Stimuli-responsive Hydrogels Research Articles

Stimuli-responsive dynamic hydrogels: design, properties and tissue engineering applications.

The field of tissue engineering and regenerative medicine has been evolving at a rapid pace with numerous novel and interesting biomaterials being reported. Hydrogels have come a long way in this regard and have been proven to be an excellent choice for tissue regeneration. This could be due to their innate properties such as water retention, and ability to carry and deliver a multitude of therapeutic and regenerative elements to aid in better outcomes. Over the past few decades, hydrogels have been developed into an active and attractive system that can respond to various stimuli, thereby presenting a wider control over the delivery of the therapeutic agents to the intended site in a spatiotemporal manner. Researchers have developed hydrogels that respond dynamically to a multitude of external as well as internal stimuli such as mechanics, thermal energy, light, electric field, ultrasonics, tissue pH, and enzyme levels, to name a few. This review gives a brief overview of the recent developments in such hydrogel systems which respond dynamically to various stimuli, some of the interesting fabrication strategies, and their application in cardiac, bone, and neural tissue engineering.

Stimuli-responsive chitosan-based injectable hydrogel for “on-demand” drug release

In this study, we developed a simplified one-step method for crafting a pH-responsive chitosan-based injectable hydrogel using dynamic Schiff's base chemistry.

Engineering metabolic cycle-inspired hydrogels with enzyme-fueled programmable transient volume changes.

An enzyme-fueled transient volume phase transition (TVPT) of hydrogels under out-of-equilibrium conditions is reported. The approach takes inspiration from the metabolic cycle, comprising nutrient intake and anabolism/catabolism followed by waste excretion. The incorporation of methacrylic acid and acrylated trypsin in a polymeric hydrogel allowed the TVPT of the gel to be fueled by lysozyme. With the intake of lysozyme as fuel, the construction/destruction of electrostatic cross-linkages induced transient shrinkage/swelling of the gel accompanied by the depletion of lysozyme activity. The system's transient response could be flexibly programmed by adjusting not only the fuel concentration but the chemical composition of materials. The lysozyme-fueled TVPT of the gel could be exploited to transient changes in the mechanical properties of the gel. Our work opens a route toward a new class of stimuli-responsive hydrogels for biomedical applications.

Swelling characteristics of DNA polymerization gels.

The development of biomolecular stimuli-responsive hydrogels is important for biomimetic structures, soft robots, tissue engineering, and drug delivery. DNA polymerization gels are a new class of soft materials composed of polymer gel backbones with DNA duplex crosslinks that can be swollen by sequential strand displacement using hairpin-shaped DNA strands. The extensive swelling can be tuned using physical parameters such as salt concentration and biomolecule design. Previously, DNA polymerization gels have been used to create shape-changing gel automata with a large design space and high programmability. Here we systematically investigate how the swelling response of DNA polymerization gels can be tuned by adjusting the design and concentration of DNA crosslinks in the hydrogels or DNA hairpin triggers, and the ionic strength of the solution in which swelling takes place. We also explore the effect hydrogel size and shape have on the swelling response. Tuning these variables can alter the swelling rate and extent across a broad range and provide a quantitative connection between biochemical reactions and macroscopic material behaviour.

Stimuli-responsive hydrogels for cancer immunotherapy

We discussed the combination of immunotherapy and stimuli-responsive hydrogels for effective cancer treatment and their potential as vaccine implants against cancer and Covid-19.

Stimuli-Responsive Polysaccharide-Based Smart Hydrogels and Their Emerging Applications

Hydrogels are a soft material that undergoes cross-linking between polymers to form a hydrophilic three-dimensional network. In fact, similarity to body tissue, soft consistency, biocompatibility, and elasticity, impart a protagonic role of hydrogel to be applied as a biomaterial. In response to external cues, stimuli-responsive hydrogels are particularly impactful, enabling remarkable levels of control over material properties. They can endure changes in swelling behavior, permeability, network structure, and mechanical strength. Nevertheless, such changes induce single-cycle or reversible transitions, so hydrogels can regain their initial state once the trigger is removed. Recently, polysaccharide-based hydrogels with stimuli-responsive properties resulted in developing biomimetic structures for a widespread biotechnological application owing to their excellent biodegradability, biocompatibility, nonimmunogenicity, functional properties, ease of gelation, and derivatization. This review will initially highlight recent advances in cross-linking methods and chemistry for preparing stimuli-responsive hydrogels. Subsequently, state-of-the-art techniques to understand the structural, chemical, and rheological behavior of polysaccharide-based stimuli-responsive hydrogel will be discussed. Additionally, the responsiveness of polysaccharide hydrogel toward diverse stimuli such as redox, temperature, light, pH, magnetism, electricity, etc., with a broad spectrum of applications will be described in detail. This review also attempts to address the lacunae of existing stimuli-responsive hydrogel and their future perspectives.

