From Concepts to Applications: A Comprehensive Review of Hydrogels

International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221, October, 2025 International Journal of Research Publication and Reviews Journal homepage: www.ijrpr.com ISSN 2582-7421 From Concepts to Applications: A Comprehensive Review of Hydrogels Prathamesh Jagdale a,b, Dr. Rajan Kalamkar b, Dr. Pankaj Mandpe a, Chandrakant Wadile a, Divyanka Bodas a, Harshal Patil a, Arati Bhadale b a Formulation, Research and Development, Micro Labs Limited, Mumbai, Maharashatra.. bVivekanad Education Society College of Pharmacy, Mumbai, Maharashtra A B S T R A C T Hydrogels have emerged as promising biomaterials for use in drug delivery systems. This is because of their special capacity for regulated release, biodegradability, and biocompatibility. An overview of the most recent advancements in hydrogel-based drug delivery systems is given in this paper, with particular attention to their synthesis, design, and uses. There is also discussion of the basic characteristics of hydrogels. We outline many classification schemes for hydrogels according to their ionic charge, responsiveness, crosslinking technique, and place of origin, as well as samples and salient features. The design considerations for hydrogels in drug delivery are also examined in this review, with a focus on the importance of mechanical qualities, biocompatibility, biodegradability, and stimuli responsiveness. Highlighted are recent developments in smart hydrogels, nanocomposite hydrogels, 3D-printed hydrogels, and injectable hydrogels, as well as their possible uses in tissue engineering, regenerative medicine, oral, transdermal, ophthalmic, and cancer therapy.We address the challenges and limitations of hydrogel-based drug delivery systems, including scale-up and manufacturing issues, regulatory concerns, and long-term biocompatibility issues. Finally, the review concludes by discussing future perspectives and emerging trends in this area, including the possibilities for personalized medicine and the integration of hydrogels with technologies such as artificial intelligence and nanotechnology. Keywords: Hydrogels, Drug delivery, Biocompatibility, Stimuli-responsive, Nanocomposite, 3D printing, Personalized medicine 1. INTRODUCTION Hydrogels are polymers that are arranged in three-dimensional networks. They have special molecular structure and physical-chemical features. contain a large amount of water, are soft, and can be easily shaped. These qualities make them suitable for many biomedical applications, as they are compatible with living tissues (1). The water absorption capacity is typically about 10-20 times their dry weight. Some superabsorbent hydrogels capable of absorbing up to 1000 times their original weight (2,3). The ability of hydrogels to absorb water comes from hydrophilic functional groups such as hydroxyl (-OH), carboxyl (-COOH), amine (-NH₂), amide (-CONH₂), and sulfonic acid (-SO₃H) groups. Hydrogen bonding allows the network to expand significantly while keeping its structure intact (3). Hydrogels usually have low elastic moduli, ranging from 100 to 100 kPa. They also have high extensibility and flexibility similar to tissue. Recent advancements have produced high-strength hydrogels with compressive moduli that can reach up to 43 MPa. This shows the potential for improving mechanical properties through innovative design strategies (4–6). Their low protein adsorption characteristics and minimal immune response make them particularly suitable for use in biomedical applications. The structural similarity to the extracellular matrix (ECM) facilitates cellular interactions and tissue integration (3,7). Their role in biomedicine is gaining attention. They improve the precision of drug delivery, support tissue engineering, and assist diagnostic techniques. This shows their importance in modern medicine (8). Conductive hydrogels possess useful features. They conduct electricity and can imitate the characteristics of natural tissues. This makes them suitable for applications in regenerative medicine and drug delivery, among other fields (9). Graphene-based hydrogels take advantage of their strong mechanical and optical properties for photo thermal applications, further increasing their usefulness in targeted, non-invasive biomedical strategies (10). Bacterial cellulose-based hydrogels are effective materials for wound dressings, tissue engineering, and drug delivery (11). Metallic nanocomposite hydrogels provide antimicrobial benefits and support new developments in drug delivery systems (12). These properties show how hydrogels contribute to progress in biomedicine and better healthcare standards (13).Hydrogels play important role in drug delivery systems due to their unique characteristics. They are biocompatible, biodegradable also possess adjustable mechanical properties and respond to different stimuli (14). These 3D polymer networks can encapsulate different therapeutic