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Frontiers in Soft Matter ·

Volume 6 - 2026 | https://doi.org/10.3389/frsfm.2026.1845065

Recent advances in stimuli-responsive hydrogels for food, biomedical, and tissue engineering applications

  • Brijitta Joseph1,2
  • Avanish Bharati1
  • Debasish Saha1*corresponding author
  1. 1Jülich Centre for Neutron Science JCNS-4 at Heinz Maier-Leibnitz Zentrum (MLZ), Forschungszentrum Jülich GmbH, Jülich, Germany
  2. 2Soft Matter Laboratory, Centre for Nanoscience and Nanotechnology, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
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Abstract

Stimuli-responsive hydrogels are hydrophilic, three-dimensional polymer network structures that dynamically adjust their properties in response to changes in their external environment, such as temperature, pH, light, electric and magnetic fields, and enzymes. The ease of tuning their physicochemical properties and network architecture gives them an advantage over conventional hydrogels in various applications. This review provides an overview of recent advances in stimuli-responsive hydrogels and critically discusses developments in tissue engineering, food technology, wound healing, controlled drug delivery, and regenerative medicine. Representative examples demonstrate how responsive hydrogel systems can improve cell delivery, tissue regeneration, active food packaging, targeted nutrient release, and infection control. In addition, we also cover a section on the role of neutron scattering techniques, including small-angle neutron scattering (SANS), neutron reflectivity (NR), and quasi-elastic neutron scattering (QENS), in elucidating the network structure of hydrogels, interfacial properties, and molecular dynamics across multiple length and time scales. Finally, current challenges related to scalability, biocompatibility, regulatory approval, and commercialization are discussed, along with future perspectives on translating smart and self-healing hydrogel technologies into practical applications in food, biomedical, and tissue engineering.

Keywords

1 Introduction

Hydrogels are soft, 3-dimensional, cross-linked network structures of hydrophilic polymer chains that can absorb and retain large amounts of water or biological fluid without modifying their 3-dimensional structure (Kopeček, 2007). Due to their biocompatibility and biodegradability, hydrogels have been studied for decades and used in various applications, including tissue engineering, drug delivery, and functional materials (Ahmed, 2015). For example, poly (2-hydroxyethyl methacrylate) (pHEMA) is known to be the first synthetic biomaterial designed for use in the human body (Wichterle and Lím, 1960). The hydrogels recently used are significantly different from those of the earlier days, as they are designed to overcome many of the earlier existing limitations, such as the lack of material strength in conventional hydrogels (Billiet et al., 2012).

A stimuli-responsive hydrogel is a smart class of hydrogel that can switch between gel and solution states or between gel and solid states in response to external stimuli. These stimuli include magnetic (Li et al., 2021), electric (Jiang et al., 2019), ultrasonic irradiation (Zhou et al., 2022), thermal heating (Eyigor et al., 2018), pH (Vegad et al., 2023), enzyme (Thornton et al., 2007), and many other external conditions (Zhang et al., 2019; Guo et al., 2023). The stimuli-responsive hydrogels have been used for several applications, including but not limited to food, biomedical, and tissue engineering (Tang et al., 2019; Li et al., 2022b; Lin et al., 2023). The incorporation of micro and nanoparticles into stimuli-responsive hydrogels makes them important candidates for optical and electronic applications (Lei et al., 2023; Dutta et al., 2024). At the molecular level, the response of stimuli-responsive hydrogels originates from reversible changes in polymer-polymer and polymer-solvent interactions within the cross-linked network (Horkay and Douglas, 2018). Upon exposure to external stimuli, the balance between attractive and repulsive forces in the network gets altered. As a result, the hydrogel can exhibit swelling or deswelling, changes in mesh size and porosity, micro- and macrophase separation, or even reversible sol-gel transitions. For example, thermo-responsive hydrogels based on poly (N-isopropylacrylamide) (PNIPAM) exhibit a volume phase transition near their lower critical solution temperature (LCST), in which the polymer chains transition from a hydrated state to a compact, dehydrated state (Dogu and Okay, 2006). Similarly, pH-responsive hydrogels based on acrylic acid or vinylpyridine can undergo swelling/deswelling due to the ionization of the acid/pyridinium groups (Arizaga et al., 2010; Thakur and Arotiba, 2018; Hu et al., 2026), while photo-responsive hydrogels with azobenzene groups can undergo structural rearrangements through UV-visible light-induced molecular cis-trans isomerization (Zhao and Stoddart, 2009).

