Stimuli-responsive Hydrogels Research Articles

Progress of Research in In Situ Smart Hydrogels for Local Antitumor Therapy: A Review.

Cancer seriously threatens human health. Surgery, radiotherapy and chemotherapy are the three pillars of traditional cancer treatment, with targeted therapy and immunotherapy emerging over recent decades. Standard drug regimens are mostly executed via intravenous injection (IV), especially for chemotherapy agents. However, these treatments pose severe risks, including off-target toxic side effects, low drug accumulation and penetration at the tumor site, repeated administration, etc., leading to inadequate treatment and failure to meet patients’ needs. Arising from these challenges, a local regional anticancer strategy has been proposed to enhance therapeutic efficacy and concomitantly reduce systemic toxicity. With the advances in biomaterials and our understanding of the tumor microenvironment, in situ stimulus-responsive hydrogels, also called smart hydrogels, have been extensively investigated for local anticancer therapy due to their injectability, compatibility and responsiveness to various stimuli (pH, enzyme, heat, light, magnetic fields, electric fields etc.). Herein, we focus on the latest progress regarding various stimuli that cause phase transition and drug release from smart hydrogels in local regional anticancer therapy. Additionally, the challenges and future trends of the reviewed in situ smart hydrogels for local drug delivery are summarized and proposed.

Catch bond-inspired hydrogels with repeatable and loading rate-sensitive specific adhesion.

Biological receptor-ligand adhesion governed by mammalian cells involves a series of mechanochemical processes that can realize reversible, loading rate-dependent specific interfacial bonding, and even exhibit a counterintuitive behavior called catch bonds that tend to have much longer lifetimes when larger pulling forces are applied. Inspired by these catch bonds, we designed a hydrogen bonding-meditated hydrogel made from acrylic acid-N-acryloyl glycinamide (AA-NAGA) copolymers and tannic acids (TA), which formed repeatable specific adhesion to polar surfaces in an ultra-fast and robust way, but hardly adhered to nonpolar materials. It demonstrated up to five-fold increase in shear adhesive strength and interfacial adhesive toughness with external loading rates varying from 5 to 500 mm min−1. With a mechanochemical coupling model based on Monte Carlo simulations, we quantitatively revealed the nonlinear dependence of rate-sensitive interfacial adhesion on external loading, which was in good agreement with the experimental data. Likewise, the developed hydrogels were biocompatible, possessed antioxidant and antibacterial properties and promoted wound healing. This work not only reports a stimuli-responsive hydrogel adhesive suitable for multiple biomedical applications, but also offers an innovative strategy for bionic designs of smart hydrogels with loading rate-sensitive specific adhesion for various emerging areas including flexible electronics and soft robotics.

Design and application of stimuli-responsive DNA hydrogels: A review.

Deoxyribonucleic acid (DNA) hydrogels combine the properties of DNAs and hydrogels, and adding functionalized DNAs is key to the wide application of DNA hydrogels. In stimuli-responsive DNA hydrogels, the DNA transcends its application in genetics and bridges the gap between different fields. Specifically, the DNA acts as both an information carrier and a bridge in constructing DNA hydrogels. The programmability and biocompatibility of DNA hydrogel make it change macroscopically in response to a variety of stimuli. In order to meet the needs of different scenarios, DNA hydrogels were also designed into microcapsules, beads, membranes, microneedle patches, and other forms. In this study, the stimuli were classified into single biological and non-biological stimuli and composite stimuli. Stimuli-responsive DNA hydrogels from the past five years were summarized, including but not limited to their design and application, in particular logic gate pathways and signal amplification mechanisms. Stimuli-responsive DNA hydrogels have been applied to fields such as sensing, nanorobots, information carriers, controlled drug release, and disease treatment. Different potential applications and the developmental pro-spects of stimuli-responsive DNA hydrogels were discussed.

