Caritas College of Pharmacy, Ettumanoor, Kerala, India
Smart hydrogels are an advanced class of polymeric materials that can respond to various physiological and environmental stimuli, including pH, temperature, light, redox conditions, enzymes, and magnetic fields. These responsive behaviours enable precise, targeted, and controlled drug release, making smart hydrogels highly promising for biomedical applications, particularly in drug delivery and tissue engineering. Unlike conventional hydrogels, smart hydrogels exhibit dynamic properties that allow them to adapt to specific biological conditions, improving therapeutic outcomes. Their classification is based on origin, crosslinking, degradability, and preparation methods. Stimuli-responsive hydrogels, including thermo-, pH-, photo-, and enzyme-sensitive variants, have demonstrated significant utility in treating chronic wounds, myocardial damage, neural and bone tissue repair, and meniscus regeneration. Despite their advantages, challenges such as balancing mechanical strength and injectability, achieving uniform crosslinking, and ensuring controlled drug release remain. Future research aims to enhance the biocompatibility, biodegradability, and responsiveness of these materials while minimizing their toxicity, paving the way for their integration into personalized and precision medicine.
Hydrogels are polymeric materials consisting of a sparse network of polymer chains embedded in an aqueous medium. Hydrogels can retain large amounts of water within their intermolecular space due to the strong hydrophilicity of the polymer chains and large porosity. Smart hydrogels, as an emerging class of material responding to external triggers, such as pH, temperature, electrical and magnetic fields, light, and concentration of biomolecules, can release the drug cargo at specific locations with controllable kinetics. Conventional hydrogels exhibit only minor alterations, characterized by swelling in response to external environmental conditions and low mechanical strength, whereas smart hydrogels are sensitive to subtle changes in external environmental conditions and can immediately adjust their physical properties. The water capture depended on the surface functional groups, crosslinking density, pore structure, and solid content. Due to their water-containing property, hydrogels are generally considered biocompatible, environmentally friendly, and biodegradable. Thus, they have been employed in biomedical applications. The properties of the hydrogels generally rely on the crosslinking density, the content of the polymer, the operation temperature, and time etc. Biodegradable hydrogels are being studied further as smart biomaterials that can help produce nanotechnological solutions that provide targeted and regulated treatment.
Classification of hydrogels [3]
Hydrogels are classified based on the following categories;
Hydrogel Classification Based on Origin
Hydrogels are broadly classified into two types based on their origin: natural and synthetic.
1. Natural hydrogels are biodegradable materials with good biocompatibility and low toxicity. The molecular structures of natural hydrogels (derived from the ECM) have the inherent properties that can naturally support cell adhesion and proliferation. Other hydrogels produced from plant-based materials are readily available and avoid any kind of viral infections that may have animal origins. However, the undefined structures of these materials allow limited control over the mechanical properties (like rigidity and flexibility), and the difficulty in reproducibility in large-scale production has limited their use in many biomedical applications.
2. Synthetic hydrogels are pre-structured hydrogels with defined chemistry based on the structure of monomers/polymers. The commonly used polymers include PEG, polyvinyl alcohol (PVA), polyethylene oxide (PEO), poly (methacrylic acid), poly(acrylamide) (PAM), poly(N-isopropylacrylamide) (PIPAM), etc. Compared to natural hydrogels, synthetic hydrogels possess the potential for advanced characteristic features such as high-water sorption capacity, improved physical and chemical stability, reproducibility, and enhanced gel strength, which are enabled by their chemically crosslinked structure.
Hydrogel Classification Based on the Preparation Method
Hydrogels have been broadly classified as homopolymeric, copolymeric, and interpenetrating polymer network (IPN) hydrogels based on the preparation method.
1. Homo polymeric hydrogels represent polymer networks that are created from a single polymer with the same repeating monomers.
2. Copolymer hydrogels contain multiple monomeric polymers with at least one hydrophilic polymer, arranged in block, random, or alternating configurations.
3. IPN hydrogels are made from two independently crosslinked natural or synthetic polymers confined in the network structure.
Hydrogel Classification Based on Degradability
Hydrogels have been categorized into biodegradable and non-biodegradable based on their degradation. The hydrogels synthesized from natural polymers such as chitosan, alginate, agarose, fibrin, etc., are completely biodegradable. Degradable gels made from water-soluble polymers such as PVA, PEG, PAM, and polyvinylpyrrolidone (PVP) degrade by the breaking of virtual or covalent crosslinks. For many biomedical applications, the biodegradable aspect is the primary criterion for the use of the material inside the body.