The mechanical properties of stimuli-responsive hydrogels largely depend on the cross-link density, volume fraction, nature of stimuli, and intermolecular interactions between the polymer segments. Rheological studies provide valuable information on the strength of the gel network and its resistance to deformation by measuring the dynamic storage modulus (G′) and loss modulus (G″). If G′ > G″ over the measured frequency range, especially with weak frequency dependence and within the linear viscoelastic region, the material exhibits elastic-dominant, solid-like behaviour. Another useful parameter is the loss tangent, tan ⁡ δ = G ″ / G ′. Values of tan ⁡ δ < 1 across the frequency sweep confirm elastic contribution dominates over viscous contribution, whereas strong frequency dependence or a crossover toward tan ⁡ δ > 1 indicates viscoelastic or liquid-like behavior. Accordingly, a temperature-responsive hydrogel will show an increase in G′ with weak frequency dependence above its LCST due to polymer chain collapse, resulting in a rigid network. When an applied stress or strain exceeds a critical value, known as the yield stress or yield strain, the gel can transition from a solid-like state to a flowing state. Such behaviour is known as the yield behaviour. Therefore, hydrogels exhibiting a controlled yield behavior are attractive injectable biomaterials because they can flow through a syringe under high shear stress and recover their structure once the stress is removed.

In this review, we provide a comprehensive overview of recent advances in stimuli-responsive hydrogels. We first introduce the different classes of stimuli-responsive hydrogels and their underlying response mechanisms, followed by a discussion of recent developments and representative applications in food science, biomedicine, and tissue engineering, including emerging smart and self-healing hydrogel systems. We also highlight the role of neutron scattering techniques, including small-angle neutron scattering (SANS), neutron reflectivity (NR), and quasi-elastic neutron scattering (QENS), in elucidating the structure, dynamics, and interfacial behaviour of hydrogels across multiple length and time scales. Finally, we discuss the current challenges, commercialization prospects, and future perspectives for translating stimuli-responsive hydrogel technologies into practical applications. Unlike previous reviews that primarily focus on specific classes of stimuli-responsive hydrogels or biomedical applications, this review provides an integrated perspective that combines food applications, biomedical engineering, tissue engineering, and the emerging role of neutron scattering techniques in hydrogel characterization, thereby offering a multidisciplinary framework for future research and technological translation.

2 Stimuli-responsive hydrogels

The formation of hydrogels follows three distinct steps (Braun et al., 2020). In the first step, water molecules form primary bound water upon contact with the hydrophilic groups of the gelator. This step is followed by the formation of secondary bound water and, finally, by the balance between the osmotic forces from gelators and cross-linkers, leading to the formation of a hydrogel. Therefore, the interaction between gelators and gelator-solvent plays a crucial role in the formation of hydrogels and their resultant stimuli-response. Stimuli-responsive hydrogels can be classified by various criteria, such as photo-responsive, thermo-responsive, electric field-responsive, pH-responsive, enzyme-responsive, magneto-responsive, and multiple-stimuli-responsive hydrogels. Photo-responsive hydrogels are externally tunable materials of a polymer network integrated with a photoreactive component (Li et al., 2019). The photochromic chromophore, which serves as the functional element, defines the efficiency of such hydrogels. Thermo-responsive hydrogels, often referred to as thermogels, are water-swollen polymeric networks in which the rapid and reversible sol-gel phase transition can be induced by changes in temperature without triggering other external factors (Klouda and Mikos, 2008). Electric field-responsive hydrogels are a distinctive class of hydrogels that undergo conformational changes in response to an external electric field (Murdan, 2003). In pH-responsive hydrogels, the monomer type, ionic charge, polymer concentration, etc., dictate the swelling and deswelling behavior of the hydrogel (Gao and Xu, 2025). Enzyme-responsive hydrogels are particularly well-suited for drug delivery, as their physicochemical and biological properties can be tuned upon interacting with specific enzymes (Hu et al., 2012). Magneto-responsive hydrogels consist of polymeric networks embedded with magnetic nanoparticles having the ability to respond to the external magnetic field (Ding et al., 2024). Unlike the above-mentioned hydrogels, in which structural changes are induced by a single external factor, multi-responsive hydrogels can undergo structural changes when exposed to multiple external factors, such as temperature, electric and magnetic fields, pH, etc. (Downs et al., 2020). All these stimuli-responsive hydrogels, including mechano-responsive, ultrasound-responsive, entity-responsive, etc., have been studied extensively over the past decades due to their diverse applications. An overview of different stimuli-responsive hydrogels and their applications have been illustrated in Figure 1.