agents and allow controlled drug release. This makes them ideal for many biomedical applications (15). Polymer-based hydrogels are hydrophilic in nature and hold large amounts of water. It is important to study physical and chemical properties and compatibility of hydrogels with biological tissues. These features allow for effective control of drug release in response to specific triggers, such as pH, temperature, or the presence of enzymes. This responsiveness aids in focused drug delivery, which may lower systemic toxicity and improve treatment accuracy(16). Hydrogels are also used for transdermal drug delivery. It can avoid degradation of drug in the digestive system and first-pass metabolism in the liver (17). Polyethylene glycol (PEG)-based hydrogels have gained attention for their role in bone regeneration. International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7208 Hydrogel act as effective carriers due to their good compatibility with biological tissues and ability to retain water (18). This review aims to provide an overview of the latest developments in hydrogel-based drug delivery systems and their role in improving therapeutic outcomes. This review focuses on different types of hydrogels, their properties, and their design for controlled, sustained, and targeted drug release. The main objective of this review is to summarize recent research on hydrogel synthesis, highlight their applications in areas such as cancer therapy, wound healing, and tissue engineering, and discuss innovative approaches such as smart and stimuli-responsive hydrogels. This review also aims to identify the challenges and future directions for making hydrogel systems more effective and clinically applicable. 2. FUNDAMENTALS OF HYDROGELS Hydrogels can be categorized in various ways. Each classification method highlights specific characteristics and potential applications. Grasping these classification systems is essential for selecting the appropriate hydrogel types for particular drug delivery purposes (19,20). Fig. 1: Classification of Hydrogels 2.1.1 Classification by Origin Natural Hydrogels are made from naturally occurring polymers like alginate, chitosan, hyaluronic acid, gelatin, collagen, and fibrin. These materials are biocompatible and biodegradable in nature. Because of batch to batch variability they may not be mechanically strong as synthetic hydrogels (7).Synthetic hydrogels are made up of synthetic polymers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyacrylic acid, and poly(2hydroxyethyl methacrylate) (PHEMA). Polymer improves uniformity, and mechanical durability. But use of synthetic polymer may cause of loss of certain natural biological functions (2). Combine natural and synthetic components become advantageous for both systems. This approach provides adjustable properties while ensuring biocompatibility (19). 2.1.2. Classification by Crosslinking Mechanism Physical Hydrogels are formed by non-covalent interactions like hydrogen bonding, electrostatic interactions, hydrophobic associations, and chain entanglements. With the change in environment these systems reversibly switch between liquid and gel states. Usually they are mechanically weaker but provide more reversibility (19,20). Chemical Hydrogels creates covalent crosslinking between polymer chains, forms permanent networks that do not dissolve in water. These hydrogels show better mechanical properties and stability, but they do not have the reversibility of physical gels (19). Hybrid Hydrogels incorporate both physical and chemical crosslinking methods at the same time. This combines the benefits of both approaches (19,20). 2.1.3. Classification by Responsiveness Conventional hydrogels display properties that remain relatively stable regardless of external conditions. Smart or stimuli-responsive hydrogels experience significant changes in their properties when exposed to external stimuli, including pH, temperature, light, electric fields, ionic strength, or biological molecules. These types of materials facilitate controlled and targeted drug release applications (19,20). International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7209 2.2.4. Classification by Ionic Charge Neutral (Non-ionic) Hydrogels contain no ionisable groups and maintain consistent properties across different pH ranges. Ionic Hydrogels include anionic (negatively charged), cationic (positively charged), and amphoteric (containing both acidic and basic groups) systems. Zwitterion Hydrogels possess both cationic and anionic functionality within each repeating unit. They often show excellent biocompatibility (19,21). 