It is of great interest to control the degradation kinetics of hydrogels for targeted applications, as it may help formulate a protocol for the synthesis of the hydrogels. Upon the implantation of a hydrogel, the full understanding of the degradation phenomenon of the hydrogel depends on a wide range of factors due to the complexity of the environment, and the stability and performance of the hydrogel are also based on the biocompatibility and inflammatory nature of the hydrogel and its breakdown products.
Hydrogel Classification Based on Crosslinking
1. Crosslinking by Ionic or Electrostatic Interactions
In general, ionic or electrostatic crosslinking occurs due to the molecular interconnection between the anionic and cationic polyelectrolytes. For example, the positively charged amine groups of chitosan, a natural polymer, and the negatively charged phosphate groups of glycerol phosphate disodium salt can form electrostatic crosslinking to formulate chitosan-based hydrogels.
2. Crosslinking by Hydrophobic Interactions
Hydrophobic interactions play a crucial role in designing tough hydrogels for large biological systems. The hydrophobic interactions can be formed by incorporating hydrophobic structural units into the hydrophilic polymer chain. Usually, the hydrogel formed by hydrophobic interactions exhibits high toughness due to the flexible movement of junction zones in the hydrogel network, which helps to dissipate energy efficiently and increase fracture toughness. Hydrophilic interactions have been actively used in associative thickeners like hydrophobically ethoxylated urethanes.
3. Crosslinking by Enzyme-catalysed Reactions
Enzymatic crosslinking is another technique that is currently gaining much attention as it provides the opportunity to manipulate the gel formation by regulating the enzyme characteristics. The formation of gels depends on many parameters, such as the specific type of enzymes, their structural arrangement, physiological conditions, etc. Compared to physical and chemical crosslinking methods, enzyme-catalysed hydrogel formation is simple and carried out under mild physiological conditions. For example, no toxic chemicals, no high temperatures, high efficiency, and no harmful radiation are involved in the crosslinking.
4. Crosslinking by Crystallization
In this process, the crystallites present or that form in the polymer chain serve as building blocks for physical crosslinking in the network, consequently resulting in the formation of a hydrogel. The PVA solution undergoes repeated freezing and thawing cycles to form a hydrogel. The properties of the resultant gel depend on many factors like molecular weight, concentration of solution, freezing time and temperature, number of cycles, etc.
Stimulus-responsive hydrogels:
Fig. 1 stimuli responsive hydrogels
Classification of Stimuli-Responsive Hydrogels (according to the stimuli they respond to)[4]
• Thermoresponsive Hydrogels
Liposomes, nanoparticles, and polymer micelles are common temperature-responsive carriers. When the ambient temperature exceeds the polymer's critical solution temperature (CST), the hydrophilic–hydrophobic equilibrium breaks and the polymer chain dehydrates, causing the drug-delivering carrier's structure to change and the contents packed in the system to be released.
• pH-Responsive Hydrogels
Warburg effect states that tumour cells produce the majority of their energy in the cytosol via increased glycolysis followed by lactic acid fermentation. This increased acid production causes cancer cells to have a lower PH. As pH levels differ from organ to organ and even tissue to tissue, the pH-responsive medicine delivery mechanism is unique. Tumours have an acidic pH compared to a slightly basic intracellular pH 2.
• Photo-Responsive Hydrogels
Precise drug release is achieved in light-responsive drug delivery systems when exposed to exogenous light (such as visible, infrared light, or ultraviolet)
For example, the doxorubicin-loaded gold nanocarrier has increased drug release under 808 nm illumination.
• Redox-Sensitive Hydrogels
An amphiphilic conjugate, coupled heparosan with deoxycholic acid via a disulfide bond, self-assembled into stable micelles to deliver doxorubicin into cancer tissues. This formulation exhibited good loading capacity and glutathione-triggered drug release behaviour.
• Enzyme-Responsive Hydrogels
In pathological conditions such as tumours or inflammations, the peptide structure or ester bonds of the stimuli-responsive carriers may be broken down by various enzymes, allowing the loaded medications or proteins to be released at specific sites to exhibit therapeutic effects
• Magneto-Responsive Hydrogels
Magneto-responsive hydrogels are advanced materials consisting of polymeric networks embedded with magnetic nanoparticles, such as iron oxide or other ferromagnetic materials. These nanoparticles are uniformly dispersed within the hydrogel matrix, giving it the ability to respond dynamically to external magnetic fields. When subjected to a magnetic field, the nanoparticles align or generate localized heating, causing changes in the hydrogel's mechanical, structural, or functional properties.