Stimuli-responsive conductive hydrogel touch sensor for electrochemical and fluorescence monitoring of acetylcholinesterase activity and inhibition

In this study, we produced a stimuli-responsive electrochemical and fluorescence biosensor using carbonized diselenide-crosslinked polymer dot-loaded polydopamine nanoparticles (PDA@dsPD) incorporated into polyvinyl alcohol/chitosan hydrogel, to examine the activity and inhibition of acetylcholinesterase (AChE). The PDA@dsPD inside the hydrogels (i.e., PDA@dsPD-Hydrogel) was sensitive to AChE in the presence of acetylthiocholine, which formed thiocholine that dissolved the diselenide bonds and simultaneously released polydopamine nanoparticles; this affected the optical and electronic performance of the hydrogel. The electronic response-based pressure and strain on the PDA@dsPD-Hydrogel shifted to 23 % when the AChE concentration was 300 U/L, while in the absence of AChE, this value shifted to 46 %. The PDA@dsPD-Hydrogels were able to visualize the AChE fluorescence signal expressed by PC-12 cells, in addition to an increase in electronic conductivity after the cleavage of the diselenide bond. In contrast, no change in the electrochemical or fluorescence signals was observed in the presence of neostigmine, an AChE inhibitor. The novel PDA@dsPD-Hydrogel can even be connected to a wireless electronic device to facilitate the detection of AChE via smartphones.

Thermal-Responsive MXene-DNA Hydrogel for Near-Infrared Light Triggered Localized Photothermal-Chemo Synergistic Cancer Therapy.

Stimuli-responsive DNA hydrogels are promising candidates for cancer treatment, as they not only possess biocompatible and biodegradable 3D network structures as highly efficient carriers for therapeutic agents but also are capable of undergoing programmable gel-to-solution transition upon external stimuli to achieve controlled delivery. Herein, a promising platform for highly efficient photothermal-chemo synergistic cancer therapy is established by integrating DNA hydrogels with Ti3 C2 TX -based MXene as a photothermal agent and doxorubicin (DOX) as a loaded chemotherapeutic agent. Upon the irradiation of near-infrared light (NIR), temperature rise caused by photothermal MXene nanosheets triggers the reversible gel-to-solution transition of the DOX-loaded MXene-DNA hydrogel, during which the DNA duplex crosslinking structures unwind to release therapeutic agents for efficient localized cancer therapy. Removal of the NIR irradiation results in the re-formation of DNA duplex structures and the hydrogel matrix, and the recombination of free DOX and adaptive hydrogel transformations can also be achieved. As demonstrated by both in vitro and in vivo models, the MXene-DNA hydrogel system, with excellent biocompatibility and injectability, dynamically NIR-triggered drug delivery, and enhanced drug uptake under mild hyperthermia conditions, exhibits efficient localized cancer treatment with fewer side effects to the organisms.

Ultrasound-Induced Drug Release from Stimuli-Responsive Hydrogels.

Stimuli-responsive hydrogel drug delivery systems are designed to release a payload when prompted by an external stimulus. These platforms have become prominent in the field of drug delivery due to their ability to provide spatial and temporal control for drug release. Among the different external triggers that have been used, ultrasound possesses several advantages: it is non-invasive, has deep tissue penetration, and can safely transmit acoustic energy to a localized area. This review summarizes the current state of understanding about ultrasound-responsive hydrogels used for drug delivery. The mechanisms of inducing payload release and activation using ultrasound are examined, along with the latest innovative formulations and hydrogel design strategies. We also report on the most recent applications leveraging ultrasound activation for both cancer treatment and tissue engineering. Finally, the future perspectives offered by ultrasound-sensitive hydrogels are discussed.

Ionic coordination strengthening of temperature-driven gradient hydrogel actuators with rapid responsiveness

Emerging applications of stimuli-responsive hydrogels as soft actuators and robotics have attracted great attention, but they face challenges in practical applications due to their poor mechanical properties, low driving force, and low actuation speed. Herein, we presented tough hydrogel actuators composed of a copolymer of N-isopropylacrylamide (NIPAM) and 3-sulfopropyl methacrylate potassium salt (SPA) monomers, and tunicate cellulose nanocrystals (TCNCs). The negatively charged TCNCs as nanofillers were gradient arranged by a direct current electric field (DC-EF) via electrophoresis. After in situ polymerization, TCNCs gradient distributed across the thickness of hydrogel, resulting in the formation of gradient crosslinking density of networks. Hydrogel actuators with high strength were obtained via Zr4+/−SO3- ionic coordination, whose tensile strength was about 200 times of hydrogel without ionic coordination. These hydrogel actuators exhibited rapid bending velocity, excellent stability, and good cycling performance in response to temperature. Importantly, these hydrogel actuators could be designed as soft robots to lift and transport objects by changing environment temperature. This work provided a facile yet efficient strategy to fabricate soft actuators with high strength and rapid responsiveness.