Schematic illustration of different stimuli-responsive hydrogels and their applications. External stimuli, including temperature, pH, light, magnetic fields, electric fields, and enzymes, induce reversible changes in the structure and properties of hydrogel networks. These adaptive materials have found broad applications in biomedical engineering, tissue, and food science. Neutron scattering techniques such as SANS, NR, and QENS provide information on their structure, interfacial behavior, and molecular dynamics.
Figure 1. Schematic illustration of different stimuli-responsive hydrogels and their applications. External stimuli, including temperature, pH, light, magnetic fields, electric fields, and enzymes, induce reversible changes in the structure and properties of hydrogel networks. These adaptive materials have found broad applications in biomedical engineering, tissue, and food science. Neutron scattering techniques such as SANS, NR, and QENS provide information on their structure, interfacial behavior, and molecular dynamics.

3 Applications of stimuli-responsive hydrogels

3.1 Tissue engineering applications

Although almost all the stimuli-responsive hydrogels have demonstrated potential for tissue engineering applications, some of them, such as thermo-responsive and mechano-responsive hydrogels, perform very well, whereas a few of them, like photo-responsive and pH-responsive hydrogels, fall behind due to their lower mechanical strength. Beyond the limit of classically obtained hydrogels, a novel class of short pentapeptides self-assembled in cell culture media into supramolecular nanofibers and robust hydrogels at very low concentrations (<3 wt%) with elastic moduli ranging from 0.2 to 20 kPa (Tang et al., 2019). Electron microscopy (TEM and Cryo-EM) studies show that the peptides self-assemble into long, twisted ribbon-like fibrils and periodicities resembling amyloid fibrils. This is further supported by molecular dynamics simulations, which show increased β-sheet content and specific solvent-accessibility patterns during self-assembly. These hydrogels exhibit shear-thinning and rapid self-healing behavior, making them particularly well-suited for injectable applications and hence were so-called “RAPID (rapidly assembling pentapeptides for injectable delivery)” (Tang et al., 2019). The RAPID-hydrogels supported encapsulation, survival, and proliferation of oligodendrocyte progenitor cells (OPCs) in three-dimensional culture. Also, the hydrogels protect cells from mechanical damage during syringe injections, reducing membrane disruption and acute cell loss compared to cells delivered without hydrogel support. This property highlights the protective capability of the material as a cell delivery vehicle for transplantation therapies (Morley et al., 2023; Yu et al., 2024).

For tissue regeneration study using hydrogel, a microporous annealed particle (MAP) hydrogel crosslinked with D-amino acid peptide (Ac-GCRDGPQdGIdWdGQDRCG-NH2, D-peptide) was evaluated in murine full-thickness skin wound models. Although the D-peptide-crosslinked MAP hydrogel degraded faster in vivo than anticipated, it showed improved healing outcomes, including enhanced tensile strength of regenerated skin, hair neogenesis, and enhanced myeloid cell recruitment. Moreover, the hydrogel exhibited a strong adaptive immune response, including antigen-specific immunity against the D-peptides and recruitment of pro-regenerative immune cell populations. Regenerative effects were dependent on an intact adaptive immune system, demonstrating that immune activation, rather than the scaffold structure alone, drives tissue regeneration (Griffin et al., 2021). Another example of such applications is to engineer human cardiac tissues with a perfusable extracellular microenvironment that closely mimics the natural structure of the human heart (Min et al., 2024). The designed biomimetic 3D scaffold, containing heart-derived extracellular matrix (HEM) hydrogel and microvascular channels, allowing nutrients and oxygen to perfuse through the tissue similar to real blood vessels. This system enabled the formation of thick, functional cardiac tissues with improved survival, maturation, and synchronized heart-cell contraction compared with conventional culture methods. The engineered tissues can be maintained for long periods and reproduce physiological features of the human heart, making them useful for studying cardiac biology and disease. A study by Meijer et al. provides insight into how mechanical stimulation affects induced pluripotent stem-cell-derived vascular smooth muscle cells (iPSC-VSMCs) cultured in a 3D hydrogel environment (Meijer et al., 2023). It was found that mechanical stimulation promotes the transition of cells toward a contractile phenotype characteristic of healthy vascular smooth muscle cells. The results show that these stem cell-derived cells exhibit phenotypic plasticity similar to that of native vascular cells when cultured in 3D hydrogels. Such hydrogel platforms are useful model systems for vascular disease studies, drug testing, and regenerative medicine applications.

