Dual-responsive Hydrogel Research Articles

Aldehyde modified cellulose-based dual stimuli responsive multiple cross-linked network ionic hydrogel toward ionic skin and aquatic environment communication sensors

Recently, materials with complicated environmentally-sensitive abilities, high stretchability and excellent conductive sensitivity are interesting actuators in future applications. Herein, we fabricated a versatile and facile polyvinyl alcohol/polyacrylic acid/dialdehyde cellulose nanofibrils-Fe3+ hydrogel integrated with programmable dual-shape memory properties, high mechanical strength, good recoverability, and heat-induced self-healing capability. Benefiting from the synergistic effect of hydrogen bonds and dual metal coordination bonds of cellulose-based dialdehyde and carboxyl with Fe3+and then heating-freeze-thawing cycle treatment, the obtained hydrogel exhibited dual shape memory abilities, high tensile strain (up to 600 %), good self-recovery, and anti-fatigue properties. Moreover, the resultant hydrogel sensors showed revealed high strain sensitivity (gauge factor = 2.95) and satisfactory electrochemical performance; and such hydrogel-based sensor could be used as ionic skin to detect various human motions in real-time and barrier-free communication in the aquatic environment. The composite hydrogel with superior and versatile performances reported in this study could offer a great promise to be applied under extreme conditions as multifunctional sensors.

PH and temperature dual-responsive hydrogel actuator with bidirectional bending behavior and ultra large bending angle

Smart hydrogels have received attentions for the great potentials in biomedical and robots applications. However, the deformation performance of hydrogels still needs to be improved, especially for the pH and thermal dual responsive hydrogels. In this study, a pH and temperature dual-responsive poly(acrylamide-acrylic acid-3-acrylamidophenylboronic acid)/Poly(N-isopropylacrylamide) (P(AAm-AAc-3-AAPBA)/PNIPAM) bilayer structures have been prepared by UV polymerization. The PNIPAM layer shrinks/swells when the temperature is higher/lower than the low critical solution temperature, while P(AAm-AAc-3-AAPBA) layer will swell/shrink when pH is too high/low. The volume change trend of the two layer is different, resulting in the bending behaviors of P(AAm-AAc-3-AAPBA)/PNIPAM hydrogel actuator. The bidirectional bending performance can be reversibly, repeatedly, and precisely controlled by pH and temperature-induced cooperative swelling-shrinking properties from both layers. The bending angle of the bilayer structure achieves about 1420° at the environment of pH 2 and 55 ℃. It takes about 70 s to convert the bending angle of the bilayer structures from 355° (10 ℃, pH 2) to −360° (55 ℃, pH 12). In addition, three kinds of biomimetic hydrogel structures, such as mechanical gripper, bionic flower and bionic hand, have been prepared and demonstrated good performance. The obtained P(AAm-AAc-3-AAPBA)/PNIPAM hydrogels exhibit excellent pH and thermal responsive bending properties, which enable them as an ideal smart hydrogel system.

RETRACTED ARTICLE: A pH/enzyme dual responsive PMB spatiotemporal release hydrogel promoting chronic wound repair

Suppressing persistent multidrug-resistant (MDR) bacterial infections and excessive inflammation is the key for treating chronic wounds. Therefore, developing a microenvironment-responsive material with good biodegradability, drug-loading, anti-infection, and anti-inflammatory properties is desired to boost the chronic wounds healing process; however, using ordinary assembly remains a defect. Herein, we propose a pH/enzyme dual-responsive polymyxin B (PMB) spatiotemporal-release hydrogel (GelMA/OSSA/PMB), namely, the amount of OSSA and PMB released from GelMA/OSSA/PMB was closely related the wound pH and the enzyme concentration changing. The GelMA/OSSA/PMB showed better biosafety than equivalent free PMB, owing to the controlled release of PMB, which helped kill planktonic bacteria and inhibit biofilm activity in vitro. In addition, the GelMA/OSSA/PMB exhibited excellent antibacterial and anti-inflammatory properties. A MDR Pseudomonas aeruginosa caused infection was effectively resolved by the GelMA/OSSA/PMB hydrogel in vivo, thereby significantly boosting wound closure during the inflammatory phase. Furthermore, GelMA/OSSA/PMB accelerated the sequential phases of wound repair.