Applications and Mechanisms of Stimuli-Responsive Hydrogels in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a global neurotrauma with high morbidity and mortality that seriously threatens the life quality of patients and causes heavy burdens to families, healthcare institutions, and society. Neuroinflammation and oxidative stress can further aggravate neuronal cell death, hinder functional recovery, and lead to secondary brain injury. In addition, the blood–brain barrier prevents drugs from entering the brain tissue, which is not conducive to the recovery of TBI. Due to their high water content, biodegradability, and similarity to the natural extracellular matrix (ECM), hydrogels are widely used for the delivery and release of various therapeutic agents (drugs, natural extracts, and cells, etc.) that exhibit beneficial therapeutic efficacy in tissue repair, such as TBI. Stimuli-responsive hydrogels can undergo reversible or irreversible changes in properties, structures, and functions in response to internal/external stimuli or physiological/pathological environmental stimuli, and further improve the therapeutic effects on diseases. In this paper, we reviewed the common types of stimuli-responsive hydrogels and their applications in TBI, and further analyzed the therapeutic effects of hydrogels in TBI, such as pro-neurogenesis, anti-inflammatory, anti-apoptosis, anti-oxidation, and pro-angiogenesis. Our study may provide strategies for the treatment of TBI by using stimuli-responsive hydrogels.

Electro and magnetoactive printed bi-functional actuators based on alginate hybrid hydrogels

Soft materials are attracting much attention for the development of biostructures able to mimic the movement of natural systems by remote actuation. Multi-sensitive hydrogels are among the best materials for obtaining dynamic and biocompatible soft structures for soft actuators and related biomedical devices. Nevertheless, bioinks based on naturally occurring and stimuli responsive hydrogels able to be 3D printed continues being a challenge for advanced applications. In this work 3D printable electrically and magnetically responsive, non-cytotoxic, hybrid hydrogels based on alginate and zero monovalent iron nanoparticles (NPs) are presented. The effect of NPs addition on the physico-chemical properties of the hydrogels is addressed, together with its effect on the functional electroactive and magnetoactive response. NPs concentration up to 10 % do not affect the mechanical stability of the gels, while promoting an increase actuation response.

Photo-responsive hydrogel-based re-programmable metamaterials

This paper explores a novel programmable metamaterial using stimuli-responsive hydrogels with a demonstration of bandgap formation and tuning. Specifically, a photo-responsive hydrogel beam that can achieve re-programmable periodicity in geometric and material properties through patterned light irradiation is designed. Hydrogels consist of polymeric networks and water molecules. Many unique properties of hydrogels, including bio-compatibility, stimuli-responsiveness, and low dissipation make them ideal for enabling re-programmable metamaterials for manipulating structural dynamic response and wave propagation characteristics. Bandgap generation and tunability in photo-responsive hydrogel-based metamaterial (in the form of a diatomic phononic chain) as well as the effects of system parameters such as light exposure pattern and photo-sensitive group concentration on the bandgap width and center frequency are systematically studied. In agreement with finite-element model simulations, it is observed that an increase in light exposure region size reduces both the bandgap width and center frequency, while an increase in the concentration of photo-sensitive group increases bandgap width, attenuation and reduces its center frequency. This work unveils the potential of stimuli-response hydrogels as a new class of low-loss soft metamaterials, unlike most other soft materials that are too lossy to sustain and exploit wave phenomena.

CuCo2S4 nanozyme-based stimulus-responsive hydrogel kit for rapid point-of-care testing of uric acid.