3.2 Food applications

Stimuli-responsive hydrogels are increasingly applied in food science due to their dynamic response to pH, temperature, light, ions, and biochemical stimuli. The in-situ detection of the fungicide thiram on fruits and vegetables was carried out using a sodium alginate hydrogel incorporating Ag+-modified carbon dots (CDs-Ag+) (Li et al., 2024). This hydrogel exhibited rapid fluorescence recovery in the presence of thiram via Ag-S bond formation and showed quantitative detection with a low limit of detection of 5 ng mL-1 within 10 min. Furthermore, the sensor also demonstrated excellent reliability in practical fruit and vegetable samples. Recent advances focus on design strategies and response mechanisms (Protsak and Morozov, 2025), enabling (i) active packaging (Niemczyk-Soczynska and Sajkiewicz, 2025) and (ii) targeted delivery applications for nutrients (Li et al., 2022a). These materials with tunable functionality are increasingly investigated for sustainable packaging alternatives and as bioactive carriers in functional foods.

Active packaging integrates hydrogels responsive to microbial activity by measuring changes upon exposure to spoilage-related stimuli, such as volatile compounds or pH shifts. Recent research highlights multi-stimuli responsive systems that merge chemical triggers with external force fields to improve detection in complex environments (Zheng et al., 2025). An active release of antimicrobial and antioxidant agents in response to physicochemical changes mitigates the risk of spoilage and improves preservation efficiency. Biopolymer-based hydrogels obtained from cellulose or starch have proven useful for eco-friendly smart packaging materials.

Targeted delivery applications for functional foods require hydrogels to protect and release encapsulated bioactives, such as vitamins or antioxidants, in specific areas of the GI tract triggered by pH gradients or enzymatic changes. This controlled release capability entails precise cross-linked network design, resulting in enhanced bioavailability and effective delivery of functional components. Hydrogels derived from food-grade polymers like chitosan and alginate support the targeted co-delivery of prebiotics with antioxidants or probiotics, improving synergy in nutraceutical formulations (Zheng et al., 2025).

The immediate use of hydrogel films in the packaging industry requires enhancing mechanical performance, scalability, and cost competitiveness while preserving dynamic responsiveness. Possible future directions involve nanocomposite reinforcement combined with multilayer hybrid packaging, precision platforms with directed sequential release, and their integration with digital monitors. Continued research into developing next-generation smart food systems is expected to address the limitations that hinder streamlined commercial and regulatory adoption.

3.3 Biomedical applications

Hydrogels have been used as effective materials for wound healing, controlled drug delivery, and tissue engineering. The use of hydrogels has addressed the limitations of conventional therapies such as sutures, standard wound dressings, and systemic chemotherapy. As traditional sutures and dressings lack antibacterial activity, a multifunctional supramolecular thermo-responsive adhesive hydrogel was developed for non-invasive wound closure and the treatment of infected wounds (Yu et al., 2022). The poly (N-isopropylacrylamide) (PNIPAM)-based supramolecular hydrogel network had quaternized chitosan, β-cyclodextrin, adenine, and polypyrrole nanotubes, and exhibited thermoresponsive contraction, strong tissue adhesion, and photothermal antibacterial activity. The gel mechanically pulled the wound edges together while maintaining adhesion. Antibacterial activity was noted against methicillin-resistant Staphylococcus aureus (MRSA). Wound healing was promoted and accelerated in both in vitro and in vivo models.

