Stimuli-responsive Hydrogels Research Articles

Designing Composite Stimuli-Responsive Hydrogels for Wound Healing Applications: The State-of-the-Art and Recent Discoveries.

Effective wound treatment has become one of the most important challenges for healthcare as it continues to be one of the leading causes of death worldwide. Therefore, wound care technologies significantly evolved in order to provide a holistic approach based on various designs of functional wound dressings. Among them, hydrogels have been widely used for wound treatment due to their biocompatibility and similarity to the extracellular matrix. The hydrogel formula offers the control of an optimal wound moisture level due to its ability to absorb excess fluid from the wound or release moisture as needed. Additionally, hydrogels can be successfully integrated with a plethora of biologically active components (e.g., nanoparticles, pharmaceuticals, natural extracts, peptides), thus enhancing the performance of resulting composite hydrogels in wound healing applications. In this review, the-state-of-the-art discoveries related to stimuli-responsive hydrogel-based dressings have been summarized, taking into account their antimicrobial, anti-inflammatory, antioxidant, and hemostatic properties, as well as other effects (e.g., re-epithelialization, vascularization, and restoration of the tissue) resulting from their use.

Stimuli-responsive peptide hydrogels for biomedical applications.

Stimuli-responsive hydrogels can respond to external stimuli with a change in the network structure and thus have potential application in drug release, intelligent sensing, and scaffold construction. Peptides possess robust supramolecular self-assembly ability, enabling spontaneous formation of nanostructures through supramolecular interactions and subsequently hydrogels. Therefore, peptide-based stimuli-responsive hydrogels have been widely explored as smart soft materials for biomedical applications in the last decade. Herein, we present a review article on design strategies and research progress of peptide hydrogels as stimuli-responsive materials in the field of biomedicine. The latest design and development of peptide hydrogels with responsive behaviors to stimuli are first presented. The following part provides a systematic overview of the functions and applications of stimuli-responsive peptide hydrogels in tissue engineering, drug delivery, wound healing, antimicrobial treatment, 3D cell culture, biosensors, etc. Finally, the remaining challenges and future prospects of stimuli-responsive peptide hydrogels are proposed. It is believed that this review will contribute to the rational design and development of stimuli-responsive peptide hydrogels toward biomedical applications.

Advances in stimuli-responsive injectable hydrogels for biomedical applications.

Injectable hydrogels, as a class of highly hydrated soft materials, are of interest for biomedicine due to their precise implantation and minimally invasive local drug delivery at the implantation site. The combination of in situ gelation ability and versatile therapeutic agent/cell loading capabilities makes injectable hydrogels ideal materials for drug delivery, tissue engineering, wound dressing and tumor treatment. In particular, the stimuli-responsive injectable hydrogels that can respond to different stimuli in and out of the body (e.g., temperature, pH, redox conditions, light, magnetic fields, etc.) have significant advantages in biomedicine. Here, we summarize the design strategies, advantages, and recent developments of stimuli-responsive injectable hydrogels in different biomedical fields. Challenges and future perspectives of stimuli-responsive injectable hydrogels are also discussed and the future steps necessary to fulfill the potential of these promising materials are highlighted.

Application of stimuli-responsive hydrogel in brain disease treatment.

Treating brain diseases presents significant challenges due to neuronal degeneration, inflammation, and the intricate nature of the brain. Stimuli-responsive hydrogels, designed to closely resemble the brain's extracellular matrix, have emerged as promising candidates for controlled drug delivery and tissue engineering. These hydrogels have the unique ability to encapsulate therapeutic agents and release them in a controlled manner when triggered by environmental stimuli. This property makes them particularly suitable for delivering drugs precisely to targeted areas of the brain, while minimizing collateral damage to healthy tissue. Their preclinical success in treating various brain diseases in animal studies underscores their translational potential for human brain disease treatment. However, a deeper understanding of their long-term behavior, biodistribution, and biocompatibility within the brain remains crucial. Furthermore, exploring novel hydrogel systems and therapeutic combinations is paramount for advancing towards more effective treatments. This review summarizes the latest advancements in this field over the past 5years, specifically highlighting preclinical progress with novel stimuli-responsive hydrogels for treating brain diseases.