An efficient analysis platform composed of nanozyme-based hydrogel kit and smartphone was constructed for on-site detection of uric acid (UA) in a rapid and realiable manner. CuCo2S4 nanoparticles (CuCo2S4 NPs) as a peroxidase mimic were successfully prepared and the peroxidase-like activity and catalytic mechanism were studied in detail. The hydrogen peroxide (H2O2) stimulus-responsive nanozyme-based hydrogel kit was manufactured by integrating agarose, CuCo2S4 NPs, and 3,3',5,5'-tetramethylbenzidine (TMB) into the cap of centrifuge tube. H2O2 generated via UA oxidation acts as stimulus signal, which triggers the oxidation of TMB to form blue product (oxTMB) under the catalysis of CuCo2S4 NPs, resulting in the color response of the constructed kit. The color image of the kit was captured by a smartphone built-in camera and converted into color intensity using ImageJ software, thus achieving the quantitative determination of UA. The portable kit possesses high selectivity and was used to monitor UA in human serum with satisfactory results (recovery was in the range 95.8-107.3% and RSD was not greater than 4.6%). The established sensing platform is convenient and reliable, which provides a new strategy for point-of-care testing of UA and has a broad prospect in the fields of chemical sensing and biomedical.

Toward Plant Cyborgs: Hydrogels Incorporated onto Plant Tissues Enable Programmable Shape Control.

Engineered living materials (ELMs) that incorporate living organisms and synthetic materials enable advanced functional properties. Here, we seek to create plant cyborgs by combining plants or plant tissues with stimuli-responsive polymeric materials. Plant tissues with integrated shape control may find applications in regenerative medicine, and the shape control of living plants enables another dimension of adaptability and response to environmental threats, which can be applied to next-generation precision farming. In this work, we develop chemistry to integrate stimuli-responsive poly(N-isopropylacrylamide) (PNIPAM) hydrogels with decellularized plant tissues assisted by 3D printing. We demonstrate programmable shape morphing in response to thermal cues and ultraviolet (UV) light. Specifically, by taking advantage of the extrusion-based 3D printing method, we deposit nanocomposite PNIPAM precursors onto silane-treated decellularized leaf surface with prescribed shapes and spatial control. When subjected to external stimuli, the strain mismatch generated between the swellable nanocomposite PNIPAM and nonswellable decellularized leaf enables folding and bending to occur. This strategy to integrate the plant tissues with stimuli-responsive hydrogels allows the control of leaf morphology, opening avenues for plant-based biosensors and soft actuators to enhance food security; such materials also may find applications in biomedicine as tissue-engineering scaffolds.

Sustainable curcumin-based smart tough fluorescent hydrogels for anti-counterfeiting applications

There is currently great interest in developing an environment-friendly, low-cost, and scalable approach for producing stimuli-responsive fluorescent hydrogels (FHs) with excellent mechanical property, rewritable fluorescence, and dual anti-counterfeiting capabilities. Herein, by applying natural, environment-friendly, and sustainable curcumin as a responsive agent, tough pH-responsive FHs (pH-FHs) are fabricated via a facile preparation strategy. These materials have outstanding mechanical performances: ultimate stress of 180 kPa, an ultimate strain of ∼2500%, and good anti-fatigue performances against compression. These pH-FHs are able to sense ammonia and formaldehyde gas, resulting in both a color change and fluorescence for dual anti-counterfeiting functionality. This sensing information is stored individually by the pH-FHs and could be externally removed using formaldehyde gas to achieve a rewritable system. Our study provides valuable insights that are expected to facilitate the development of smart FHs for information encryption and anti-counterfeiting applications.

Novel Photo- and Thermo-Responsive Nanocomposite Hydrogels Based on Functionalized rGO and Modified SIS/Chitosan Polymers for Localized Treatment of Malignant Cutaneous Melanoma.

Melanoma is an aggressive type of skin cancer that accounts for over 75% of skin cancer deaths despite comprising less than 5% of all skin cancers. Despite promising improvements in surgical approaches for melanoma resection, the survival of undetectable microtumor residues has remained a concern. As a result, hyperthermia- and drug-based therapies have grown as attractive techniques to target and treat cancer. In this work, we aim to develop a stimuli-responsive hydrogel based on chitosan methacrylate (ChiMA), porcine small intestine submucosa methacrylate (SISMA), and doxorubicin-functionalized reduced graphene oxide (rGO-DOX) that eliminates microtumor residues from surgically resected melanoma through the coupled effect of NIR light-induced photothermal therapy and heat-induced doxorubicin release. Furthermore, we developed an in silico model to optimize heat and mass transport and evaluate the proposed chemo/photothermal therapy in vitro over melanoma cell cultures.