Building on the concept of smart hydrogels, a 4D-printed adhesive and thermo-contractile hydrogel dressing was developed to address chronic diabetic wounds (Lu et al., 2024). Using digital light processing 3D printing, a mixture of N-isopropylacrylamide, curcumin-loaded Pluronic F127 micelles, and dopamine-modified PEG diacrylate was fabricated into a hydrogel with tissue adhesion, biodegradability, and antibacterial activity. The thermoresponsive polymer network brought wound edges together, promoting faster closure. In vivo experiments in MRSA-infected diabetic wound models confirmed accelerated closure, reduced inflammation, and enhanced tissue regeneration (He et al., 2023).

Janus bioactive glass-PNIPAM sponge was engineered to control bleeding in incompressible traumatic wounds where conventional compression-based haemostasis is ineffective (Zhang et al., 2025). The sponge had an asymmetric structure comprising a hydrophilic bioactive glass layer and a hydrophobic PNIPAM layer integrated into a porous polyvinyl alcohol (PVA) sponge. The hydrophilic layer absorbed blood and released calcium and silicate ions to activate coagulation. The outer PNIPAM layer provided breathability, antibacterial protection, and reduced blood leakage. Both in vitro and in vivo studies demonstrated enhanced coagulation, strong erythrocyte adhesion, and a significant reduction in blood loss.

A hydrogel composed of poly (acrylic acid)-grafted sodium alginate and electroresponsive poly (3,4-ethylenedioxythiophene) nanoparticles loaded with chloramphenicol enabled precise antibiotic release in response to electrical stimulation and pH changes (Resina et al., 2023). Under normal conditions, only minimal passive diffusion occurred, whereas significant release was achieved under acidic conditions with electrical stimulation, maintaining antibacterial activity and cytotoxic effects against cancer cells. A dual-responsive nanomicellar drug delivery system for melanoma therapy was reported (Wang et al., 2021). PEG-PLA micelles, PNIPAM, gold nanorods, and doxorubicin were combined to enable temperature- and near-infrared-responsive release. Localized heating by gold nanorods induced PNIPAM phase transition, accelerating doxorubicin release, improving tumour targeting, and reducing systemic toxicity. This resulted in enhanced cytotoxicity and tumour suppression.

Composite silk fibroin (SF)-biosurfactant hydrogels were investigated to understand the influence of biosurfactant assemblies on gelation and nanoscale network organization. Incorporation of pH-sensitive sophorolipids accelerated the transition of SF from random coil to β-sheet conformations, promoting faster gelation (Lassenberger et al., 2021). An injectable self-healing SF hydrogel was prepared by combining regenerated SF with stearyl methacrylate (C18M) and an alginate ionic network, where reversible hydrophobic interactions act as sacrificial bonds that dissipate energy and improve mechanical properties (Meng et al., 2020). These hydrophobic interactions allowed the gel to recover quickly after deformation and exhibited autonomous self-healing without the need for an external stimulus. Table 1 summarizes the different stimuli-responsive hydrogels, their key properties, and applications.

TABLE 1. Summary of different stimuli-responsive hydrogels.

Hydrogel types/StimuliKey propertiesApplicationsLimitationsRelevant references
Photo-responsivePhoto control of mechanical stiffness and degradation rate, Spatial patterningDrug delivery, Tissue engineeringLimited deep tissue penetrationLi et al. (2019), Guo et al. (2025)
Thermo-responsiveBiocompatibility and Biodegradability, Critical solution temperature dependent reversibilityDrug delivery, Tissue engineering, Biosensors and microfluidicsPoor mechanical strengthKlouda and Mikos (2008), Suvarna et al. (2026)
Electric-field responsiveDeswelling, BendingDrug delivery, Tissue engineering, Electro-chemical biosensingLow mechanical strength, slow responseMurdan (2003), Ouyang et al. (2026)
pH-responsiveMechanical adaptability, Tuneable permeability, Swelling and de-swelling, Biocompatibility and BiodegradabilityTargeted drug delivery, Tissue engineering, BiosensingLimited by intra- and intercellular pH variabilityGhauri et al. (2021), Gao and Xu (2025)
Enzyme responsiveHigh Selectivity, Biocompatibility and Biodegradability, Local activationTargeted Drug delivery, Tissue engineering, BiosensorsSlow response time, complex fabricationHu et al. (2012), 2026
Magneto-responsiveMagnetothermal response, Anisotropy, Stiffness modulation, BiocompatibilityTargeted Drug Delivery, Cancer Hyperthermia, Soft RoboticsPotential cytotoxicity, limited spatial control, mechanical instabilityLi et al. (2021), Ding et al. (2024)
Multiple-stimuli responsiveHigh mechanical strength, Swelling and de-swelling, Biocompatibility and Biodegradability, Self-healing capabilitiesDrug Delivery, Tissue engineering, Soft roboticsComplex synthesis, mechanical weaknessDowns et al. (2020), Dixit and Sarkar (2025)