Correlating structural changes in thermoresponsive hydrogels to the optical response of embedded plasmonic nanoparticles.

Stimuli-responsive microgels, composed of small beads with soft, deformable polymer networks swollen through a combination of synthetic control over the polymer and its interaction with water, form a versatile platform for development of multifunctional and biocompatible sensors. The interfacial structural variation of such materials at a nanometer length scale is essential to their function, but not yet fully comprehended. Here, we take advantage of the plasmonic response of a gold nanorod embedded in a thermoresponsive microgel (AuNR@PNIPMAm) to monitor structural changes in the hydrogel directly near the nanorod surface. By direct comparison of the plasmon response against measurements of the hydrogel structure from dynamic light scattering and nuclear magnetic resonance, we find that the microgel shell of batch-polymerized AuNR@PNIPMAm exhibits a heterogeneous volume phase transition reflected by different onset temperatures for changes in the hydrodyanmic radius (RH) and plasmon resonance, respectively. The new approach of contrasting plasmonic response (a measure of local surface hydrogel structure) with RH and relaxation times paves a new path to gain valuable insight for the design of plasmonic sensors based on stimuli-responsive hydrogels.

Injectable smart stimuli-responsive hydrogels: pioneering advancements in biomedical applications.

Hydrogels have established their significance as prominent biomaterials within the realm of biomedical research. However, injectable hydrogels have garnered greater attention compared with their conventional counterparts due to their excellent minimally invasive nature and adaptive behavior post-injection. With the rapid advancement of emerging chemistry and deepened understanding of biological processes, contemporary injectable hydrogels have been endowed with an "intelligent" capacity to respond to various endogenous/exogenous stimuli (such as temperature, pH, light and magnetic field). This innovation has spearheaded revolutionary transformations across fields such as tissue engineering repair, controlled drug delivery, disease-responsive therapies, and beyond. In this review, we comprehensively expound upon the raw materials (including natural and synthetic materials) and injectable principles of these advanced hydrogels, concurrently providing a detailed discussion of the prevalent strategies for conferring stimulus responsiveness. Finally, we elucidate the latest applications of these injectable "smart" stimuli-responsive hydrogels in the biomedical domain, offering insights into their prospects.

Recent advances in injectable hydrogel therapies for periodontitis.

Periodontitis is an immune-inflammatory disease caused by dental plaque, and deteriorates the periodontal ligament, causes alveolar bone loss, and may lead to tooth loss. To treat periodontitis, antibacterial and anti-inflammation approaches are required to reduce bone loss. Thus, appropriate drug administration methods are significant. Due to their "syringeability", biocompatibility, and convenience, injectable hydrogels and associated methods have been extensively studied and used for periodontitis therapy. Such hydrogels are made from natural and synthetic polymer materials using physical and/or chemical cross-linking approaches. Interestingly, some injectable hydrogels are stimuli-responsive hydrogels, which respond to the local microenvironment and form hydrogels that release drugs. Therefore, as injectable hydrogels are different and highly varied, we systematically reviewed the periodontal treatment field from three perspectives: raw material sources, cross-linking methods, and stimuli-responsive methods. We then discussed current challenges and opportunities for the translation of hydrogels to clinic, which may guide further injectable hydrogel designs for periodontitis.