Synthesis and characterization of stimuli-responsive hydrogels: evaluation of external stimuli influence on L929 fibroblast viability

In this study, poly(2-hydroxyethyl methacrylate) [p(HEMA)] based hydrogels responsive to the pH, temperature and magnetic field were synthesized. The surface properties of p(HEMA) were improved by designing the stimuli-responsive hydrogels made of MAGA, NIPAAm and methacrylate-decorated magnetite nanoparticles as a function of pH-, thermo- and magnetic responsive cell culture surfaces. These materials were then modified an abundant extracellular matrix component, type I collagen, which has been considered as a biorecognition element to increase the applicability of hydrogels to cell viability. Based on results from scanning electron microscopy (SEM) and thermal gravimetric analysis (TGA), stimuli-responsive hydrogel demonstrated improved non-porous structures and thermal stability with a high degree of cross-linking. Mechanical analyses of the hydrogels also showed that stimuli-responsive hydrogels are more elastomeric due to the polymeric chains and heterogeneous amorphous segments compared to plain hydrogels. Furthermore, surface modification of hydrogels with collagen provided better biocompatibility, which was confirmed with L929 fibroblast cell adhesion. Produced stimuli-responsive hydrogels modulated cellular viability by changing pH and magnetic field.

Jammed Microgel-Based Inks for 3D Printing of Complex Structures Transformable via pH/Temperature Variations.

Structure changes mediated by anisotropic volume changes of stimuli-responsive hydrogels are useful for many research fields, yet relatively simple structured objects are mostly used due to limitation in fabrication methods. To fabricate complex 3 dimensional (3D) structures that undergo structure changes in response to external stimuli, jammed microgel-based inks containing precursors of stimuli-responsive hydrogels are developed for extrusion-based 3D printing. Specifically, the jammed microgel-based inks are prepared by absorbing precursors of poly(acrylic acid) or poly(N-isopropylacrylamide) in poly(acrylamide) (PAAm) microgels, and jamming them. The inks exhibit shear-thinning and self-healing properties that allow extrusion of the inks through a nozzle and rapid stabilization after printing. Stimuli-mediated volume changes are observed for the extruded structures when they are post-crosslinked by UV light to form interpenetrating networks of PAAm microgels and stimuli-responsive hydrogels. Using this method, a dumbbell-shaped object that can transform to a biconvex shape, and a gripper that can grasp and lift an object in response to stimuli are 3D-printed. The jammed microgel-based 3D printing strategy is a versatile method useful for variety of applications as diverse types of monomers absorbable in the microgels can be used to fabricate complex 3D objects transformable by external stimuli.

Advances of Stimulus-Responsive Hydrogels for Bone Defects Repair in Tissue Engineering.

Bone defects, as one of the most urgent problems in the orthopedic clinic, have attracted much attention from the biomedical community and society. Hydrogels have been widely used in the biomedical field for tissue engineering research because of their excellent hydrophilicity, biocompatibility, and degradability. Stimulus-responsive hydrogels, as a new type of smart biomaterial, have more advantages in sensing external physical (light, temperature, pressure, electric field, magnetic field, etc.), chemical (pH, redox reaction, ions, etc.), biochemical (glucose, enzymes, etc.) and other different stimuli. They can respond to stimuli such as the characteristics of the 3D shape and solid–liquid phase state, and exhibit special properties (injection ability, self-repair, shape memory, etc.), thus becoming an ideal material to provide cell adhesion, proliferation, and differentiation, and achieve precise bone defect repair. This review is focused on the classification, design concepts, and research progress of stimulus-responsive hydrogels based on different types of external environmental stimuli, aiming at introducing new ideas and methods for repairing complex bone defects.