2.3. Synthesis of Hydrogel It involves different approaches that can be grouped into physical and chemical crosslinking methods. The choice of synthesis method greatly affects the final properties, structure, and performance of the resulting hydrogel (21,22).Physical crosslinking method based on non-covalent interactions to create a three-dimensional network structure. These methods have several advantages, such as allowing for mild processing conditions, and not using potentially toxic crosslinking agents. Crystallization-Based Gelation involves forming crystalline regions that serve as physical crosslinks. This is commonly seen in poly(vinyl alcohol) systems through freeze-thaw cycles. Hydrogen Bonding uses intermolecular hydrogen bonding between polymer chains, which is often improved by the presence of complementary functional groups. Electrostatic Interactions involve ionic complexation between oppositely charged polymers or the interaction of charged polymers with multivalent ions, such as in alginate-calcium systems (21,23). Chemical crosslinking forms covalent bonds between polymer chains. This process creates permanent network structures with improved mechanical properties (19,22,24). Bifunctional or multifunctional small molecules act as crosslinking agents. Common crosslinkers include glutaraldehyde, glyoxal, N,N'- methylenebisacrylamide (MBA), and ethylene glycol dimethacrylate (EGDMA) (19,22,24). Polymer–polymer Crosslinking method involves direct covalent bonding between functionalized polymer chains, which eliminate requirement of external crosslinking agents (24).Radiation-induced crosslinking is a modern synthesis technique that offers unique benefits for preparing hydrogels (25,26).Gamma radiation synthesis method employs high-energy gamma rays (usually from Cobalt-60 sources) to induce crosslinking through free radical mechanisms (25,26).Electron Beam and UV Radiation are alternative radiation methods provide similar benefits but differ in penetration depths and processing characteristics (26).Microfluidic synthesis technique allows for precise control over hydrogel size, shape, and composition. This method is useful for making uniform microparticles and complex shapes. Advanced 3D Printing method enables the creation of complex, patient-specific hydrogel structures with controlled architecture and distribution of components. Template directed synthesis is a new approach which employs sacrificial templates to form hydrogels with specific porosity, morphology, or internal structure (19,27). Table 1. Classification of Hydrogels Classification Basis Type Representative Examples Key Characteristics Drug Delivery Advantages Reference ORIGIN Natural Alginate, Chitosan, Collagen, Hyaluronic acid, Gelatin, Pectin Biocompatible, biodegradable, inherent bioactivity, batch variability Low toxicity, cell recognition, ECM mimicry, enzymatic degradation (16,28) Synthetic Poly(acrylic acid) (PAA), Poly(N-isopropylacrylamide) (PNIPAM), Polyethylene glycol (PEG), Poly(vinyl alcohol) (PVA) Tunable properties, reproducible, precise control, high mechanical strength Controlled release kinetics, scalable production, customizable functionality (20,24) Hybrid/Semisynthetic Alginate-PEG, Chitosan-PVA, Collagen-PEG, DextranPNIPAM Combines natural biocompatibility with synthetic tunability Enhanced mechanical properties with biocompatibility, optimized drug release (16,28) CROSSLINKING MECHANISM Physical/Reversibl e Hydrogen bonding (Gelatin), Ionic interactions (AlginateCa²⁺), Hydrophobic associations, Chain entanglements Thermoreversible, mild formation conditions, injectable, self-healing Easy processing, in situ gelation, minimal cytotoxicity, thermoresponsive release (20,24) Chemical/Permane nt Covalent crosslinking via glutaraldehyde, N,N'- methylenebisacrylamide (MBA), Photo-crosslinking, Permanent networks, high mechanical stability, controlled degradation Sustained drug release, structural integrity, predictable kinetics (24,29) International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7210 Classification Basis Type Representative Examples Key Characteristics Drug Delivery Advantages Reference Click chemistry Enzymatic Transglutaminase-mediated (Gelatin-Chitosan), Horseradish peroxidase (Tyramine-modified polymers) Mild conditions, substrate specificity, biocompatible, in situ formation Biocompatible crosslinking, controlled gelation kinetics, cellfriendly environment (20) STIMULIRESPONSIVENESS pH-Responsive Poly(acrylic acid), Guar gum succinate, Chitosan derivatives, Kappacarrageenan/PVA pH-triggered swelling/deswelling, ionizable groups (- COOH, -NH₂) Site-specific release (gastric vs intestinal), tumor targeting (acidic microenvironment) (30,31) TemperatureResponsive PNIPAM, Pluronic F127, PLGA-PEG-PLGA triblock copolymers LCST ~32°C, sol-gel transition Injectable systems, body temperature triggered gelation, hyperthermiaactivated release (31,32) Light-Responsive Azobenzene-containing polymers, o-nitrobenzyl derivatives, Spiropyranmodified hydrogels Photoisomerization, photodegradation, reversible/irreversible changes Spatiotemporal control, on-demand release, noninvasive activation, precise dosing (33) Dual/MultiResponsive Chitosan-PNIPAM-itaconic acid, Lysine-modified PVCL Multiple stimuli sensitivity, enhanced targeting specificity Tumor-specific