All-in-one dual responsive hydrogels for thermoelectrochromic (TEC) devices

The development of new functional materials plays a pivotal role in creating novel materials for devices such as displays or smart windows, offering new possibilities for indoor comfort and energy saving. Most devices only respond to a single external stimulus (electrical, light, thermal) missing on the potential of incorporating multiple responses. Herein, all-in-one thermo- and electrochromic hydrogels for dual responsive displays are presented. In these multifunctional materials, different viologens and thermoresponsive polymers (poly(N-isopropylacrylamide) or poly(N-vinylcaprolactam)) were incorporated simultaneously into hydrogels. By applying these hydrogels on simple sandwich type FTO based devices, it was possible to create single layered dual responsive devices. These devices could change their opacity and color due to their thermochromic (TC) and electrochromic (EC) properties, being able to combine both changes at the same time. The devices showed high optical contrasts, from their almost fully transparent bleached state to their TC and EC states (<5% and ≈70% transmittance at 600 nm, respectively). All phase changes were proven to be reversible by cycling between the bleached, TC, EC and dual TEC states for consecutive times. Therefore, these hydrogels can offer new simple smart window or display designs.

Dual responsive self-healing hydrogels with wide stability and excellent mechanical strength based on aliphatic polycarbonate

The wide development of hydrogels had been used in many filed due to the high water-containing and tough three-dimensional structure, however, the poor mechanical and multi-functional properties of hydrogel can be limited in its applications deeply. Herein, the dual responsive self-healing hydrogels with tough mechanical properties were manufactured by dual-physical cross-linking based on biodegradable aliphatic polycarbonate. Choosing the soft and hard segments to design the polymeric hydrogel not only can facilitate the dual-dynamic bonding interactions but also the resilient hydrogels possess robust and controllable mechanical strength (6.51 MPa). Furthermore, the results of swelling and stability tests of the materials indicated that the swelling ability of the biodegradable hydrogels can be regulated by the hydrophilic group, and the maximal swelling ratio in water and the equilibrium water content is 66% and 40%, respectively. It is worth mentioning that the tough hydrogels embrace dual-responsive high efficiency of self-healing ability, and the self-healing time is 2 h at 50 °C or 10 h under pH = 5, suggesting that the obtained hydrogels can respond to temperature and pH value to drive the fracture interface for fast self-healing, which will offer new opportunities for stimuli-responsive materials and wound healing.

Ir-reversible on/off switching hydrogel for efficient dye capture and release

Effective removal of pollutants and efficient separation of pollutants from spent hydrogel are equally important for assessing the wastewater treatment capacity of adsorbents. Here, a novel pH and temperature dual-responsive hydrogel (TZP-hydrogel) with unique ir-reversible on/off switching property is designed to develop a novel regeneration system. The stimulus response signal of hydrogel can achieve the high-efficiency desorption of dyes and regeneration of hydrogel. The transition of flocculation-adsorption for pollutants can be realized by the pH-responsive sol-gel transition of the hydrogel to achieve a widening of flocculation window. The maximum adsorption capacity of MB by TZP-hydrogel can reach 1611 mg/g (20 °C), 1435 mg/g (40 °C) and 1100 mg/g (60 °C), and the adsorption isotherms were consistent with Sips model. Moreover, the synergistic effect of temperature and pH stimulus makes it potential to enhance the selective recovery of hydrogel from waste eluent. The release rate of MB can reach more than 91% at pH 1 and 60 °C, which can effectively realize the recycling and reuse of TZP-hydrogel. The maximum adsorption capacity of MB by TZP-hydrogel still reached 1551 mg/g (20 °C) after 5 regeneration cycles. Therefore, this work demonstrates that the unique ir-reversible on/off switching property provides great potential for designing recyclable hydrogel adsorbent.