Applications of smart hydrogels
1. Application of smart?responsive hydrogels in chronic wound tissue repair
Smart?responsive hydrogels have very broad prospects in the fields of biomedical engineering and tissue repair. The complex process of chronic wound repair and four sequential yet intersecting stages leads to potentially different requirements for active substances during different stages of healing.[5] Over the past few decades, gauze, films, foams, sprays, and hydrogels have been used to treat chronic wounds. These dressings are easy to absorb blood and exudate secreted by the wound and have certain antibacterial and anti-inflammatory effects.[6]
2. Application of smart?responsive hydrogels in the repair of damaged myocardial tissue
Due to the current scarcity of cardiac donors and immune complications, these patients eventually face death. In recent years, the exploration of novel and promising HF treatment strategies has become a research hotspot. Injectable hydrogel as a minimally invasive technique overcomes the clinical and surgical limitations of traditional stent implantation.[7] [8]
3. Application of smart?responsive hydrogels in nervous tissue repair
The presence of the blood–brain barrier results in poor permeability of therapeutic molecules such as drugs or proteins, ultimately resulting in limited therapeutic efficacy.[9] [10] To address the limitations of current drug delivery, hydrogels hold superior promise for in situ treatment of brain tissue?damaging diseases. Considering the microenvironmental characteristics of brain tissue injury sites (such as acidic pH, platelet activation, ROS concentration, and enzyme concentration), some smart?responsive hydrogel?based strategies have been used for brain injury tissue repair[11] [12]
4. Bone and Cartilage Tissue Engineering
Cartilage has limited ability for self-repair, thereby prompting the researchers to look for an alternative substitute that can repair cartilage defects. The hydrogel class of materials has been looked upon as ideal substitutes that can repair cartilage defects due to their mechanical properties, swelling ability, and lubricating behaviour, which mimics the ECM of the articular cartilage. Hydrogels can encapsulate stem cells and can be loaded with growth factors, proteins that are essential for the promotion of cell differentiation. Hydrogel scaffolds have shown promising results in tissue engineering of bone and cartilage and seem to be an effective strategy for bone and cartilage tissue repair. [13]
5. Meniscus Tissue Engineering
Meniscal tissue has a limited capacity to regenerate once they are damaged. The injectable hydrogel-based systems have provided an alternative to conventional meniscus treatment by being minimally invasive. The meniscus plays an essential role in maintaining the homeostasis of the knee joint, and tissue engineering approaches are of great importance to repair and regenerate damaged meniscus tissues in this area. Enzyme-based methods were employed to fabricate tissue adhesive hydrogels for meniscus repair. Specific body tissues, such as cartilage and meniscus, have limited or no blood supply, and this makes them incapable of healing if they are damaged. By injecting a hydrogel loaded with repair cells or drugs into the damaged area, it may help in stimulating tissue regeneration.[14]
Recent advances in hydrogels
1) Physical?responsive hydrogels
a) Thermoresponsive hydrogels
Most Thermoresponsive hydrogels can form hydrogels at higher temperatures and can return to the liquid state at lower temperatures within a certain range. The phase transition process does not require the help of any other factors and is considered to be a benign phase transition process.[15]
b) Light/photoresponsive hydrogels
The first is that the hydrogels undergo a phase transition?triggered response after absorbing photons of certain energy by grafting photosensitive groups, which is the most common photo-response mechanism. The commonly used photoactive groups include azobenzene, diaryne, spiropyrans, photo-reversible dimerization groups (e.g., coumarin, anthracene, and pyrimidine derivatives), and nitrobenzyl derivatives.[16] The second light?responsive mechanism is that the hydrogels contain photoactive molecules, leading to reactions with the network structure of the hydrogels or swelling due to the changes in osmotic pressure [17]. Third, hydrogels containing photosensitive compounds can change their properties in response to changes in the environment by absorbing photon energy.[18]
c) Magnetic responsive hydrogels
Magnetic-responsive hydrogels were designed and prepared by adding magnetic nanomaterials into the hydrogel, which have great potential in tissue repair due to their fast magnetic responses, precise spatiotemporal control, and non-invasive remote actuation.[19] Magnetic nanomaterials generally refer to iron oxides (Fe3O4, γ?Fe2O3), transition metal ferrites (CoFe2O4, MnFe2O4, etc.), and transition metal alloys (FePt).[20] [21]
d) Ultrasound?responsive hydrogels
high?performance hydrogel and successfully applied it in the anti?inflammatory treatment of sepsis. Using endotoxin-induced systemic inflammation as a model, ultrasound-responsive constant pressure pulse stimulation of vagal nerve stimulators significantly inhibited the production of proinflammatory cytokines. The work provided a new strategy for developing implantable soft nanogenerators for radio-frequency stimulation of the nervous system. [22]
e) pH-responsive hydrogels