release (pH + temperature), enhanced therapeutic efficacy (31,32) MagneticResponsive Magnetite nanoparticles/poly(acrylamide) composites Magnetic fieldinduced pore opening, remote activation External control, deep tissue targeting, pulsatile release (30) EnzymeResponsive MMP-cleavable peptides, Hyaluronidase-sensitive HA Substrate-specific degradation, biological trigger recognition Disease-specific activation, targeted degradation, biological responsiveness (30) IONIC CHARGE Nonionic PEG hydrogels, PNIPAM, PVA No ionizable groups, pH-independent swelling Stable drug release across pH range, reduced protein adsorption (28,30) Anionic PAA, Alginate, Carboxy methylcellulose Negatively charged, pH-sensitive (basic conditions) Cationic drug loading, gastric protection, intestinal release (20) Cationic Chitosan, PDMAEMA, Quaternized polymers Positively charged, pH-sensitive (acidic conditions) Anionic drug encapsulation, mucoadhesive properties, antimicrobial activity (24) International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7211 Classification Basis Type Representative Examples Key Characteristics Drug Delivery Advantages Reference Amphoteric/Zwitt erionic Containing both acidic and basic groups pH-dependent charge switching, protein resistance Reduced biofouling, biocompatible, dual drug loading (28) 3. HYDROGEL DESIGN CONSIDERATIONS FOR DRUG DELIVERY The design of hydrogels for drug delivery requires careful consideration of several interconnected factors. These factors collectively influence the performance, safety, and effectiveness of the delivery system. Biocompatibility is a important requirement for any hydrogel used in drug delivery. It involves multiple aspects of evalution and optimization of biological compatibility (30) Hydrogels must decreases immune reactions of drug to ensure safe and effective drug delivery. Natural hydrogels usually have better biocompatibility because of their similarity. Synthetic hydrogels may need surface modification or addition of bioactive molecules to achieve optimal biocompatibility (34–36). Recent developments in hydrogel design focus on immunomodulating hydrogels that actively manage immune responses. These systems can be designed to recruit specific immune cells, like dendritic cells for cancer treatment, while preventing undesirable inflammatory responses (20,35). Avoiding cytotoxic effects is crucial for successful drug delivery applications. Potential sources of toxicity include unreacted monomers, crosslinking agents, initiators, and degradation products. For example, commonly used photoinitiators like Irgacure can reduce cell viability, even at low concentrations. Therefore, purifying hydrogels through dialysis or thorough washing is often necessary to remove harmful residues (36,37). The design should include features that encourage positive cellular interactions, such as suitable mechanical properties, surface chemistry, and the presence of cell adhesion sites. Hydrogels that mimic the water content (70-90%) and mechanical properties of target tissues show better biocompatibility and integration (36,37). The degradation rate must be adjusted to match the desired drug release profile and application needs. Key factors that influence degradation are crosslinking density, and seversl environmental factors such as pH, temperature and ionic strength (38). Enzyme-responsive hydrogels provide excellent specificity for targeted drug delivery. For instance, hydrogels that can be cleaved by matrix metalloproteinases (MMP) can release drugs specifically in tumors, where MMPs are overexpressed. Likewise, hydrogels that are sensitive to colonic bacteria-specific enzymes allow for targeted drug delivery in the colon (38,39). Performance of hydrogels is affected by their mechanical properties. It influences drug release rates, tissue integration and patient comfort. Hydrogels show a unique viscoelastic nature that combines both elastic and viscous properties. It should enable controlled deformation, which helps in releasing the drug when needed (15,40,41). Recent advancements have produced hydrogels with remarkable mechanical properties. These enhanced properties are achieved through innovative crosslinking techniques such as double-network designs and the integration of sacrificial . Compressive properties are significant for load-bearing applications and injectable hydrogels. It must keep their structure under physiological pressures. Sacrificial weak bonds systems use a densely crosslinked polyelectrolyte network combined with a loosely crosslinked network. Breakdown of weak bonds absorbs energy and stops cracks from spreading (15,41). Table 2. Degradation and release mechanism of hydrogels Hydrogel Type Examples Degradation Characteristics Drug Release Mechanism Clinical Applications Reference Natural Hydrogels Alginate Ca²⁺-crosslinked alginate Ionic dissolution, enzymatic (alginate lyase) Diffusion-controlled, pH-responsive Oral, wound healing (42) Chitosan