Overview of Injectable Hydrogels for the Treatment of Myocardial Infarction

Myocardial infarction (MI) triggers adverse remodeling mechanisms, thus leading to heart failure. Since the application of biomaterial-based scaffolds emerged as a viable approach for providing mechanical support and promoting cell growth, injectable hydrogels have garnered substantial attention in MI treatment because of their minimally invasive administration through injection and diminished risk of infection. To fully understand the interplay between injectable hydrogels and infarcted myocardium repair, this review provides an overview of recent advances in injectable hydrogel-mediated MI therapy, including: I) material designs for repairing the infarcted myocardium, considering the pathophysiological mechanism of MI and design principles for biomaterials in MI treatment; II) the development of injectable functional hydrogels for MI treatment, including conductive, self-healing, drug-loaded, and stimulus-responsive hydrogels; and III) research progress in using injectable hydrogels to restore cardiac function in infarcted myocardium by promoting neovascularization, enhancing cardiomyocyte proliferation, decreasing myocardial fibrosis, and inhibiting excessive inflammation. Overall, this review presents the current state of injectable hydrogel research in MI treatment, offering valuable information to facilitate interdisciplinary knowledge transfer and enable the development of prognostic markers for suitable injectable materials.

Synthesis and characterization of a pH/temperature-dual responsive hydrogel with promising biocompatibility features for stimuli-responsive 5-FU delivery.

The tunable properties of stimuli-responsive copolymers or hydrogels enable their application in different fields such as biomedical engineering, tissue engineering, or even drug release. Here we introduce a new PNIPAM-based triblock copolymer material comprising a controlled amount of a novel hydrophobic crosslinker 2,4'-diacryloyloxy benzophenone (DABP) and acrylic acid (AAc) to achieve lower critical solution temperature (LCST) between ambient and body temperatures. The dual stimuli-responsive p(NIPAM-co-DABP-co-AAc) triblock copolymer material and hydrogel were synthesized, and their temperature and pH-responsive behaviors were systematically investigated. The hydrogel exhibited excellent temperature and pH-responsive properties with an LCST of around 30 °C. Moreover, the synthesized copolymer has been demonstrated to be nontoxic both in vitro and in vivo. When the hydrogel was preloaded with the model drug 5-fluorouracil (5-FU), the designed hydrogel released the drug in a temperature and pH-controlled fashion. It was observed that the prepared hydrogel has the ability to entrap 5-FU, and the loading is more than 85%. In the case of temperature-controlled release, we observed almost complete release of 5-FU at lower temperatures and sustained release behavior at higher temperatures. In addition, the hydrogel matrix was able to retard the release of 5-FU in an acidic environment and selectively release 5-FU in a basic environment. By realizing how the hydrogel properties influence the release of drugs from preloaded hydrogels, it is possible to design new materials with myriad applications in the drug delivery field.

ROS/pH dual-responsive quercetin-loaded guanosine borate supramolecular hydrogel enema in dextran sulfate sodium-induced colitis in mice.

Ulcerative colitis (UC) is an inflammatory bowel disease that predominantly impacts the colon, typically starting in the rectum. A significant characteristic of UC is its propensity to affect the distal colon, which is particularly beneficial for targeted treatments such as enemas. This localized approach ensures that the medication is delivered directly to the affected areas, resulting in minimal systemic absorption. In this research, we have formulated a novel stimuli-responsive quercetin-loaded guanosine borate supramolecular hydrogel (named GBQ hydrogel), designed to prolong the residence time of the drug and protect the ulcerated intestinal tissues. The GBQ hydrogel has exhibited excellent injectability, self-healing capabilities, and biocompatibility, rendering it an ideal candidate for enema administration. In vitro studies have highlighted its ROS/pH dual-responsive release profile, which mimics the microenvironment of intestinal inflammation. Furthermore, we assessed the efficacy of the GBQ hydrogel on dextran sulfate sodium (DSS)-induced colitis, a common animal model for UC. Our findings indicate that the GBQ hydrogel significantly reduces disease activity, mitigates oxidative stress, restores the intestinal mucosal barrier, and prevents colonic cell apoptosis. Collectively, this study underscores the therapeutic potential of the GBQ hydrogel in managing inflammatory bowel conditions and paves the way for a novel hydrogel enema-based treatment strategy for UC.

Stimuli-responsive Ti3C2Tx MXene-based hydrogels: preparation and applications

MXene-based stimuli-responsive hydrogels have emerged as a new class of smart soft materials and have shown great potential in various applications such as sensing, biomedicine, actuators and energy-related applications.