An ionic/thermal-responsive agar/alginate wet-spun microfiber-shaped hydrogel combined with grooved/wrinkled surface patterns and multi-functions

A dual stimuli-responsive wet-spun microfiber-shaped hydrogel is prepared by injecting a hot blend of two stimuli biopolymers alginate (i.e., ionic-responsive) and agar (i.e., temperature-responsive) into a pre-cooling and metal cation containing coagulation bath. Experimental results indicate the fiber microstructure could be manipulated by the extrusion rate and cooling temperature, achieving an anisotropic shrinkage characteristic and novel grooved/wrinkled surface patterns. Importantly, the integration of metal cations (e.g., Ca2+and/or Zn2+) was confirmed to significantly improve the hydrogel mechanical properties (i.e., double networks) and enhanced blue fluorescent intensity as a typical metal-polymer complexation formed within the agar gel matrix. Moreover, the functionality-independent double networks enabled typical pH-shape memory and sustainable antibacterial properties have also been demonstrated. Therefore, combing the facile fabricating approach and multifunctionality, this study would advance the development of stimuli-responsive hydrogel microfiber for complex biomedical systems.

Fabrication of pectin-based stimuli responsive hydrogel for the controlled release of ceftriaxone

Fabrication of pectin-based stimuli responsive hydrogel for the controlled release of ceftriaxone

A Tissue Paper/Hydrogel Composite Light-Responsive Biomimetic Actuator Fabricated by In Situ Polymerization.

Stimulus-responsive hydrogels are an important member of smart materials owing to their reversibility, soft/wet properties, and biocompatibility, which have a wide range of applications in the field of intelligent actuations. However, poor mechanical property and complicated fabrication process limit their further applications. Herein, we report a light-responsive tissue paper/hydrogel composite actuator which was developed by combining inkjet-printed tissue paper with poly(N-isopropylacrylamide) (PNIPAM) hydrogel through simple in situ polymerization. Due to the high strength of natural tissue paper and the strong interaction within the interface of the bilayer structure, the mechanical property of the composite actuator was highly enhanced, reaching 1.2 MPa of tensile strength. Furthermore, the light-responsive actuation of remote manipulation can be achieved because of the stamping graphite with high efficiency of photothermal conversion. Most importantly, we also made a few remotely controlled biomimetic actuating devices based on the near-infrared (NIR) light response of this composite actuator. This work provides a simple strategy for the construction of biomimetic anisotropic actuators and will inspire the exploration of new intelligent materials.

Stimuli-responsive metal–organic framework hydrogels endow long carbon fiber reinforced polyetheretherketone with enhanced anti-inflammatory and angiogenesis and osteogenesis

The ideal orthopedic implant has sufficient biomechanical strength and physiological activity to coordinate with the intricate physiological healing process of the tissue. Herein, multifunctional stimuli-responsive metal–organic framework (MOF) hydrogels on the surface of the sulfonated long carbon fiber reinforced polyetheretherketone (LCFRPEEK) implant using the UV-grafting method is constructed to coordinate with the osseointegration process. The hydrogels are composed of nano-hydroxyapatite cored magnesium-gallic acid (HAP@Mg-GA) MOF nanoparticles and methacryloylchitosan. The stimuli-responsive MOF hydrogels exhibit outstanding pH-sensitive biomolecule release capabilities. The outcomes of in vitro cell experiments demonstrate that the multifunctional sulfonated LCFRPEEK could actively and precisely perform immunomodulation, timely scavenge excess ROS and reduce NO production under the immune environment (low pH), as well as promote angiogenesis and osteogenic differentiation benefiting from the cooperation of GA, Mg2+ and Ca2+. Furthermore, the in vivo SD rat subcutaneous implantation and rabbit tibia defect models further demonstrate that the implant has superior in vivo immunomodulation, angiogenesis, osteogenic differentiation, and osseointegration abilities. Therefore, the study provides a new multifunctional orthopedic implant that can achieve osseointegration, which broadens the effective application of LCFRPEEK biomaterials in orthopedics.

Hydrogel based materials: A progressive approach towards advancement in biomedical applications

Hydrogels have received immense attraction due to their exceptional properties as well as various applications in the biomedical field in the past decade. The 3D porous structure constructed through a cross-linked polymer network represents the hydrogels that exhibit hydrophilic properties along with adjustable physical and chemical properties. They are ideal candidates for drug delivery, implants, and/or tissue engineering applications due to their unique properties. Smart or stimuli-responsive hydrogels significantly control their material’s properties as a response to external stimuli like pH, temperature, and biological components. This controllable property of the hydrogel system enables inventive approaches in healthcare through advanced treatment strategies against various diseases including wound healing as well as tissue engineering. As the research work on the synthesis of hydrogel systems is rapidly expanding and becoming very voluminous, we are presenting here the last three years’ progress. The first part of this review summarises the classification and synthesis process of hydrogels. While the second part of this review is focused on recently synthesized hydrogels utilized for biomedical applications. Mainly polysaccharides, polyether and ester-based hydrogels are discussed in this review to provide an overview of recent work.