TPP-crosslinked chitosan Enzymatic (chitinase, lysozyme) pH-responsive swelling/deswelling Oral, antimicrobial delivery (41) Gelatin Thermallycrosslinked gelatin Thermal melting, enzymatic (collagenase) Temperaturetriggered release Injectable, tissue engineering (2) Synthetic Hydrogels Hyaluronic Acid EDC/NHS crosslinked HA Enzymatic (hyaluronidase) Enzyme-responsive degradation Ocular, joint injection (3) PNIPAM Thermosensitive PNIPAM Hydrolytic degradation of crosslinks Temperatureresponsive (LCST ~32°C) Injectable, hyperthermia therapy (3,43) PAA (Poly(acrylic acid)) Chemically crosslinked PAA Hydrolysis of ester bonds pH-responsive swelling Oral, colon targeting (44) PVA Physically Crystalline domain dissolution Physical dissolution Transdermal, (41) International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7212 Hydrogel Type Examples Degradation Characteristics Drug Release Mechanism Clinical Applications Reference crosslinked PVA contact lenses PEG-based Photo-crosslinked PEG Photodegradable linkers, hydrolysis Light-responsive, diffusion-controlled On-demand release, tissue engineering (45) Hybrid / Composite Hydrogels PAM/Gelatin Dual-crosslinked PAM/Gel Combination of physical/chemical Dual-responsive (pH/temperature) Dual drug delivery, wound healing (11) Chitosan-PVA Blended CS-PVA Sequential degradation pH-responsive with sustained release Transdermal, controlled release (2) Alginate-PEG Covalently linked Alg-PEG Dual degradation pathways Enhanced mechanical stability Injectable, cell delivery (42) Tough / Reinforced Hydrogels Double Network PAMPS/PAAm DN Sacrificial bond mechanism Mechanicallytriggered release Load-bearing applications (44) Nanocomposite Clay-reinforced PNIPAM Clay-polymer network breakdown Mechanical stressresponsive Injectable, high-strength applications (44) IPN (Interpenetrating Network) Gelatin/PAM IPN Independent network degradation Sequential drug release Multi-drug delivery systems (11) StimuliResponsive Hydrogels pH-responsive Chitosan-itaconic acid pH-triggered network breakdown Site-specific release (gastric vs intestinal) Oral, colon targeting (3) Temperatureresponsive PLGA-PEGPLGA Sol-gel transition reversibility Injectable, body temperature gelation Localized injection, cancer therapy (3) Light-responsive Azobenzenemodified Photoisomerization/photocleavage Spatiotemporal controlled release On-demand therapy, precise dosing (3) Relationship To Drug Release High Modulus (>100 kPa) Synthetic, tough hydrogels Slower degradation Sustained release (weeks–months) Long-term therapy (45) Medium Modulus (10– 100 kPa) Natural, hybrid hydrogels Moderate degradation Controlled release (days–weeks) Most drug delivery applications (46) Low Modulus (<10 kPa) Soft, injectable hydrogels Rapid degradation Burst/immediate release (hours–days) Acute therapy, injections (3,46) Advanced hydrogel systems can deliver multiple drugs simultaneously with independent release profiles. It is possible by using different strategies such as compartmentalized systems, layered hydrogels or differential loading (47). The successful design of hydrogel drug delivery systems requires integrated consideration of all design parameters. Biocompatibility must be maintained while achieving desired mechanical properties and release kinetics. Stimuli-responsiveness should complement rather than compromise other design requirements (36,37). Recent advances in computational modelling and machine learning are enabling more sophisticated design optimization, predicting optimal formulations based on desired performance criteria. This integrated approach promises to accelerate the development of next-generation hydrogel drug delivery systems with unprecedented precision and therapeutic efficacy (47) International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7213 4. Recent Advances in Hydrogel-Based Drug Delivery Systems Hydrogel-based drug delivery systems have made significant dvelopment in recent years. This progress from improvements in materials science, nanotechnology, and manufacturing techniques. Each advancement helps overcome the limits of traditional drug delivery methods and supports more effective treatment strategies (15,48). 4.1. Smart Hydrogels Smart hydrogels also known as stimuli-responsive hydrogels. They respond dynamically to environmental changes. These materials can alter their properties in response to specific stimuli, allowing precise control over drug release and targeting. Their ability to react to physiological condition makes them particularly useful for solving complex medical challenges (42). 