Harnessing multifunctional collagen mimetic peptides to create bioinspired stimuli responsive hydrogels for controlled cell culture.

The demand for synthetic soft materials with bioinspired structures continues to grow. Material applications range from in vitro and in vivo tissue mimics to therapeutic delivery systems, where well-defined synthetic building blocks offer precise and reproducible property control. This work examines a synthetic assembling peptide, specifically a multifunctional collagen mimetic peptide (mfCMP) either alone or with reactive macromers, for the creation of responsive hydrogels that capture aspects of soft collagen-rich tissues. We first explored how buffer choice impacts mfCMP hierarchical assembly, in particular, peptide melting temperature, fibril morphology, and ability to form physical hydrogels. Assembly in physiologically relevant buffer resulted in collagen-like fibrillar structures and physically assembled hydrogels with shear-thinning (as indicated through strain-yielding) and self-healing properties. Further, we aimed to create fully synthetic, composite peptide-polymer hydrogels with dynamic responses to various stimuli, inspired by the extracellular matrix (ECM). Specifically, we established mfCMP-poly(ethylene glycol) (PEG) hydrogel compositions that demonstrate increasing non-linear viscoelasticity in response to applied strain as the amount of assembled mfCMP content increases. Furthermore, the thermal responsiveness of mfCMP physical crosslinks was harnessed to manipulate the composite hydrogel mechanical properties in response to changes in temperature. Finally, cells relevant in wound healing, human lung fibroblasts, were encapsulated within these peptide-polymer hydrogels to explore the impact of increased mfCMP, and the resulting changes in viscoelasticity, on cell response. This work establishes mfCMP building blocks as versatile tools for creating hybrid and adaptable systems with applications ranging from injectable shear-thinning materials to responsive interfaces and synthetic ECMs for tissue engineering.

Multiscale elasticity mapping of biological samples in 3D at optical resolution

The mechanical properties of biological tissues have emerged as an integral determinant of tissue function in health and disease. Nonetheless, characterizing the elasticity of biological samples in 3D and at high resolution remains challenging. Here, we present a µElastography platform: a scalable elastography system that maps the elastic properties of tissues from cellular to organ scales. The platform leverages the use of a biocompatible, thermo-responsive hydrogel to deliver compressive stress to a biological sample and track its resulting deformation. By surrounding the specimen with a reference hydrogel of known Young's modulus, we are able to map the absolute values of elastic properties in biological samples. We validate the experimental and computational components of the platform using a hydrogel phantom and verify the system's ability to detect internal mechanical heterogeneities. We then apply the platform to map the elasticity of multicellular spheroids and the murine lymph node. With these applications, we demonstrate the platform's ability to map tissue elasticity at internal planes of interest, as well as capture mechanical heterogeneities neglected by most macroscale characterization techniques. The µElastography platform, designed to be implementable in any biology lab with access to 3D microscopy (e.g., confocal, multiphoton, or optical coherence microscopy), will provide the capability to characterize the mechanical properties of biological samples to labs across the large community of biological sciences by eliminating the need of specialized instruments such as atomic force microscopy. Statement of significanceUnderstanding the elasticity of biological tissues is of great importance, but characterizing these properties typically requires highly specialized equipment. Utilizing stimulus-responsive hydrogels, we present a scalable, hydrogel-based elastography method that uses readily available reagents and imaging modalities to generate resolved maps of internal elasticity within biomaterials and biological samples at optical resolution. This new approach is capable of detecting internal stiffness heterogeneities within the 3D bulk of samples and is highly scalable across both imaging modalities and biological length scales. Thus, it will have significant impact on the measurement capabilities of labs studying engineered biomaterials, mechanobiology, disease progression, and tissue engineering and development.