Preparation of temperature-pH dual-responsive hydrogel from hydroxyethyl starch for drug delivery

Preparation of temperature-pH dual-responsive hydrogel from hydroxyethyl starch for drug delivery

Controlled 5‐FU Release from P(NIPAM‐co‐VIm)‐g‐PEG Dual Responsive Hydrogels

Abstract5‐fluorouracil (5‐FU) forms the basis of many chemotherapy regimens and is one of the most widely used chemotherapeutic drugs in the treatment of solid malignancies. In this study, (i) Poly N‐isopropyl acrylamide (PNIPAM) synthesized by free radical polymerization method, (ii) temperature and pH responsive P(NIPAM‐co‐VIm) synthesized by copolymerization of N‐isopropyl acrylamide (NIPAM) with 1‐vinyl imidazole (VIm) and (iii) the 5‐FU release of P(NIPAM‐co‐VIm)‐g‐PEG prepared by grafting with polyethylene glycol (PEG). In the temperature and pH sensitivity analyzes revelaed that the LCST value increased as a result of the treatment of PNIPAM with VIm and PEG, on the other hand the hydrogel in the swollen phase in the acidic environment, the hydrogel turned into a precipitated form as the environment became alkaline. To investigate the utilize of hydrogels, release mediums of two different pHs (pH 5.5 and 7.4) and two different temperatures (25 °C and 37 °C) were applied. The cumulative release results showed that the release ratio of 5‐FU was 95 % when the release medium pH was 7.4 and ambient temperature 37 °C. Consequently, P(NIPAM‐co‐VIm)‐g‐PEG hydrogels at different pH and temperature mediums could be beneficially utilized as an material with a potential to be used in targeted drug delivery systems.

A dual responsive ionic liquid-based polymeric hydrogel: a promising drug delivery vehicle for the treatment of breast cancer

Designing cancer therapeutics that can ameliorate the high dose related side effects of chemotherapy and are safer, more effective, and site specific with a stimuli response has received attention in recent times.

Dual-Responsive Hydrogels with Three-Stage Optical Modulation for Smart Windows

Since room temperature management consumes a large amount of building energy, thermochromic smart windows have been extensively used for temperature regulation and energy management. However, the development of the smart window is still limited by its simple thermochromic performance, unreasonable thermochromic temperature, and the lack of additional stimulation conditions. In this work, a dual-responsive hydrogel was developed by introducing sodium dodecyl sulfate (SDS) and sodium chloride into the cross-linking network of poly(N-isopropylacrylamide) (PNIPAM) and polyacrylamide (PAM) for energy-saving and privacy protection. By controlling the temperature from low (<15 °C) to medium (15-28 °C) to high (>28 °C), the dual-responsive hydrogel achieved a reversible three-stage transition of opaque-transparent-translucent. The hydrogel exhibited a satisfactory solar modulation ability (Tlum = 80.3%, ΔTsol,15-18°C = 72.9%, ΔTsol,18-35°C = 42.7%) and effective IR and UV shielding at high (or low) temperatures. Moreover, compared with traditional windows, smart windows made of dual-responsive hydrogels could offer better thermal insulation and heat preservation. The electrochromic properties of the dual-responsive hydrogel presented a facile strategy to meet the needs of different situations. The dual-responsive hydrogel features energy-saving, privacy protection, three-stage optical modulation, and multistimulus responsiveness, making it an ideal smart window candidate.

Bacteria-Activated Dual pH- and Temperature-Responsive Hydrogel for Targeted Elimination of Infection and Improved Wound Healing.