4.1.1. pH-Responsive Hydrogels pH-responsive hydrogels exploit the natural pH variations throughout the human body to achieve site-specific drug delivery. It offers great potential for focused therapeutic interventions. Ionizable functional groups that response to local pH changes. It undergoes protonation or deprotonation and resulting in swelling or deswelling behaviours that control drug release. The pH difference from the acidic environment of the stomach (pH 1.2-3.0) to the neutral-to-alkaline conditions in the small intestine (pH 6.8-7.4) is ideal for oral drug delivery. It also supports targeted cancer treatment as tumour tissues (pH 6.0-6.8) are more acidic than normal tissues (pH 7.4) (47,49). Recent advancements in pH-responsive systems have shown great precision in controlling drug release. New formulations using carboxyl and amino groups have achieved almost complete drug release (93%) at physiological pH, while releasing very little under acidic conditions. We now understand that drug release can occur through swelling-induced changes in mesh size and drug diffusion, as well as through the disruption of ionic interactions between the drug and polymer (47,49).The versatility of pH-responsive hydrogels extends to combination therapy approaches, where dual-drug delivery systems can simultaneously release multiple therapeutic agents that work well together. Liu's pioneering work on pH-responsive peptide nanogels showed the simultaneous release of gemcitabine and paclitaxel specifically within tumor microenvironments. This method boosts anti-tumor effectiveness while reducing the chances of drug resistance. This represents a significant step forward in tackling the complex issue of cancer drug resistance through coordinated multi-drug delivery strategies (47,50). 4.1.2. Temperature-Responsive Hydrogels Temperature-responsive hydrogels use thermal changes to control drug release. Poly(N-isopropylacrylamide) (PNIPAM) is the classic thermosensitive polymer because of its lower critical solution temperature (LCST) near body conditions. These systems undergo large volume phase changes at certain temperatures. This allows for precise control over drug release through temperature-triggered swelling or shrinking. The LCST phenomenon lets these hydrogels be injectable solutions at room temperature while quickly solidifying upon injection at body temperature, forming local drug depots for sustained delivery (51,52). Recent innovations in temperature-responsive systems focus on improving response times and broadening therapeutic uses. The combination of melamine functionalized PNIPAM copolymers has produced dual pH and temperature-responsive systems. Thus system can release nearly 100% of drugs for both hydrophilic (5-fluorouracil) and hydrophobic (ibuprofen) under specific conditions (pH 4.0, 45°C). These developments reveal the potential for creating flexible platforms that can deliver diverse drug classes with customized release profiles (53). Temperature-responsive hydrogels are very beneficial in ocular drug delivery. Innovative approch of thermosensitive hydrogel systems with furan and maleimide groups for intravitreal injection achieve immediate sol-gel changes when exposed to body temperature. These systems showed sustained release for 13-35 days for various therapeutic agents (51). These hydrogels have also shown promise in cancer treatment. PNIPAM-based systems allow for targeted delivery of anti-cancer agents using localized heat. Their temperature sensitivity near body conditions enables precise timing and location control of drug release, minimizing overall exposure while maximizing effectiveness at target sites (51,54). International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7214 Fig. 2: Smart Hydrogels 4.1.3. Light-Responsive Hydrogels Light-responsive hydrogels offer better control in drug delivery. They provide non-invasive and focused treatment through light stimulation. These systems feature photosensitive components that change structure when exposed to light. It allow accurate control over drug release by adjusting light conditions like intensity, wavelength, exposure time, and beam size. The key mechanisms for light-responsive drug delivery include three main pathways. Photoisomerization systems that change shape reversibly, photochemical systems that involve breaking or forming bonds, and photothermal systems that convert light to heat for drug release (55,56). The development of light-responsive systems has moved from early ultraviolet (UV) activated platforms to more advanced near-infrared (NIR) responsive systems. UV systems are mostly restricted to in vitro use due to their potential for cellular harm and limited tissue penetration. NIR systems have changed the field by enabling deep tissue penetration and safer in vivo applications It makes them more viable for clinical use (55,57). Recent advancements in photosensitizer technology have greatly increased the versatility of lightresponsive hydrogels. The integration of upconversion nanoparticles (UCNPs) and two-photon excitation systems allows for using NIR light to trigger responses that normally need UV light. It combines the precision of UV systems with the safety and depth advantages of NIR light. This creates new way for treating deep-seated conditions while maintaining precise control over drug release (55,58). The clinical uses of light-responsive hydrogels cover a wide range of therapeutic areas. In cancer therapy photocleavable hydrogels allow for precise targeting of tumors while limiting systemic exposure to harmful chemotherapy drugs. The ability to repeatedly trigger drug release with controlled light exposure gives unprecedented flexibility in treatment plans (55,59). 