Stimuli-responsive Double Network CMC-based Hydrogel Nanocomposite with enhanced mechanical properties for proliferation and differentiation of PC12

ABSTRACT A novel double network (DN) hydrogel nanocomposite with good compressive strength has been prepared by using Carboxymethyl Cellulose-g-Acrylic acid-Iron Oxides Nanoparticles (CMC-g-AA-IONs) as the primary network and polyacrylamide as the secondary network. The structure of the synthesized DN hydrogel nanocomposite was investigated by Fourier transform infrared (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), thermogravimetric analysis (TGA), and mechanical strength measurement. The synthesized DN hydrogel showed high mechanical strength (σ of 0.238 MPa), despite the water content of 90%. Its biocompatibility effect on sensitive nerve cells was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) test. The results showed that the DN hydrogel nanocomposite has no cytotoxicity on these cells and did not cause any disturbance or inhibit their growth and proliferation.

Liquid crystalline composite hydrogels with large pH-triggered anisotropic swelling for embolotherapy

Inspired by the anisotropic structure of biological tissues, anisotropic hydrogels have been developed using various nanofillers, however, it remains a big challenge to synthesize hydrogels with large swelling anisotropy. Herein a single molecule filler, α-helical polypeptide, instead of nanoscale fillers, was used to synthesize anisotropic hydrogels. First nematic liquid crystal of poly(γ-benzyl l-glutamate) (PBLG) was prepared by shearing and stabilized by embedding in a crosslinked polymer matrix. The resulting PBLG composite gels were then converted to poly(L-glutamic acid) (PLGA) composite gels by debenzylation. The rigid rod-like structure of α-helical PBLG chains makes them easy to be orientated. The pH-sensitivity of PLGA makes the resulting composite gels pH-sensitive without the need to couple with a stimuli-responsive hydrogel matrix. In response to pH change PLGA composite gels swell anisotropically with a much larger swelling degree in the radial direction than in the axial direction. The swelling anisotropy (3.43) is much higher than most anisotropic hydrogels, particularly the stimuli-responsive ones reported previously. The composite gel also exhibits anisotropic mechanical properties with a larger Young's modulus in the axial direction than that in the radial direction. Preliminary test demonstrated that the composite gels have potential in embolotherapy thanks to its large pH-triggered anisotropic swelling. Statement of SignificanceAnisotropic hydrogels have important biomedical applications. Introduction of oriented nanofillers has been demonstrated a popular and versatile method for their synthesis, however, it remains a big challenge to achieve large swelling anisotropy. Herein a single molecule filler, α-helical polypeptide, instead of nanoscale fillers, was used to synthesize anisotropic hydrogels. This filler can be easily oriented by shearing. More importantly, as single molecule filler, it can constrain the swelling of hydrogel matrix more effectively. Using this filler, a pH-sensitive hydrogel with large swelling anisotropy (3.43) was successfully synthesized. Thanks to its large pH-triggered anisotropic swelling the hydrogel was successfully used as embolic agent to occlude vessels.

Advances in Stimuli-Responsive Chitosan Hydrogels for Drug Delivery Systems.

Sustainable and controllable drug transport is one of the most efficient ways of disease treatment. Due to high biocompatibility, good biodegradability, and low costs, chitosan and its derivatives are widely used in biomedical fields. Specifically, chitosan hydrogel enables drugs to pass through biological barriers because of their abundant amino and hydroxyl groups that can interact with human tissues. Moreover, the multi-responsive nature (pH, temperature, ions strength, and magnetic field, etc.) of chitosan hydrogels makes precise drug release a possibility. Here, the synthesis methods, modification strategies, stimuli-responsive mechanisms of chitosan-based hydrogels, and their recent progress in drug delivery are summarized. Chitosan hydrogels that carry and release drugs through subcutaneous (dealing with wound dressing), oral (dealing with gastrointestinal tract), and facial (dealing with ophthalmic, ear, and brain) are reviewed. Finally, challenges toward clinic application and the future prospects of stimuli-responsive chitosan-based hydrogels are indicated.

Stimuli-Responsive Protein Hydrogels: Their Design, Properties, and Biomedical Applications.