At chronic wound sites, pH-responsive hydrogels rapidly released silver nanoparticles (Ag NPs) to effectively kill bacteria, while the drug deferoxamine (DFO) accelerated the remodelling of new blood vessels, thereby accelerating the repair of chronic skin wounds.[23]
f) Glucose?responsive hydrogels
There has been no effective clinical treatment for diabetic chronic wounds at present. Yang et al.104 designed a glucose-responsive multifunctional hydrogel that could modify the wound microbiome in chronic diabetic wound sites. On the contrary, it accelerated the release of zinc ions and DFO, showing synergistic antibacterial and proangiogenic functions. This innovative design strategy may have great potential for application in chronic wound therapy. Furthermore, Xu et al.105[24] [25]. designed a novel glucose?responsive hydrogel by modifying phenylboronic acid (PBA) onto a hyaluronic acid chain and then combining it with polyethylene glycol diacrylate. The multifunctional hydrogel could realize the controllable release of myricetin with antioxidant activity under glucose conditions and effectively scavenge reactive oxygen species
2) Biological?responsive hydrogels
a) Enzyme?responsive hydrogels
Gliomas are the most aggressive primary malignant brain tumours. Temozolomide (TMZ) is a clinical drug for the treatment of glioma after surgery, but its therapeutic effect is not good. Zhao et al.69 prepared a matrix metalloproteinase (MMP) enzyme?responsive injectable drug?loaded hydrogel for the removal of residual drug?resistant gliomas after surgery. Drugs were released under the action of high concentrations of MMP enzymes after glioma surgery, significantly improving the efficiency of TMZ in inhibiting glioma growth.[26]
b) Antigen/antibody?responsive hydrogels
Antigen/antibody?responsive hydrogels can be prepared by incorporating antigens into hydrogels or by chemically conjugating antigens or copolymerizing their binding fragments with hydrogels.[27]
CHALLENGES IN FORMULATION
1. Inconsistency between the hydrogels' injectability and mechanical strength
While injectable hydrogels typically have low mechanical strength and are unable to offer efficient mechanical support, high mechanical strength hydrogels are either poorly injectable or cannot be injected.[28] [29]
2. The density of crosslinking is irregular.
Hydrogels are inherently susceptible to biotoxicity when chemical cross-linking agents are added, and their limited water solubility severely restricts their clinical use.[30]
3. Unauthorized release
decrease the disease's therapeutic impact and raise the drug's harmful side effects. [31]
FUTURE PERCEPTIONS
In the future, developing smart?responsive hydrogel platforms targeting tissue disease microenvironments is a potential area of research. In addition, it is also a good option to develop a programmatic delivery hydrogel platform that can respond to both the external environment and the disease microenvironment. Although significant progress and diversification have been made in the preparation of smart?responsive hydrogels, their biodegradability, responsiveness, microstructure, inflammation, and immune response are still important challenges in the preparation process. They will severely limit the application field expansion and clinical medical translation of smart?responsive hydrogels. Therefore, more attention should be paid to the preparation of smart?responsive hydrogels in the future, including their minimal immune response and optimal biosafety. Different solvents used in the preparation of smart?responsive hydrogels will also pose additional toxicity risks. Therefore, the use of natural polymers and cross?linking agents with good water solubility is also an important topic for further research in the future.
Smart?responsive hydrogels can be applied in a wider range of fields, including but not limited to tissue repair in the future. It is foreseeable that with the emergence of personalized precision medical technology, smart?responsive hydro gels will also receive more application prospects and attention in clinical practice.
CONCLUSION:
Smart hydrogels are a revolutionary development in the fields of regenerative medicine and drug delivery. Many of the drawbacks of conventional delivery methods are overcome by their capacity to react to a range of internal and external stimuli, enabling precise, regulated, and site-specific drug release. Smart hydrogels' adaptability—in terms of their biodegradability, tunable mechanical characteristics, and compatibility with biological tissues—makes them perfect for a variety of applications, including cartilage, heart, and brain tissue engineering, as well as chronic wound healing. Even so, there are still issues to be resolved, like obtaining the best possible mechanical strength, guaranteeing biocompatibility, and facilitating predictable degradation and drug release profiles. To overcome these constraints and realize the full clinical potential of smart hydrogels, more multidisciplinary research is necessary. Smart-responsive hydrogels should become more prevalent as technology develops.
ACKNOWLEDGEMENTS:
The authors express their gratitude to caritas college of pharmacy for providing the necessary facilities and opportunity to work on this topic.
REFERENCES
Lena Sara Varghese, Anit Joji George, Sr. Swapna Paul, Aswin C Elias, Ashmy Benny, Krishnapriya Sunil, Smart Hydrogels for Enhanced Drug Delivery, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 7, 3810-3819. https://doi.org/10.5281/zenodo.16532084
10.5281/zenodo.16532084