4.2. Nanocomposite Hydrogels Nanocomposite hydrogels combine nanotechnology and hydrogel science. Merging the best features of both to create multifunctional drug delivery platforms improves their performance. These hybrid systems incorporate various nanoparticles within hydrogel matrices to achieve properties that neither could accomplish alone. This includes better mechanical strength, greater drug loading capacity, responsive behaviors to stimuli, and the ability to deliver drugs while also providing imaging (60–62).The design flexibility of nanocomposite hydrogels allows for the use of various nanoparticle types. Carbon-based nanoparticles like carbon nanotubes (CNTs) and graphene are biocompatible and enhance mechanical, electrical, and thermal qualities. These materials are especially useful in applications needing electrical conductivity, such as nerve tissue engineering and heart-related applications where electrical signaling is crucial (60,62). Recent developments in nanocomposite hydrogels have aimed at achieving synergistic effects between nanoparticles and polymer matrices. Thiol-functionalized gold nanoparticles can form chemical bonds with polymer networks which improves mechanical properties. These enhanced interactions affect not only mechanical strength but also drug release rates and biological reactions (61). Nowadays nanocomposite hydrogels have widely used in drug deliver. It shows potential in cancer treatment, wound healing and tissue engineering. In oncology they enable combination therapies that merge chemotherapy, photothermal therapy, and photodynamic therapy in single platforms. Through targeted delivery of multiple therapeutic agents with separate release profiles helps solve the complex problem of cancer treatment (62).Metallic nanoparticles such as gold and silver offer unique optical, antimicrobial, and catalytic properties. Gold nanoparticles enhance imaging and allow for photothermal therapy. Silver nanoparticles provide strong antimicrobial action for wound healing. Incorporating these metallic nanoparticles into hydrogel networks creates multifunctional platforms (63,64). International Journal of Research Publication and Reviews, Vol 6, Issue 10, pp 7207-7221 , October, 2025 7215 4.3. 3D-Printed Hydrogels 3D printing technology has transformed hydrogel drug delivery. It enable creation of complex, customized therapeutic devices with precise control over structure, composition, and drug distribution. Merging 3D printing with hydrogel science has created new way for building advanced drug delivery systems previously impossible to produce through traditional methods (65,66). Polypills created with 3D-printed hydrogel systems are highly beneficial. These devices can combine multiple drugs with various release profiles into a single dosage form. This approach addresses the complex medication regimens often needed for chronic conditions. Integration of immediate-release and extended-release within single devices improves patient. It is particularly important for elderly patients managing multiple health issues(66). Recent advancements in 3D printing materials has widened the range of polymers that can be used in hydrogel drug delivery. For crating drug loading filaments biocompatible polymers such as polylactic acid (PLA), polycaprolactone (PCL), and polyvinyl alcohol (PVA) have been used effectively. Compatibility of this material with various drugs supports versatile platform development for many therapeutic applications (67,68). The personalized medicine applications of 3D-printed hydrogels can encompass complex patient-specific requirements.. By using this technology it is possible to create devices with custom shapes based on individual drug processing rates. This level of customization marks a significant advancement toward truly personalized treatment approaches (69,70). The clinical application of three-dimensional (3D) printed hydrogel systems has demonstrated significant potential in pediatric and geriatric populations. It has capacity to develop age-appropriate formulations with precise dosing and acceptable palatability addresses. Capability for on-demand manufacturing facilitates the production of medications with limited shelf life or patient-specific requirements. By this way it become viable alternatives to conventional compounding pharmacy practices (69). 