Antibacterial treatment that provides on-demand release of therapeutics that can kill a broad spectrum of pathogens while maintaining long-term efficacy and without developing resistance or causing side effects is urgently required in clinical practice. Here, we demonstrate the development of a multistimuli-responsive hydrogel, prepared by cross-linking N-isopropylacrylamide with acrylic acid and loaded with ultrasmall silver nanoparticles (AgNPs), offering the on-demand release of Ag+ ions triggered by changes in the wound microenvironment. We demonstrate that this dual-responsive hydrogel is highly sensitive to a typical wound pH and temperature change, evidenced by the restricted release of Ag+ ions at acidic pH (<5.5) while significantly promoting the release in alkaline pH (>7.4) (>90% release). The pH-dependent release and antibacterial effect show minimal killing at pH 4 or 5.5 but dramatically activated at pH 7.4 and 10, eliminating >95% of the pathogens. The in vivo antibacterial efficacy and safety showed a high potency to clear Staphylococcus aureus wound infection while significantly accelerating the wound healing rate. This multifunctional hydrogel presents a promising bacteria-responsive delivery platform that serves as an on-demand carrier to not only reduce side effects but also significantly boost the antibacterial efficiency based on physiological needs. It offers great potential to improve the way wound infections are treated with direct clinical implications, providing a single platform for long-lasting application in wound management.

Intelligent temperature-pH dual responsive nanocellulose hydrogels and the application of drug release towards 5-fluorouracil

As the typical bio-macromolecules, cellulose and its derivates are widely studied due to the fact that they are green and renewable resources in nature. In this work, intelligent temperature-pH sensitive nanohydrogels consisting of nanocellulose, thermal responsive monomer (N-isopropylacrylamide, NIPAM), and pH responsive monomer (acrylic acid, AA; acrylamide, AM) were prepared [NFC-g-(AA/AM)]-g-NIPAM, the [NFC-g-(AA/AM)]-g-NIPAM was characterized by FTIR, scanning electron microscope (SEM), thermogravimetric analysis (TGA) and automatic gas adsorption analysis (BET). The results showed that the copolymerization of AA, AM and NIPAM were carried out successfully. The specific surface area, total pore volume, average pore diameter and thermal stability of the modified nano-cellulose were increased. In addition, the as-prepared nanohydrogels with 5-fluorouracil (5-FU) released more 5-FU at 40 °C and acidic condition compared to the room temperature and neutral pH, showing the characteristics of the temperature-PH dual response functionalization. The [NFC-g-(AA/AM)]-g-NIPAM have been proved to be the promising drug release nanohydrogels towards 5-FU, and the valuable findings might provide an idea for maximizing the potential of the nanocellulose-based nanohydrogels for the application of environmental pollution control.

Research progress and clinical application of stimuli-responsive hydrogels in cervical cancer

Cervical cancer is the fourth most common malignancy in women worldwide and poses a great risk to women's health. There is an urgent need to develop a range of effective and innovative therapeutic options to overcome the shortcomings of conventional treatments: poor efficacy and toxic side effects. As an alternative therapy, a number of advances have been made in hydrogel-based drug delivery systems that enable targeted and localized therapy, as well as controlled release of drugs at the tumor site. These advantages can effectively increase drug concentration and reduce damage to normal sites caused by chemical drug toxicity. This paper reviews the progress of research applications of stimuli-responsive hydrogels in cervical cancer. The response mechanisms of hydrogels and the principles of enhanced drug efficacy are discussed in focus. These include thermal-responsive hydrogels, pH-responsive hydrogels, light-responsive hydrogels, enzyme-responsive hydrogels, and dual-responsive hydrogels. It is also argued that through the increasing understanding of hydrogels, it can be used clinically as an effective and durable therapeutic tool.

Brain Microenvironment Responsive and Pro-Angiogenic Extracellular Vesicle-Hydrogel for Promoting Neurobehavioral Recovery in Type 2 Diabetic Mice After Stroke.