Modular stimuli-responsive hydrogel sealants for early gastrointestinal leak detection and containment

Millions of patients every year undergo gastrointestinal surgery. While often lifesaving, sutured and stapled reconnections leak in around 10% of cases. Currently, surgeons rely on the monitoring of surrogate markers and clinical symptoms, which often lack sensitivity and specificity, hence only offering late-stage detection of fully developed leaks. Here, we present a holistic solution in the form of a modular, intelligent suture support sealant patch capable of containing and detecting leaks early. The pH and/or enzyme-responsive triggerable sensing elements can be read out by point-of-need ultrasound imaging. We demonstrate reliable detection of the breaching of sutures, in as little as 3 hours in intestinal leak scenarios and 15 minutes in gastric leak conditions. This technology paves the way for next-generation suture support materials that seal and offer disambiguation in cases of anastomotic leaks based on point-of-need monitoring, without reliance on complex electronics or bulky (bio)electronic implantables.

Recent advances in engineering hydrogels for niche biomimicking and hematopoietic stem cell culturing.

Hematopoietic stem cells (HSCs) provide a life-long supply of haemopoietic cells and are indispensable for clinical transplantation in the treatment of malignant hematological diseases. Clinical applications require vast quantities of HSCs with maintained stemness characteristics. Meeting this demand poses often insurmountable challenges for traditional culture methods. Creating a supportive artificial microenvironment for the culture of HSCs, which allows the expansion of the cells while maintaining their stemness, is becoming a new solution for the provision of these rare multipotent HSCs. Hydrogels with good biocompatibility, excellent hydrophilicity, tunable biochemical and biophysical properties have been applied in mimicking the hematopoietic niche for the efficient expansion of HSCs. This review focuses on recent progress in the use of hydrogels in this specialized application. Advanced biomimetic strategies use for the creation of an artificial haemopoietic niche are discussed, advances in combined use of hydrogel matrices and microfluidics, including the emerging organ-on-a-chip technology, are summarized. We also provide a brief description of novel stimulus-responsive hydrogels that are used to establish an intelligent dynamic cell microenvironment. Finally, current challenges and future perspectives of engineering hydrogels for HSC biomedicine are explored.

Dual Stimuli-Responsive Polysaccharide Hydrogels Manufactured by Radiation Technique

This paper describes the results of the radiation-induced crosslinking of polysaccharides modified with hydroxypropyl and carboxymethyl functional groups, hydroxypropylcellulose (HPC) and carboxymethylcellulose (CMC), respectively, without and with poly(ethylene glycol) diacrylate (PEGDA) as a crosslinking agent, to obtain dual stimuli-responsive hydrogels. The gels were characterized in terms of water uptake and gel fraction, parameters that mainly depend on the HPC–CMC compositions, but also on the macromer crosslinker content and the absorbed dose. The swelling of hydrogels is controlled by both the temperature, due to the amphiphilic character of HPC and pH, due to the anionic functional groups of CMC. In spite of a similar degree of substitution in both cellulose derivatives, 1.4 for HPC and 1.2 for CMC, the pH response of hydrogels with an equal content of both polysaccharides is considerably higher—a reduction in swelling of up to 95% with a decrease in the pH to 2 was recorded—than the response to thermal-stimulus—wherein a reduction in swelling of less than 70% with an increasing in temperature to 55 °C was found. These biopolymers-based hydrogels of specific, stimuli-responsive swelling properties are anticipated in applications where a combination of two stimuli is essential and biodegradation may be required.

Dual stimuli-responsive hydrogels for colon targeted drug delivery.

Colon targeted drug deliverysystems are promising for the treatment of local diseases. The colon possessesa diverse microbiome that secretes a number of biomolecules, such as enzymes,that can be exploited for targeted drug delivery. Here, we report the synthesisof 2-hydroxyethyl methacrylate and methacrylic acid  copolymer hydrogels crosslinked with an enzyme-sensitivecrosslinking agent. The swelling and drug release properties of hydrogels were observedin pH 1.2, pH 6.5 and pH 7.4, and in the presence of rat cecal content. Swellingstudies revealed pH responsivity of the hydrogels while the release kinetics ofmetronidazole from hydrogels containing an enzyme-labile crosslinker were fasterin the presence of rat cecal content. The results show that dual responsive hydrogelscould provide a promising platform for colonic drug delivery

Glucose-Responsive Injectable Thermogels via Dynamic-Covalent Cross-Linking of Pluronic Micelles.