Protein-based hydrogels are considered ideal biomaterials due to their high biocompatibility, diverse structure, and their improved bioactivity and biodegradability. However, it remains challenging to mimic the native extracellular matrices that can dynamically respond to environmental stimuli. The combination of stimuli-responsive functionalities with engineered protein hydrogels has facilitated the development of new smart hydrogels with tunable biomechanics and biological properties that are triggered by cyto-compatible stimuli. This review summarizes the recent advancements of responsive hydrogels prepared from engineered proteins and integrated with physical, chemical or biological responsive moieties. We underscore the design principles and fabrication approaches of responsive protein hydrogels, and their biomedical applications in disease treatment, drug delivery, and tissue engineering are briefly discussed. Finally, the current challenges and future perspectives in this field are highlighted.

Porosity Engineering of Dried Smart Poly(N-isopropylacrylamide) Hydrogels for Gas Sensing.

A recent study unveiled the potential of acrylamide-based stimulus-responsive hydrogels for volatile organic compound detection in gaseous environments. However, for gas sensing, a large surface area, that is, a highly porous material, offering many adsorption sites is crucial. The large humidity variation in the gaseous environment constitutes a significant challenge for preserving an initially porous structure, as the pores tend to be unstable and irreversibly collapse. Therefore, the present investigation focuses on enhancing the porosity of smart PNiPAAm hydrogels under the conditions of a gaseous environment and the preservation of the structural integrity for long-term use. We have studied the influence of polyethylene glycol (PEG) as a porogen and the application of different drying methods and posttreatment. The investigations lead to the conclusion that only the combination of PEG addition, freeze-drying, and subsequent conditioning in high relative humidity enables a long-term stable formation of a porous surface and inner structure of the material. The significantly enhanced swelling response in a gaseous environment and in the test gas acetone is confirmed by gravimetric experiments of bulk samples and continuous measurements of thin films on piezoresistive pressure sensor chips. These measurements are furthermore complemented by an in-depth analysis of the morphology and microstructure. While the study was conducted for PNiPAAm, the insights and developed processes are general in nature and can be applied for porosity engineering of other smart hydrogel materials for VOC detection in gaseous environments.

High speed underwater hydrogel robots with programmable motions powered by light

Stimuli-responsive shape-changing hydrogels are attractive candidates for use as underwater soft robots. The bottleneck lies in the low actuation speed inherently limited by the water diffusion between hydrogels and their surrounding environment. In addition, accessing complex motions is restricted by the material fabrication methods. Here we report a hitherto unknown mechanism to achieve high-speed and programmable actuations for a disulfide crosslinked thermally responsive hydrogel. The dynamic photo-activated disulfide bond exchange allows photo-mechanical programming to introduce spatio-selective network anisotropy. This gives rise to an actuation behavior dominated by thermally driven conformation change of the locally oriented polymer chains instead of the common mass-diffusion-based mechanism. With the incorporation of photothermal fillers, light-powered oscillation at frequencies as high as 1.7 Hz is realized. This, coupled with the versatility of the programming, allows access to robots with diverse high-speed motions including continuous swimming, step-wise walking, and rotating.

Stimulus-Responsive Hydrogels as Drug Delivery Systems for Inflammation Targeted Therapy.

Deregulated inflammations induced by various factors are one of the most common diseases in people's daily life, while severe inflammation can even lead to death. Thus, the efficient treatment of inflammation has always been the hot topic in the research of medicine. In the past decades, as a potential biomaterial, stimuli-responsive hydrogels have been a focus of attention for the inflammation treatment due to their excellent biocompatibility and design flexibility. Recently, thanks to the rapid development of nanotechnology and material science, more and more efforts have been made to develop safer, more personal and more effective hydrogels for the therapy of some frequent but tough inflammations such as sepsis, rheumatoid arthritis, osteoarthritis, periodontitis, and ulcerative colitis. Herein, from recent studies and articles, the conventional and emerging hydrogels in the delivery of anti-inflammatory drugs and the therapy for various inflammations are summarized. And their prospects of clinical translation and future development are also discussed in further detail.