Stroke patients with diabetes have worse neurological outcomes than non-diabetic stroke patients, and treatments beneficial for non-diabetic stroke patients are not necessarily effective for diabetic stroke patients. While stem cell-derived extracellular vesicles (EVs) show potential for treating stroke, the results remain unsatisfactory due to the lack of approaches for retaining and controlling EVs released into the brain. Herein, a glucose/reactive oxygen species dual-responsive hydrogel showing excellent injectability, biocompatibility, and self-healing capability is introduced as an EVs-loading vehicle and an intelligent EVs sustained releasing system in the brain. These EVs-hydrogels are developed via crosslinking of phenylboronic acid-modified hyaluronic acid and Poly vinyl alcohol, and fusion with neural stem cell-derived EVs. The results show EVs are stably incorporated into the hydrogels and can be controllably released in response to the brain microenvironment after stroke in type 2 diabetic mice. The EVs-hydrogels exert an excellent angiogenic effect, increasing the migration and tube formation of human umbilical vein endothelial cells. In addition, injection of EVs-hydrogels into the ischemic mouse brain enhances EVs retention and facilitates sustained release, promotes angiogenesis, and improves neurobehavioral recovery. These results suggest such a microenvironment responsive and sustained release EVs-hydrogel system offers a safe, and efficient therapy for diabetic stroke.

A dual-responsive polydopamine-modified hydroxybutyl chitosan hydrogel for sequential regulation of bone regeneration

Delayed inflammatory reaction and poor osteogenesis are the two main causes of failure for bone-defect healing. Accordingly, in the present study, a dual-responsive hydrogel composite was successfully fabricated in which near-infrared (NIR)-light-responsive polydopamine-coated magnesium‐calcium carbonate microspheres are incorporated into a thermo-responsive hydroxybutyl chitosan hydrogel to provide sequential delivery of the anti-inflammatory drug aspirin and osteogenic bone morphogenetic protein 2 (BMP-2). By initially releasing aspirin rapidly, the hydrogel composite efficiently ameliorates early-stage inflammatory reaction and promotes transition to the regenerative phase. Then, the hydrogel composite allows NIR-light-responsive release of BMP-2, which maximizes its osteoinductive effects. Using an SD rat calvaria-defect model, the sequential and controllable release achieved by the hydrogel is demonstrated to promote new-bone formation. Thus, the current study provides an efficient alternative strategy for developing multifunctional therapeutic biomaterials for bone tissue engineering.

A Dioscorea opposita Thunb Polysaccharide-Based Dual-Responsive Hydrogel for Insulin Controlled Release

A novel hydrogel (DOP/PEI-PBA) based on the “three-component” reaction of 2-formylphenylboric acid (2-FPBA), the primary amine group of polyethyleneimine (PEI) and the cis-o-dihydroxy groups of Dioscorea opposita Thunb polysaccharide (DOP) was designed in this work. The hydrogel can be easily prepared by simply mixing the three reactants at room temperature. The hydrogel had dual responsiveness to glucose and pH, and can realize the controllable release of insulin. Moreover, the hydrogel combining insulin and DOP can inhibit the reactive oxygen species (ROS) level and malondialdehyde (MDA) content, and promote glucose consumption as well as the level of superoxide dismutase (SOD), in high-glucose-induced injury in HL-7702 cells, which reflects the synergistic effect of insulin and DOP to protect hepatocytes from oxidative stress at the same time. Further in vitro cytotoxicity studies showed that the hydrogel had good biocompatibility and no obvious toxicity to cells. These indicate that the prepared hydrogel (DOP/PEI-PBA) can be expected to be applied in the clinical treatment of insulin deficiency in diabetes.

Synthesis of magnetic/pH dual responsive dextran hydrogels as stimuli-sensitive drug carriers

Hydrogels loaded with magnetic nanoparticles have been widely researched recently as biomaterials, due to their good biocompatibility and unique magnetic characteristics. In this study, water-soluble superparamagnetic iron oxide nanoparticles (Fe3O4) prepared by coprecipitation were physically doped into the dextran hydrogels which were formed via Schiff base reactions between ethylenediamine and oxidized dextran. The combination of magnetic nanoparticles and chemical cross-linked hydrogels leads to magnetic/pH dual-sensitive hydrogels which can be used as stimuli-responsive carrier. Magnetic properties, swelling, and rheology behaviors of the resulted magnetic hydrogels were strongly affected by the Fe3O4 nanoparticle content. Moreover, doxorubicin (DOX⋅HCl) was embedded into the magnetic hydrogels and pH/magnetic sensitive release profiles were identified. The release mechanism analysis indicated that the release behaviors of DOX⋅HCl were controlled by the diffusion, swelling, and erosion processes simultaneously. The prepared hydrogel/Fe3O4 composites with dual magnetic/pH stimuli-responsiveness hold the promise to be used in various applications such as drug release.

