INTRODUCTION:

Hydrogels are polymeric networks that are three-dimensional and hydrophilic, allowing them to absorb and retain large volumes of water or biological fluids. Hydrophilic functional groups in primary polymer chain of hydrogels are carboxyl, amine, hydroxyl and sulphate groups¹. Hydrogels were first documented to be used in the contact lens business in 1960. The structure and functionality of early hydrogels were comparatively straightforward. But over the past years, there have been, more advanced hydrogels have emerged, such as bioactive composite hydrogels, self-healing hydrogels, stimuli-responsive (smart) hydrogels, and injectable systems.

Hydrogels are essentially composed of synthetic or natural polymers that have been crosslinked to form a porous matrix. They are particularly well suited for applications requiring interaction with biological tissues or fluid transfer because of their structure, which enables them to swell in aqueous environment. Hydrogels swell because of their strong thermodynamic affinity for solvents. The porous matrixes swell but do not dissolve in water in a short period of time². The absorption of water or biological fluids by hydrogels is due to the swelling character it is monitored by the swelling media, crosslinking bonding strength and hydrophilicity of the attached functional groups. Crosslinking regulates the absorption of water and aids in preserving the network structure when it is swollen³.

Hydrogels are ideal candidates for an array of biomedical applications, including as drug administration, tissue engineering, wound healing, and biosensing, due to their special qualities, which include high water content, softness, flexibility, biocompatibility, minimal protein adsorption because of their low surface tension, and resemblance to the structure of extracellular matrix⁴. In addition, hydrogels react to an array of stimuli, including ionic strength, temperature, biological molecules, magnetic and electric forces. Because of their mucoadhesive and bioadhesive properties, many hydrogels can extend the duration of a medication's residence, making them excellent candidates for drug carriers⁵.

In reaction to specific physical and chemical stimuli, hydrogels experience a notable volume phase change or gel-sol phase transition. The kind of monomer, charge density, pendant chains, and degree of cross-linkage all have a major impact on how hydrogels react to outside stimuli. Additionally, there is a clear correlation between the strength of the reaction and the applied external stimuli. The benefits of hydrogels include improved biocompatibility, adjustable biodegradability, appropriate mechanical strength, porous structure, and more. However, the viability of using hydrogels is still restricted because of their poor mechanical strength and delicate nature⁶.

Crosslinking between the network chains in hydrogels gives them the ability to retain water in their structure without dissolving. They produce insoluble properties as a result of crosslinking. Entanglements, crystallites, Vander Waals forces, and intramolecular or intermolecular hydrogen bonds are the main components of physical crosslinking. These cross-linked structures provide the network its physical stability⁷.

Fig. 1: Structure of Hydrogels⁸

Classification of Hydrogels:^9-15

Numerous characteristics, including as their origin or source, composition, structural configuration, cross-linking, network charge, durability, and response to stimuli, are used to categorize hydrogels.

Synthesis of Hydrogels:

Hydrogels consist of polymer chains, and their characteristics are determined by the properties of the used polymer. Cross-links connecting polymer chains build a three-dimensional framework in hydrogels. The hydrogel's properties like elasticity, viscosity, solubility, glass transition temperature, toughness, and melting point are all impacted by cross-linking. Molecular weight of the polymer chains increases as cross-linking occurs, further decreasing solubility and translational movement. The cross-linking density, which rises as interactions between the solvent molecules and polymer chains decreases, determines how much solvent the hydrogel absorbs¹⁶.

The fundamental techniques that produce hydrogels are both physical and chemical cross-linking. Depending on the kind of bonding that occurs between polymer chains, each method creates networks with distinct operational and structural characteristics.

A vast variety of polymers, which may be generally divided into natural, synthetic, and semi-synthetic varieties, make up hydrogels. Every type has distinct qualities that make it ideal for a variety of applications. Due to its remarkable biodegradability, and capacity to replicate the extracellular matrix, natural polymers including chitosan, alginate, agarose, hyaluronic acid, carrageenan, pectin, and starch are frequently utilized in biomedical and pharmaceutical applications. Synthetic polymers, including polyethylene glycol, polyacrylamide, poly(N-isopropylacrylamide), polyacrylic acid, poloxamers (Pluronics), and polyurethane, are valued for their consistent purity, mechanical strength, and tunable physicochemical properties.