4.4. Injectable Hydrogels Injectable hydrogels is a unique method for minimally invasive drug delivery. They combine the ease of liquid formulations with the long-term release benefits of solid matrices through gelation processes that occur in the body. These systems start as low-viscosity solutions for preparation and injection. Once exposed to physiological conditions, they quickly turn into semi-solid gels. This transformation creates localized drug depots with controlled release. The development of injectable hydrogels meets important clinical needs for accurate drug targeting while reducing pain and the complexity of procedures (71,72,73).The main principle behind injectable hydrogel systems is gelation under certain physiological conditions. Temperature-triggered gelation is the most common method. Triblock copolymers like poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) change from liquid to gel near body temperature. These systems stay stable as injectable solutions at room temperature but solidify quickly when warmed to 37°C, creating drug depots in place with predictable gelation timing (71,72,74). pH-dependent gelation is another method for injectable hydrogel systems. It useful for targeting tissues with unique pH levels. The ability to change due to pH allows the creation of forces between polymer segments. It leads to reversible crosslinks and controllable release rates. The varying pH in chronic wounds, which ranges from 5.4 to 8.9 depending on the location and level of damage, offers potential for pH-responsive injectable systems in treating wounds (74).Recent progress in injectable hydrogel formulation has focused on improving flow properties for better injection and ensure quick gelation after administration. During injection shear-thinning enables smooth flow through small needles. This feature reduces the force needed for injection and lessens patient discomfort. Thixotropic recovery allows the structure to reform rapidly after the force is removed. These improvements are vital for applications that require injection through small catheters or into tight spaces (73,75). The clinical applications of injectable hydrogel systems cover different therapeutic fields. They are succesfully used in cancer treatment, pain management, and tissue engineering. Hydrogel systems also supports combination therapy where multiple treatment methods are combined into one platform. Hybrid hydrogel systems can include both chemotherapy agents and photosensitizers used for combined chemotherapy and photodynamic therapy. Systems that include both drugs and growth factors enable simultaneous treatment and tissue healing. These multifunctional strategies meet the complex needs of modern treatments. Also it offers convenience and precision of minimally invasive delivery (71,76). 5. APPLICATIONS OF HYDROGELS IN DRUG DELIVERY Hydrogel-based systems for oral drug delivery provide an effective way of drug delivery. Recent advancement in oral hydrogel delivery protects drugs from gastric degradation and allows targeted release in the intestines. This is especially true for sensitive biologics, proteind and peptides that can degrade in harsh conditions. Their stimuli-responsive features allow for targeted release in specific areas of the digestive tract (77). Hydrogel basaed transdermal drug delivery is a non-invasive and avoid first-pass liver metabolism and gastrointestinal irritation and allow for sustained release of drugs. When applied to the skin, these systems form semi-occlusive layers that concentrate drugs within polymer matrices and facilitate controlled absorption through the skin barrier. Hydrogels can carry a higher drug load than alternatives like liposomes and nanoparticles.It allows for effective transdermal transport with controlled release and minimal degradation (78,79). Hydrogel-based systems for delivering drugs to the eye pass barriers of the eye. These barrier include various tissue barriers, quick clearance mechanisms, and the need to maintain steady drug concentrations. The eye's defense systems, such as blinking, tear drainage, and corneal barriers, often lead to poor bioavailability and rapid loss of conventional eye drop treatments (79,80).Stimuli-responsive hydrogel systems allowing liquid-to-gel transitions upon contact with the eye. This greatly increases how long the drug stays in place and improves comfort for patients. These smart hydrogels respond to changes in temperature, pH, or ionic strength. These gels that enable prolonged drug release and reduce frequency of drug application (80). Recent developmemt in ocular hydrogel formulations have been particularly successful in treating diseases affecting the back part of the eye. Hydrogel systems can overcome ocular barriers thus maintain sustaine drug release. Combining hydrogels with nanoparticles, liposomes, and dendrimers has shown promise in improving drug stability and targeting specific eye tissues (81).Hydrogels are widely used in cancer treatments. They offer targeted local treatment while minimizing systemic toxicity and keeping high drug concentrations at the tumor site. Hydrogels address the challenge of drug resistance and enhances overall treatment effectiveness. Multifunctional