A conductive double-network hydrogel (PPTZ hydrogel) composed of poly (vinyl alcohol) (PVA), phytic acid (PA), tannic acid (TA), and Zn2+ ions was further evaluated in a diabetic infected wound model in Sprague-Dawley rats, along with electrical stimulation (ES) therapy. The PPTZ hydrogel exhibited reduced bacterial infection, decreased inflammation, enhanced angiogenesis, and accelerated tissue regeneration in the PPTZ-treated groups (Zheng et al., 2024). In another study, a multi-responsive hydrogel dressing for diabetic wound healing, based on phenylboronic acid-modified carboxymethyl chitosan (CMCS-PBA) and oxidized dextran (OXD), was developed and crosslinked through dynamic Schiff base and phenylboronate ester bonds and functionalized with insulin-like growth factor-1 C domain peptide (IGF-1C) and deferoxamine-loaded polydopamine nanoparticles (D@P) (Dai et al., 2024). The hydrogel accelerated wound closure, reduced chronic inflammation, enhanced neovascularization, and improved tissue regeneration in a streptozotocin-induced diabetic mouse wound model.

4 Neutron scattering for hydrogel characterization

Although scattering techniques such as light, Raman, and Brillouin scattering have been widely used to investigate the structure and dynamics in hydrogel systems, neutron scattering is a less-explored but non-destructive tool for probing structures over a wide range of length and time scales, making it well-suited for studying water-rich systems like hydrogels (Jeon et al., 2017; Rossi et al., 2018). Small-Angle Neutron Scattering (SANS) measurements provide information on network structure, mesh size, crosslinking density, pore size, aggregation behaviour, and polymer-rich and polymer-poor phases. For example, SANS was used to explore the microstructure of copolymer hydrogels composed of N,N-dimethylacrylamide (DMA) or N-isopropylacrylamide (NIPA) and 2-(N-ethylfluorooctanesulfonamido)ethyl acrylate (FOSA) (Tian et al., 2004). The analysis of SANS data revealed the shape of domains, information about cluster formation, and the large-scale inhomogeneities in the cluster. In a similar hydrogel system, the stress-induced nanostructural changes were investigated using SANS. The ability of creating different contrasts under SANS provided information about deformation and relaxation of the FOSA nanodomains and network chains with stress dissipation at different contrast conditions (Wiener et al., 2017). The nanostructure formation of the polymer network in the thermo-responsive grafts PNIPAm in a hydrophilic covalently cross-linked polymer network has been investigated by SANS. The mechanical toughening of the hydrogel, which depends on the weight ratios of PNIPAm grafts, also triggers the structural modification and rearrangement of PNIPAm domains in the network. SANS allowed to extract such information and helped to establish a relation between structure formation and mechanical toughening in such hydrogels (Mussault et al., 2019). SANS was also employed to understand the interaction of oppositely charged ionic surfactants with Epoxy-Based Hydrogels. The structural changes of hydrogels were analyzed using the Percus–Yevick hard-sphere (HS) model and rescaled mean spherical approximation (RMSA), respectively. This study unraveled the organization of ionic surfactants inside polymer hydrogels, which plays an important role in their application (Krakovský et al., 2025).

