treatment

Numerous studies in the literature have proposed the use of thermo-responsive hydrogels for filling cavities after tumor resection. However, optimizing the injection process is challenging due to the complex interplay of various multi-physics phenomena, such as the coupling of flow and heat transfer, multi-phase interactions, and phase-change dynamics. Therefore, gaining a fundamental understanding of these processes is crucial. In this study, we introduce a thermo-sensitive hydrogel formulated with poloxamer 407 and Gellan gum as a promising filling agent, offering an ideal phase-transition temperature along with suitable elastic and viscous modulus properties.We performed multi-physics simulations to predict the flow and temperature distributions during hydrogel injection. The results suggested that the hydrogel should be kept at 4 °C and injected within 90 s to avoid reaching the transition temperature. Cavity filling simulations indicated a symmetric distribution of the hydrogel, with minimal influence from the syringe's position.The temperature gradient at the cavity edge delays gelation during injection, which is essential to guarantee its administration as a liquid. The hydrogel's viscosity follows a sigmoidal function relative to temperature, taking five minutes to reach its maximum value. In summary, the multi-physics simulations carried out in this study confirm the potential of thermo-responsive hydrogels for use in post-tumor surgery treatment and define the conditions for a proper administration. Furthermore, the proposed model can be widely applied to other thermo-responsive hydrogels or under different conditions.

Synthesis and characterization of methacryl glycol chitosan as a novel functionally advanced thermogel for biomedical applications

Thermo-responsive hydrogels (thermogels), known for their sol-gel transition capabilities, have garnered significant interest for biomedical applications over recent decades. However, conventional thermogels are hindered by intrinsic physicochemical and functional limitations that impede their broader utility. This study introduces methacryl glycol chitosan (MGC) as a novel thermogel, offering enhanced functionality and addressing these limitations. MGCs, synthesized through N-methacrylation of glycol chitosan, exhibit tunable thermogelling and photo-crosslinking behaviors. The thermo-reversible sol-gel transition of MGCs occurs within a 21–54 °C range, adjustable by polymer concentration and methacryl substitution degree. Photo-crosslinking using UV light further enhances the mechanical properties of MGC thermogels, creating thermo-irreversible, chemically crosslinked hydrogels. MGCs show no cytotoxic effects and effectively support cell encapsulation. In vivo studies demonstrate stable crosslinking with minimal UV-induced skin damage. Due to their unique thermo-sensitivity, multi-functionality, and customizable properties, MGC thermogels are promising novel biomaterials for various biomedical applications, particularly injectable tissue engineering and cell encapsulation, thus overcoming the limitations of conventional thermogels.

Thermo-Responsive Hydrogel Based on Lung Decellularized Extracellular Matrix for 3D Culture Model to Enhance Cancer Stem Cell Characteristics.

Cancer stem cells (CSCs) are most likely the main cause of lung cancer formation, metastasis, drug resistance, and genetic heterogeneity. Three-dimensional (3D) ex vivo cell culture models can facilitate stemness improvement and CSC enrichment. Considering the critical role of extracellular matrix (ECM) on CSC properties, the present study developed a thermo-responsive hydrogel using the porcine decellularized lung for 3D cell culture, and the cell-laden hydrogel culturing model was used to explore the CSC characteristics and potential utilization in CSC-specific drug evaluation. Results showed that the lung dECM hydrogel (LEH) was composed of the main ECM components and displayed excellent cellular compatibility. In addition, lung cancer cells 3D cultured in LEH displayed the overexpression of metastasis-related genes and enhanced migration properties, as compared with those in two-dimensional (2D) conditions. Notably, the CSC features, including the expression level of stemness-associated genes, colony formation capability, drug resistance, and the proportion of cancer stem-like cells (CD133+), were also enhanced in 3D cells. Furthermore, the attenuation effect of epigallocatechin gallate (EGCG) on CSC properties in the 3D model was observed, confirming the potential practicability of the 3D culture on CSC-targeted drug screening. Overall, our results suggest that the fabricated LEH is an effective and facile platform for 3D cell culture and CSC-specific drug evaluation.

Digital Light Processing of Thermoresponsive Hydrogels from Polyproline-Based Star Polypeptides.

The first report of star poly(L-proline) crosslinkers is disclosed for digital light processing 3D printing of thermoresponsive hydrogels. Through chain end functionalization of star poly(L-proline)s with methacryloyl groups, access to high-resolution defined 3D hydrogel structures via digital light processing is achieved through photoinitiated free radical polymerization. Changing the poly(L-proline) molecular weight has a direct influence on both thermoresponsiveness and printability, while shape-morphing behavior can be induced thermally.