1. Physical Cross-Linking Method:^17,18

Physically cross-linked hydrogels develop through non-covalent interactions—including hydrogen bonding, ionic associations, hydrophobic effects, Van der Waals forces, and coordination bonds. In addition to imparting exceptional qualities like self-healing and thermal reversibility, these reversible interactions allow dynamic structural adaptation under environmental changes like temperature, pH, or ionic strength. These hydrogels are usually particularly sensitive to water, but they break down quickly (from a few days to around a month) under physiological settings, which makes them perfect for temporary drug delivery systems. They are also more biocompatible as they lack of harmful covalent cross-linking agents, which is an additional advantage for biomedical applications.

2. Chemical cross-linking method:

Physical gels formation arises from the molecular clustering of polymer chains, which results in the formation of free chain loops. These loops, which are temporary flaws in the network design, lead to structural inhomogeneities¹⁹. Chemically cross-linked hydrogels, on the other hand, provide more control over the stability and development of networks. In these systems, chemical events like polymerization or cross-linking agent-mediated procedures establish covalent connections between polymer chains. Significantly increased mechanical strength and resilience to environmental variations are displayed by the resultant three-dimensional network of linked macromolecules²⁰. Long-term structural stability is provided by the covalent structure of the cross-links, which makes the hydrogel less prone to deterioration or changes in properties under different conditions of pH and temperature. As a result, chemically cross-linked hydrogels exhibit exceptional mechanical strength, endurance, and appropriateness for applications needing continuous performance under stressful conditions. In contrast to physical hydrogels, chemically crosslinked hydrogels are simpler to manage because their manufacturing and applications are independent of pH²¹.

3. Irradiation Based Cross-Linking Method:

Irradiation-based crosslinking has emerged as an attractive strategy for hydrogel synthesis, particularly in instances where rapid gelation and cost efficiency are paramount. This method uses ultraviolet irradiation and light-sensitive functional moieties to initiate crosslinking, which facilitates effective hydrogel production quickly. Such instantaneous gelation increases the possibility of a variety of biological uses, such as medication administration, wound healing, and tissue engineering²².

Irradiation-based techniques have two key advantages over traditional chemical crosslinking techniques. In the first place, they facilitate quick manufacturing since hydrogel networks may be formed under UV light in a matter of minutes, significantly cutting down on processing time as compared to techniques requiring for more prolonged reactions. Second, they are more economical since the procedure can reduce or eliminate the requirement for pricey catalysts or crosslinking agents, which lowers production costs overall²³.

Stimuli Responsive Hydrogels:

Stimuli-sensitive hydrogels are a unique family of hydrogels that may change their volume, shape, or other characteristics in response to particular conditions. These hydrogels are divided into groups according on the kinds of stimuli they react to: (i) chemical stimuli like pH, redox potential, ionic strength, CO₂, and glucose; (ii) physical stimuli like light, pressure, temperature, electric or magnetic fields, and ultrasound; and (iii) biological stimuli like enzymes, antigens, glutathione, and DNA.

The source of these stimuli during in vivo application might further categorize them as internal or exterior. With the exception of temperature, which can function as an internal or external trigger, physical stimuli are often external, whereas chemical and biological stimuli are regarded as internal. These hydrogels are sometimes referred to as "smart" or "intelligent" hydrogels because of their capacity to detect a stimulus and react with a change in physical or chemical behaviour, frequently leading to the controlled release of an encapsulated medication²⁴.

1. pH Sensitive Hydrogels:

pH-sensitive hydrogels contain charged pendant groups that ionize in response to changes in pH. Their presence induces swelling, which is influenced by a number of variables such as the ionic charge, the ionizable groups pKa or pKb, the degree of ionization, hydrophilicity, polymer concentration, and the surrounding pH. Among these, the nature of pendant groups and the environment's pH are the most important in regulating the swelling behaviour²⁵.