Neutron reflectivity (NR) provides insight into the interfacial structure of hydrogels, including layer thickness, polymer density profiles, and swelling behavior at solid-liquid interfaces (Saffer et al., 2014). NR was used to understand the effect of specific interactions of polyelectrolyte brushes of poly (acrylic acid) with D2O-swollen hydrogels of polyacrylamide and poly (N,N-dimethylacrylamide). The results showed that brushes at neutral condition interacts strongly with the hydrogel by forming hydrogen bonds. On the other hand, brushes turned non-interactive with the hydrogel at higher pH (Sudre et al., 2014). The switching kinetics of a thermo-responsive hydrogel were also investigated using NR. Using in situ NR, Zhong et al. observed a two-stage swelling process of poly (monomethoxy-diethyleneglycol-acrylate) (PMDEGA) hydrogel films at room temperature (Zhong et al., 2012). The increase in temperature led to a critical response in the swollen PMDEGA films, which was attributed to shrinkage, reorganization, and reswelling of the film. In another study, the swelling of thin UV-polymerized self-initiated photografting and photopolymerization (SIPGP) hydrogel films in air under different relative humidities was investigated using NR (Ederth and Ekblad, 2018). NR measurements were performed with hydrogels grafted from both silica and gold substrates. The results showed a clear difference in swelling with the type of substrate due to the inhomogeneities in the chain segment density distribution for films grafted from the silicon substrate.

Quasi-elastic neutron scattering (QENS) measurements provide information on the dynamics of hydrogels, including the diffusion and relaxation behavior of water and polymer chains, as well as localized and long-range motions, such as rotational and translational diffusion, over nanometre length scales and picosecond to nanosecond time scales (Papadakis et al., 2024). The water dynamics on the molecular scale in widely used polysaccharide hydrogels was explored using QENS (Middendorf et al., 1994; Cavalieri et al., 2006). The study showed that a fraction of water is dynamically quenched for an increasing polymer concentration. QENS was used for studying the dynamics of water in hyaluronate-based hydrogels (Chiapponi et al., 2012). Combining measurements from two QENS spectrometers with different energy resolutions, the results provided the microscopic dynamics of segmental biopolymer motion. The recent advancement of QENS in terms of available energy window and resolution enables us to resolve many questions, such as the different dynamics in hydrogels, etc.

Neutrons provide the privilege of contrast variation (hydrogen/deuterium substitution in the solvent/samples), using which specific components in multicomponent systems can be selectively highlighted. SANS, neutron reflectivity, and QENS are therefore very useful tools for probing structural changes under different stimuli, such as temperature, pH, or external fields, as well as for monitoring gelation kinetics and interactions between nanoparticles and polymer networks, which are crucial for designing hydrogels towards food, biomedical applications, tissue engineering scaffolds, and controlled drug delivery systems (Wiener et al., 2017; Papadakis et al., 2024). A summary of the principles, information obtained, and representative applications of these neutron scattering techniques is presented in Table 2.

TABLE 2. Summary of neutron scattering techniques commonly used for hydrogel characterization, and representative applications in stimuli-responsive hydrogel systems.

TechniquePrincipleInformation obtainedHydrogel applications
SANSElastic scattering at small anglesMesh size, pore size, crosslink density, nanostructureNetwork characterization, gelation, phase separation
NRReflection of neutrons from interfacesLayer thickness, swelling, density profileThin films, hydrogel coatings, interfaces
QENSLimiting case of inelastic/quasi-elastic neutron scatteringWater diffusion, polymer dynamics, relaxationMolecular dynamics, solvent mobility, chain motion

5 Future perspectives

The integration of stimuli-responsive hydrogels into food, biomedical, and tissue engineering applications remains limited by toxicity, biocompatibility, scalability, commercialization, and regulatory challenges. Future work should aim at developing hydrogels with reproducible performance, cost-effectiveness, longer shelf stability, sterilization compatibility, and distinct advantages over current technologies (Salehi et al., 2023; Protsak and Morozov, 2025). Commercialization will entail the use of a stable supply chain of food- or medical-grade polymers, compatibility with existing packaging and processing setups, and their integration into streamlined processing routes. Commercial implementation of active and intelligent food-contact materials is contingent on meeting the safety assessment, authorization requirements, and compliance with regulations and consumer acceptance (European Commission, 2009, European Food Safety Authority (EFSA), 2009). A translation growth trajectory in the biomedical and tissue engineering applications will depend on successful clinical validation, controlled degradation, and economical manufacturing (Salehi et al., 2023).

Toxicity and biocompatibility are fundamental to hydrogels’ safety owing to the presence of residual initiators, catalysts, nanoparticles, and degradation byproducts. Therefore, future studies should carry out specific evaluations of inflammatory response, cytotoxicity, product stability, and in vivo performance to meet the ISO 10993-based biological evaluation standards of medical materials (U.S. Food and Drug Administration, 2023).