An injectable mitochondria-targeted nanodrug loaded-hydrogel for restoring mitochondrial function and hierarchically attenuating oxidative stress to reduce myocardial ischemia-reperfusion injury

Timely reperfusion is the common treatment for myocardial infarction. However, ischemia-reperfusion (I/R) therapy can lead to oxidative stress and mitochondrial dysfunction that further aggravate myocardial injury, and no effective therapy is currently available for alleviating myocardial I/R injury. Herein, we engineer a mitochondria-targeted Szeto-Schiller (SS31) peptide modified-amphiphilic polymer (PTPS) that self-assembles into nanomicelles (PTPSCs) for loading cyclosporine A (CsA). The PTPSCs are then encapsulated into a pH/ROS dual responsive injectable hydrogel crosslinked with reversible imine and boronic ester bonds. The loaded PTPSCs are controllably delivered from the hydrogel matrix in response to the low pH and high ROS microenvironment of the I/R heart, thus realizing reconstruction of mitochondrial function and unprecedented hierarchical attenuation of oxidative stress. The boronic ester in the hydrogel consumes the ROS in cardiac microenvironment, and the mitochondria-targeted delivery of CsA is revealed to inhibit mitochondria-mediated apoptosis signaling pathway to prevent cardiomyocyte apoptosis, meanwhile attenuating the mitochondrial ROS output to reduce the level of cytosolic ROS. Additionally, SS31 can also serve as an antioxidant to consume ROS in the mitochondria. In rat model of myocardial I/R injury with administration of this injectable hydrogel, the targeted release of PTPSCs efficiently restores mitochondrial and cardiac function.

Injectable Acylhydrazone‐Linked RAFT Polymer Hydrogels for Sustained Protein Release and Cell Encapsulation (Adv. Healthcare Mater. 7/2022)

Injectable Hydrogels In article number 2101284 by Chien-Chi Lin and co-workers, a biocompatible and pH/thermo dual responsive injectable hydrogel is synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization and acylhdrazone click chemistry. Upon injection, sol-gel transition occurs rapidly at body temperature and the porous hydrogels degrade slowly under mild acidic condition due to pH-sensitive cleavages of acylhydrazone bonds. The slow hydrogel degradation may be leveraged for long-term sustained protein delivery.

Liposome Loaded Ion/Temperature Dual Responsive Gellan Gum Hydrogel as Potential Nasal-To-Brain Delivery System.

Intranasal administration, which can bypass the blood-brain barrier (BBB), is widely recognized as a promising strategy for high-efficiency drug delivery to the brain. Herein, for the purpose of effectively delivering drugs to the brain via intranasal administration, glutathione (GSH)-modified gellan gum (GSH-GG) with ion/temperature dual responsive properties was synthesized and encapsulated on galanthamine hydrobromide (GH)-loaded liposomes (GH-Lipo) for effective GH delivery to the brain (GH-Lipo@GSH-GG). Our results demonstrated that GSH-GG greatly decreased the gelation temperature of GG from 44.0 °C to 22.1 °C without compromising its ion responsiveness. Moreover, GSH-GG had a good protection ability for GH-loaded liposomes without affecting its drug release. Most importantly, the finally obtained GH-Lipo@GSHGG showed acceptable targeted delivery of GH to the brain upon in vivo administration. Therefore, this formulation can be employed as a potential delivery system in nasal-to-brain delivery.