Anionic hydrogels, such carboxymethyl chitosan, swell in basic media, allowing intestinal distribution at pH 7.4, whereas cationic hydrogels, like chitosan, swell in acidic circumstances because of the protonation of amino groups, making them appropriate for stomach-targeted drug delivery. Polyelectrolyte complex hydrogels, which are made of cationic and anionic polymers and stabilized by electrostatic interactions, are a safer alternative that do not require harmful crosslinkers²⁶.

Swelling of hydrogels in water or physiological fluids is driven by osmotic pressure, polymer hydrophilicity, fixed charges, and counter ions. The three phases of the process are (i) diffusion of water into the network of polymers, (ii) hydration and chain loosening, and (iii) network expansion as chains relax. Prior to interacting with exposed hydrophobic areas, water first binds to hydrophilic groups (primary bound water). Osmotic forces cause more water to enter, while elastic crosslinking prevents this, resulting in free water at equilibrium.

Drug release from pH-sensitive hydrogels can be regulated chemically, via swelling, or by diffusion. Their remarkable sensitivity allows them to detect even the smallest pH changes, as little as 10−5 pH units. Because of their broad measurement range, hydrogels show promise for pH sensing²⁷. Fick's law governs the diffusion-controlled release of small drug molecules, whereas the polymer network may impose restrictions on bigger molecules. Water absorption in swelling-controlled release causes network expansion and polymer chain relaxation, enabling progressive drug desorption; the rate is determined by the crosslink density and hydrogel composition. Chemically-controlled release can be either reaction-diffusion controlled, where both diffusion and polymer degradation contribute, or kinetically controlled, where bond cleavage is rate-limiting. It involves the hydrolytic or enzymatic breakdown of the polymer chains. Drug size, hydrogel structure, and ambient pH influence the mechanism selection, which makes pH-sensitive hydrogels flexible platforms for precise and regulated drug delivery.

2.Temperature-Sensitive Hydrogels:

Temperature-responsive hydrogels (TRHs) can alter their shape, size, and volume in response to physiological temperature changes, primarily due to hydrophobic groups such as propyl, ethyl, and methyl on their polymer chains. Therapeutic compounds can be loaded in liquid form and solidified upon administration since they normally exist as liquids or semi-solids at room temperature and go through a sol-to-gel transition at body temperature^28,29.

In general, structures of temperature-sensitive hydrogels have both hydrophobic and hydrophilic components, and the phenomenon of heat sensitivity results from the precise interplay between the hydrophobic and hydrophilic regions of the polymer monomer. Temperature can cause a change in the cross-linked network's solubility and the so-gel phase transition by altering how hydrophilic and hydrophobic regions of the polymer interact with water molecules³⁰. The gel phase retains its structural integrity and is non-flowing, whereas the sol phase is characterized as a flowing fluid. The cross-linked network's macroscopic dissolving state in an aqueous solution is determined by the ratio of hydrophilicity to hydrophobicity³¹.

Lower critical solution temperature (LCST) and Upper critical solution temperature (UCST) hydrogels are the two categories into which TRHs reside. When heated over their transition temperature, LCST hydrogels lose their solubility because of increasing hydrophobic interactions, while UCST hydrogels become soluble. For most polymers UCST is below 25°C, which limits their biomedical applications; as a result, LCST-based TRHs are most frequently used in the distribution of drugs³².

Through a combination of swelling, diffusion, and polymer breakdown processes, drugs are released from thermosensitive hydrogels. It is easy to integrate drugs into the hydrogel because it stays in a liquid sol form at low temperatures. The system passes through a sol–gel transition at physiological temperature, creating a cross-linked network that traps the medication. The drug molecules are then progressively released by the hydrogel's water-filled pores, the breakdown and erosion of the polymer chains, or the swelling of the polymer network, which enlarges the mesh size.

3. Bio-Responsive Hydrogels:

Bio-responsive hydrogels are dynamic systems that react to or stimulate specific impulses by means of biological processes. Both natural and artificial biomacromolecules, including enzymes, antibodies, nucleic acids and small bioactive molecules like peptides or carbohydrates, can be employed for these purposes³³.