Scalability is key to practical implementation of multifunctional stimuli-responsive hydrogels. Many advanced hydrogels rely on complex synthesis routes and advanced strategies, such as microfabrication, photopolymerization, or 3D/4D printing. Since these strategies are difficult to scale up at industrial scale, scalable hydrogel systems should focus on green processing routes, facilitated handling, standardized property control, and stimulus-response kinetics (Protsak and Morozov, 2025). Industrially viable hydrogels should consider scalability and cost-effectiveness at the earliest design stages by using abundant raw materials, low-energy and short production cycles, fewer purification steps, efficient packaging-line integration, and long shelf life (Wei and Huang, 2025). Industrial translation in biomedical applications requires quality-by-design and process-validation approaches to manufacturing to meet international standards (ICH. Q8R2, 2009). For medical device applications, regulatory requirements should be implemented within an ISO 13485-compliant quality management system (Goodall and Bos, 2026). These regulatory considerations are essential for the successful commercialization of stimuli-responsive hydrogels.

Regulatory pathways are to be imposed at the initial stage of material design. Food-grade hydrogels need to be classified as food-contact materials, active packaging systems, or edible matrices. EFSA and EU regulations require safety assessments of food-contact substances, including identity, function, exposure, migration, and toxicology tests (European Commission, 2009; European Food Safety Authority EFSA, 2009). In the United States, FDA evaluation of active substances similarly focuses on composition, function, and dietary exposure (U.S. Food and Drug Administration, 2007).

Although significant progress has been made in developing stimuli-responsive hydrogels, there exist inherent advantages and limitations towards their translational potential. For example, thermoresponsive hydrogels can be injected with minimal invasive administration; however, they have mechanical weakness. pH-responsive hydrogels are limited by intra- and intercellular pH variability. Magneto-responsive hydrogels containing magnetic nanoparticles can generate localized heat in an alternating magnetic field, enabling targeted hyperthermia treatment that destroys tumor cells while simultaneously facilitating controlled drug release. However, such treatments need external equipment to trigger the stimuli.

Future success will depend on translation-oriented multifunctional hydrogel design in which reproducible responsiveness, scalability, manufacturability, mechanical strength, toxicity, and regulatory compliance are improved simultaneously. Such systems must demonstrate clear advantages over current food, biomedical, and regenerative technologies.

6 Conclusion

This review summarizes the increased focus on stimulus-responsive hydrogel functionalization to tailor the physicochemical and biological properties for specific applications in the fields of food, tissue engineering, and drug delivery. These multifunctional materials with responsiveness will be highly relevant for active food packaging, active encapsulation, targeted drug delivery, and functional tissue scaffolds. Emphasis on sustainability will drive the use of biodegradable and environmentally friendly hydrogels that align with the UN Sustainable Development Goals (SDGs). Edible and biodegradable hydrogel-based food packaging materials have the potential to attract both scientific and commercial interest. Their greatest potential lies in freshness-responsive packaging, preservation of probiotics, and constrained release of antimicrobials or antioxidants. Self-dissolving and drug-releasing hydrogel patches can enhance wound care by eliminating the need for bandage removal and facilitating localized drug delivery. Reusable hydrogel scaffolds can be an important candidate to support long-term cell culture and regenerative applications in tissue engineering. Such innovations have the potential for the development of sustainable and next-generation hydrogel technologies. Design for future technologies should be translation-oriented instead of only stimulus-response. Overall, the landscape of the field’s progress depends on the ability to convert smart hydrogel concepts into safe, scalable, and application-specific technologies with advantages over current platforms.

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Footnotes

Edited by: Vanessa Naciuk Castelo-Branco, Fluminense Federal University, Brazil

Reviewed by: Shailendra Yadav, AKS University, India

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Author contributions

BJ: Writing – original draft, Conceptualization, Writing – review and editing. AB: Writing – review and editing, Writing – original draft. DS: Writing – original draft, Supervision, Writing – review and editing, Conceptualization.

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Citation

Joseph, B., et al. (2026). Recent advances in stimuli-responsive hydrogels for food, biomedical, and tissue engineering applications. Frontiers in Soft Matter, Volume 6. https://doi.org/
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6 - 2026

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Copyright © 2026 Joseph, Bharati and Saha.

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*Correspondence: Debasish Saha

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