Stimuli-responsive hydrogels are an area of active discovery for approaches to deliver therapeutics in response to disease-specific indicators. Glucose-responsive delivery of insulin is of particular interest in better managing diabetes. Accordingly, hydrogels have been explored as platforms that enable both a rate and dose of insulin release aligning with the real-time physiological disease state; materials often include glucose sensing by dynamic-covalent cross-linking between phenylboronic acids (PBAs) and diols, with competition from ambient glucose reducing cross-link density of the material and accelerating release of encapsulated insulin. Yet, these materials historically have challenges with insulin leakage, offer limited glucose-responsive release of the insulin payload, and require unreasonably high injection pressures for syringe administration. Here, a thermogel platform prepared from temperature-induced micelles formed into a network by PBA-Diol cross-linking is optimized using a formulation-centered approach to maximize glucose-responsive insulin delivery. Importantly, the dual-responsive nature of this platform enables a low-viscosity sol at ambient temperature for facile injection, solidifying into a stable viscoelastic hydrogel network once in the body. The final optimized formulation affords acceleration in insulin release in response to glucose and enables single dose blood glucose control in diabetic rodents when subjected to multiple glucose challenges.

Recent developments in stimuli‐responsive hydrogels for biomedical applications

Hydrogels exhibit a performance similar to that of the extracellular matrix and are compatible with human tissues and organs. Stimuli-responsive hydrogels that can respond smartly to a variety of stimuli have recently attracted extensive interest for biomedical applications. The response of these hydrogels to various single/multiple stimuli shows great potential for drug delivery, biosensors, wound dressing, cancer therapy, and tissue engineering. This review summarises the recent advances in the design of different stimuli-responsive hydrogels and their biomedical applications. We herein describe the mechanisms underlying the stimulus–response, and summarise the strategies for fabricating stimuli-responsive hydrogels that can respond to single or multiple stimuli from endogenous (i.e. pH, enzymes, glucose, and reactive oxygen species) or exogenous (i.e. magnetic and electric fields, temperature, and photo) sources. The current challenges faced by stimuli-responsive hydrogels are discussed and an outlook on future research directions is provided.

Acousto-Photolithography for Programmable Shape Deformation of Composite Hydrogel Sheets.

Stimuli-responsive hydrogels with programmable shapes produced by defined patterns of particles are of great interest for the fabrication of small-scale soft actuators and robots. Patterning the particles in the hydrogels during fabrication generally requires external magnetic or electric fields, thus limiting the material choice for the particles. Acoustically driven particle manipulation, however, solely depends on the acoustic impedance difference between the particles and the surrounding fluid, making it a more versatile method to spatially control particles. Here, an approach is reported by combining direct acoustic force to align photothermal particles and photolithography to spatially immobilize these alignments within a temperature-responsive poly(N-isopropylacrylamide) hydrogel to trigger shape deformation under temperature change and light exposure. The spatial distribution of particles can be tuned by the power and frequency of the acoustic waves. Specifically, changing the spacing between the particle patterns and position alters the bending curvature and direction of this composite hydrogel sheet, respectively. Moreover, the orientation (i.e., relative angle) of the particle alignments with respect to the long axis of laser-cut hydrogel strips governs the bending behaviors and the subsequent shape deformation by external stimuli. This acousto-photolithography provides a means of spatiotemporal programming of the internal heterogeneity of composite polymeric systems.

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.

Hydrogels for localized drug delivery: A special emphasis on dermatologic applications.

Skin disease treatment is a complex and time-consuming process due to the complex etiology, numerous side effects of conventional therapies, and difficulties in determining primary causes of the disease. Superficial wounds are often easy to treat. However, treatment of severe wounds caused by burn is challenging for clinicians. Optimum therapeutic benefits are based on the site-specific delivery of medicaments at the right time for a prolonged duration. Systemic toxicity and frequent dosing are the major challenges associated with the use of conventional therapeutics. Hydrogels are material of choice for drug delivery because of their high biocompatibility and ability to hold and release therapeutic agents. The number of hydrogels available for use in cosmetology and dermatology continues to grow during the past 1-2 decades. However, new hydrogel materials with high biocompatibility, antibacterial properties, and the ability to stimulate skin regeneration processes are in high demand. These are three-dimensional networks, which absorb a large amount of biological fluids and water. Hydrogels can be used as a biosensor, carrier systems for cells, drug delivery carriers especially for topical applications and in contact lenses. Hydrogels are highly porous carriers containing about 90% water. Stimuli-responsive hydrogels cause a change in network structure that is completely reversible in nature. The present review describes the applications of hydrogels in pharmaceutical formulations with a special emphasis on the treatment of dermatologic conditions such as acne, psoriasis, and mycosis.