Hydrogels that respond to enzymes and glucose are two of the most sophisticated types of bioresponsive materials for targeted drug delivery³⁴. In order to facilitate the creation or breakdown of polymeric networks, Enzyme-responsive Hydrogels (ERHs) are usually engineered with peptide sequences or functional side groups (such as glutamine, lysine, tyrosine, or phenol) that are cleaved or crosslinked by enzymes like transglutaminase (TGlu), matrix metalloproteinases (MMPs), or horseradish peroxidase (HRP). Because of these structural changes, ERHs are extremely beneficial for cancer or tissue-regeneration treatments because they enable drug release to be preferentially triggered in diseased tissues that are rich in enzymes³⁵.

The structural motifs of Glucose-responsive Hydrogels (GRHs), on the other hand, include glucose oxidase (GOx) enzymes incorporated in the matrix, phenylboronic acids (PBAs), and boronic acid–diol complexes. GOx lowers pH and causes hydrogel to swell or collapse, which regulates insulin release in situ. It also catalyses the conversion of glucose to gluconic acid. ERHs and GRHs are therefore prime examples of how molecular-level structural design, whether it be glucose-sensitive motifs or enzymatically responsive links, converts certain biological triggers into accurate, stimuli-responsive drug delivery systems³⁶.

4. Light Sensitive Hydrogels:

Light is a unique stimulus that is clean, precise, and non-invasive, which makes photoresponsiveness very beneficial. Light eliminates hazardous byproducts since it does not need extra reagents as chemical triggers. The degree of photoreactions and the degree of hydrogel swelling, degradation, or functional alteration can be controlled by adjusting its characteristics, which include intensity, wavelength, and irradiation period³⁷.

Photo-responsive hydrogels on exposure to light undergo structural and functional changes, giving their characteristics precise spatiotemporal control³⁸. Light modulates hydrophilicity and crosslinking density, causing gel-sol transitions, network contraction and expansion, and swelling and shrinking. Photoisomerization (azobenzene–cyclodextrin complexes, spiropyran units) is a reversible mechanism that modifies the length or polarity of polymer chains, resulting in changes in volume; conversely, backbone cleavage is often necessary for irreversible treatments. Reversible covalent bonds, such as disulfides and trithiocarbonates, can be introduced to enable recurrent modification of the hydrogel's integrity³⁹.

In addition to mechanical reactions, light can directly modify wettability, bioadhesion, or catalytic activity by regulating the expression of functional groups within networks by photodimerization, photocaging, or photoactivation. Photochemical reactions including photoisomerization (azobenzene units), photocleavage of crosslinkers, or reversible bond exchange (disulfides, trithiocarbonates) affect the hydrogel's porosity, hydrophilicity, or crosslinking density when it is exposed to radiation. These modifications control the diffusion paths of drugs that are encapsulated, enabling either continuous release (via swelling/shrinkage cycles) or burst release (through gel–sol transition or network disintegration). These photo-responsive devices are especially useful in dynamic cell microenvironments, remote-controlled actuators, and on-demand medication administration, where non-invasive and reversible control is crucial.

CONCLUSION:

Hydrogels are multipurpose polymer networks that exhibit great swelling, stimuli-responsiveness and biocompatibility. Wide-ranging biological uses are rendered possible by their structural flexibility and crosslinking methods. More complex biomedical and technological applications are now possible because to the advent of smart hydrogels, which have revolutionized the field by introducing materials that can react to stimuli like temperature, pH, light, and bioactive molecules. These viewpoints highlight hydrogels as a dynamic material class that connects basic polymer research with useful advancements. Because of their adaptability, hydrogels will remain essential to the development of engineered systems and next-generation treatments.

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Received on 04.12.2025 Revised on 08.01.2026

Accepted on 12.02.2026 Published on 21.04.2026

Available online from April 24, 2026

Res. J. Pharma. Dosage Forms and Tech.2026; 18(2):141-146.

DOI: 10.52711/0975-4377.2026.00022

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