Nanoarchitectonics in Macromolecular Science: Integrating Molecular Dynamics with Smart Materials

Nanoarchitectonics represents a transformative approach in macromolecular science, extending beyond traditional nanotechnology by emphasizing the precise design and construction of complex materials through controlled molecular interactions. This review explores the integration of nanoarchitectonics with molecular dynamics, a powerful computational tool that enables the prediction and optimization of material behavior at the atomic level. The synergy between these two fields allows for the rational design of smart materials that respond dynamically to environmental stimuli, such as temperature, light and mechanical stress. These materials, including thermo-responsive hydrogels, photochromic polymers and self-healing coatings, demonstrate the significant potential of nanoarchitectonics in creating materials with tailored properties for diverse applications. By leveraging molecular dynamics, researchers can gain insights into the energy landscapes and interaction patterns that drive the self-assembly and functionality of these materials, leading to enhanced performance and novel functionalities. This review also examines the future perspectives of nanoarchitectonics, highlighting the potential of integrating artificial intelligence and machine learning with it to further revolutionize material design. As the field advances, the combination of nanoarchitectonics and molecular dynamics is expected to unlock new possibilities in macromolecular science, offering innovative solutions for applications ranging from biomedical devices to environmental remediation. The review concludes by discussing the challenges and opportunities in translating these innovations from the laboratory to real-world applications, emphasizing the need for interdisciplinary collaboration to fully realize the potential of nanoarchitectonic materials in addressing global challenges.

Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal angiogenesis

Retinal neovascularization is a leading cause of blindness. While current anti-VEGF drugs effectively inhibit pathological angiogenesis, some patients develop resistance or reduced responsiveness to treatments over time, leading to diminished effectiveness. In this study, we identified high activation of the cGAS-STING signaling pathway, which exacerbated pathological neovascularization and vessel leakage. We developed an injectable thermo-responsive supramolecular hydrogel loaded with an anti-STING drug. The hydrogel, made of Pluronic F127 demonstrated excellent transparency and biocompatibility. Importantly, the thermo-sensitive property allowed for precise spatial release of the drug, extending the effective treatment duration of C-176, which suppressed STING activation in the retina, reduced inflammation and protected retinal tissue. HydroC-176 effectively inhibited microglial cell infiltration and the release of inflammatory angiogenic factors, highlighting its enhanced efficacy. While demonstrating slightly lower effectiveness compared to traditional anti-VEGF therapy, HydroC-176 exhibited more robust capabilities in regulating ocular microenvironmental inflammation. This approach may assist in enhancing the sensitivity and effectiveness of anti-VEGF therapy for reducing ocular inflammation, potentially improving patients’ response to traditional treatment. These results have suggested innovative and comprehensive strategies for the management of retinal neovascularization.

Synthesis and in vitro study of biodegradable and thermoresponsive polymer based on polysuccinimide for drug delivery

Hydrogels, defined as polymer networks with a high water content and insoluble in water, have emerged as pivotal materials in biomedical research due to their resemblance to the natural extracellular matrix. The aim of this study is to develop an injectable, thermoresponsive, and biodegradable hydrogel. The hydrogel (PSI-t) was derived from poly (aspartic acid) (PSI) by grafting hydrophobic dodecylamine (DA) and hydrophilic ethanolamine (EA) groups onto its backbone. PSI-t was found to exhibit a unique sol state at room temperature, which facilitates facile injection, and undergoes rapid gelation at physiological temperatures, highlighting its potential as an injectable thermosensitive hydrogel for targeted drug delivery. In vitro tests confirmed the biocompatibility of the thermosensitive hydrogel, and sustained drug release studies using the model drug, acetaminophen (AP), underscored the efficacy of the hydrogel as a controlled release vehicle. Furthermore, the hydrogel was found to be easily eliminated through bio-hydrolysis, thus enabling prolonged drug effects while mitigating any potential toxicity. These findings suggest that PSI-t is a promising candidate for an innovative and injectable drug delivery system in biomedical applications.

Thermo-Responsive Hydrogel Containing Microfluidic Chitosan Nanoparticles Loaded with Opuntia ficus-indica Extract for Periodontitis Treatment.

Periodontitis is a chronic inflammatory disease resulting from the dysbiosis of periodontal bacteria and the host's immune response, leading to tissue degradation and sustained inflammation. Traditional treatments, such as mechanical debridement and antimicrobial agents, often fail to fully eradicate pathogenic bacteria, especially in deep periodontal pockets. Consequently, the need for novel therapeutic approaches has increased the interest in bioactive natural extracts, such as that of Opuntia ficus-indica, known for its anti-inflammatory, antioxidant, and antimicrobial properties. This study investigates the encapsulation of Opuntia ficus-indica extract in OFI-loaded chitosan nanoparticles (OFI-NPs) via ionotropic gelation using a microfluidic system, allowing precise control over nanoparticle characteristics and enhancing protection against enzymatic degradation. To achieve localized and sustained release in periodontal pockets, a thermo-responsive hydrogel comprising hyaluronic acid and Pluronic F127 (OFI@tgels) was developed. The transition of OFI@tgels from a solution at low temperatures to a solid at body temperature enables prolonged drug release at inflammation sites. The in vitro application of the optimized formulation eradicated biofilms of S. mutans, P. aeruginosa (PAO1), and P. gingivalis over 36 h and disrupted extracellular polymeric substance formation. Additionally, OFI@tgel modulated immune responses by inhibiting M1 macrophage polarization and promoting a shift to the M2 phenotype. These findings suggest that OFI@tgel is a promising alternative treatment for periodontitis, effectively reducing biofilm formation and modulating the immune response.