Stimuli-responsive colorimetric sensor based on bifunctional pyrophosphate-triggered controlled release and enhancing activity of CoOOH nanozyme

As a class of intelligent materials, stimuli-responsive hydrogels enable attractive sensors for sensitive and selective detection along with the potential for low production costs. Herein, we proposed a stimuli-responsive colorimetric sensor based on Cu2+-crosslinked alginate hydrogel loaded with CoOOH nanozyme. Upon binding of Cu2+ to pyrophosphate ion (PPi), the hydrogel would be disassembled by PPi, which controlled the release of CoOOH nanoflakes. Interestingly and importantly, it was found that PPi and PPi-Cu2+ could further enhance the catalytic activity of the released CoOOH nanozyme. Since alkaline phosphatase (ALP) can catalyze the hydrolysis of PPi to phosphate ion (Pi), a sensitive colorimetric sensor for ALP detection was constructed based on PPi-triggered controlled release and enhancing activity of CoOOH nanozyme. The as-constructed sensor exhibited good linear response to ALP over the range from 0.1 to 250 mU/mL with a detection limit of 0.07 mU/mL. Additionally, this sensor was also extended to measure two typical ALP inhibitors (Na3VO4 and EDTA) with reasonable results. Last but not least, it was confirmed that the detection results of ALP in real serum samples with the proposed sensor were in accordance with the data from clinical test, which indicates the robustness and practicability of this stimuli-responsive colorimetric sensor.

Two-Dimensional and Three-Dimensional Ultrathin Multilayer Hydrogels through Layer-by-Layer Assembly

Stimuli-responsive multilayer hydrogels have opened new opportunities to design hierarchically organized networks with properties controlled at the nanoscale. These multilayer materials integrate structural, morphological, and compositional versatility provided by alternating layer-by-layer polymer deposition with the capability for dramatic and reversible changes in volumes upon environmental triggers, a characteristic of chemically cross-linked responsive networks. Despite their intriguing potential, there has been limited knowledge about the structure-property relationships of multilayer hydrogels, partly because of the challenges in regulating network structural organization and the limited set of the instrumental pool to resolve structure and properties at nanometer spatial resolution. This Feature Article highlights our recent studies on advancing assembly technologies, fundamentals, and applications of multilayer hydrogels. The fundamental relationships among synthetic strategies, chemical compositions, and hydrogel architectures are discussed, and their impacts on stimuli-induced volume changes, morphology, and mechanical responses are presented. We present an overview of our studies on thin multilayer hydrogel coatings, focusing on controlling and quantifying the degree of layer intermixing, which are crucial issues in the design of hydrogels with predictable properties. We also uncover the behavior of stratified "multicompartment" hydrogels in response to changes in pH and temperature. We summarize the mechanical responses of free-standing multilayer hydrogels, including planar thin coatings and films with closed geometries such as hollow microcapsules and nonhollow hydrogel microparticles with spherical and nonspherical shapes. Finally, we will showcase potential applications of pH- and temperature-sensitive multilayer hydrogels in sensing and drug delivery. The knowledge about multilayer hydrogels can advance the rational design of polymer networks with predictable and well-tunable properties, contributing to modern polymer science and broadening hydrogel applications.

Critical review on buccal mucoadhesive drug delivery systems

Traditional oral dosage forms prone to first pass metabolism and degra­dation due to enzymes but mucoadhesive dosage form able to bypass first pass metabolism and related degradation. It also offers more patient compliance without risk of chocking in case of paediatric and geriatric patients. Buccal mucosa is considered as a convenient and easily accessible site for the drug administration for both local and systemic delivery. Mucoadhesion is a process involving chemical interactions between mucin and polymers. The use of mucoadhesive polymers in buccal drug delivery has gained a great attention. Various mucoadhesive dosage forms, including tablets, patches, disks, wafers, ointments and gels have recently been developed. Amongst them, buccal patches offer greater flexibility and comfort than the other forms. Smart materials such as stimuli-responsive hydrogels, liposome-based patches, polymeric micelles, etc. play a vital role in the development of these drug delivery systems by their efficient carrier capacity, prolonging the residence time of the drug at the site of absorption, improved drug bioavailability, reduced dosing frequency and improved patience compliance.