Hydrogel as advance drug delivery system

 Corresponding author: Gawade Ankita A Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Hydrogel as advance drug delivery system Gawade Ankita A *, Gawade Ankita V and Chaitali Dhale R Department of pharmaceutical from vidya Niketan college of pharmacy, lakhewadi. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 Publication history: Received on 06 October 2025; revised on 15 November 2025; accepted on 18 November 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.24.2.1012 Abstract Hydrogels three-dimensional, hydrophilic polymer networks capable of absorbing large amounts of water have emerged as versatile platforms for advanced drug delivery. This review synthesizes foundational concepts, materials and fabrication methods, mechanisms of drug loading and release, stimuli-responsive and multifunctional hydrogel systems, and translational considerations including biocompatibility, sterilization, regulatory perspectives, and commercialization challenges. Emphasis is placed on injectable, in situ-forming hydrogels, hydrogel–nanoparticle hybrids, and applications in cancer therapy, wound healing, ocular delivery, and RNA/biologic delivery. The review concludes with critical gaps and future directions to accelerate clinical translation. Keywords: Biocoptiable; Crystallization; Microencapsulation method; Enzymatic method; physical crosslinking; Refractive index 1. Introduction A great deal of scientific study has been conducted in the area of biomaterials that affect human health [1]. One of the primary subjects of biomaterials research is hydrogels, which we examine in this article. Hydrogels are threedimensional networks of in-soluble polymers that, because of the hydrophilic groups in their structure, can absorb a lot of water or biological fluid from the body [2]. During the past few decades, hydrogels have been in use for biomedical applications such as drug delivery systems,[3] The chemical structure of the hydrogel, its morphology and equilibrium swelling affect properties such as mechanical strength and intracellular and extracellular transport [4]They can be flexible and soft, which are results of their water absorption ability [5]the variable compositions including collagen, gelatin and polyethylene glycol (PEG)-based hydrogels correspond to fibrous, macro porous, and nanoporous architctures .Hydrogels have a specific attraction for a variety of medical applications, including tissue engineering and the release of therapeutic agents (proteins, medicines, or genes). These properties Include water absorption, soft structure, biocompatibility, low protein due to low surface tension and similarity to ECM Structure. Wound dressings and contact lenses [6] 2. Mechanism of Hydrogel Formation Polymers are carbohydrate materials that have been widely used to make physical and chemical hydrogels due to their availability, presence of modifiable functional groups, biocompatibility and other properties [7] By choosing a particular type of monomer or polymer and hydrogel formation reactions, hydrogels can be tailored to a particular use. There are two ways to create hydrogels: Chemical crosslinking and physical crosslinking [8] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 439 Figure 1 physical and chemical cross linking 2.1. Chemical crosslinking: Chemical cross linkable hydrogels are a type of hydrogel that can be converted from a liquid to a solid by covalent bonding. This method is also used in in situ hydrogel systems. In this method, various reactions such as optical polymerization, enzymatic reactions and click reactions are used to form hydrogels. In this section, the mentioned methods for making these hydrogels will be discussed [9] Chemically Cross-linked hydrogels have gained attention because to their high Mechanical strength [10] 2.2. Graft Copolymerization and Irradiation Crosslinking Among the various techniques for grafting polymers, gamma radiation has been successfully developed to graft polymers onto polymeric materials [11]. This technique does not require initiators or additives that may be harmful and difficult to remove [12]. Figure 2 illustrates this technique, requiring no initiator or cross-linking agent, and can be used with virtually any vinyl monomer. Both the polymerization reaction and the cross-linking can be started at room temperature. This radiation acts as an initiator of the copolymerization process between the polymer matrix (the material) and the molecule to be grafted (monomer). This method allows radiation to act on the polymer matrix, inducing the formation of reactive sites that may interact with a molecule to be grafted, initiating a free radical polymerization process [13]. Figure 2 Prestation of graft polymerization World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 440 2.3. Enzymatic Method The main advantage of the enzymatic method is that the cross-linking of the hydrogel occurs under mild conditions without the need for the use of low molecular weight compounds (monomers, initiators, cross-linking agents), irradiation, or prior polymer functionalization to favor its cross-linking [14,15]. Enzymes often exhibit a high degree of substrate specificity, potentially avoiding side reactions during cross-linking. This advantage makes it possible to control and predict the cross-linking kinetics and control the overall cross-linking rate. For this reason, this method is suitable for in situ gelation systems [15,16]. Figure 4 illustrates this method by unionizing the enzyme and the available substrate, forming a covalent bond within the cross-linking structure Figure 3 Schematic illustration of enzymatic method 2.4. Physical crosslinking Hydrogels formed by physical bonding can be obtained by modifying intramolecular forces such as hydrogen bonding, hydrophobic interaction, and electrostatic ionic force. In order to prevent the possible increase in the toxicity of the crosslinker in the chemical method, this method makes it possible to prepare hydrogel with simple and safe processes. Physical cross-linking methods include ionic methods, temperature-dependent methods and pH-dependent methods for cross-linking [17] 2.5. Crystallization Physical cross-linking of a polymer to form a hydrogel can also be achieved by crystallization through freeze–thaw cycles in homopolymer systems or by forming stereo complexes. The crystallization and degree of crystallinity determine the final properties of the resulting polymers. Polymeric crystallization can occur from dilute solutions or the molten state [18]. In the first case, crystallization occurs by evaporating the solvent, resulting in the appearance of single crystals based on a chain-folded model, which presents aligned chains [19]. Figure 4 Formation of Crystallization by physical crosslinking method World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 441 2.6. Amphiphilic Copolymers Amphiphilic hydrogels containing both hydrophilic and hydrophobic units represent one of the major polymeric biomaterials [20], as Figure 1 shows. In other words, amphiphilic copolymers can aggregate in water to form micelles and hydrogels in which the hydrophobic segments of the polymer self-assembly [21]. Copolymers typically form hydrogels with fragments of different nature or modified copolymers. The latter can be formed by a water-soluble polymer to which hydrophobic fragments have been attached or hydrophobic chains modified by water-soluble fragments [22]. Figure 5 Schematic illustration of an amphiphilic polymer 3. Types of hydrogels 3.1. Natural hydrogel Natural polymer-derived hydrogels, sourced from plants or animals like polysaccharides and proteins, play a crucial role in encapsulating pesticides [23] Natural hydrogels are gels whose polymers are obtained from natural sources. The use of natural polymers to form hydrogels has advantages such as biocompatibility, biodegradability and non-toxicity. The use of natural polymers in the manufacture of hydrogels depends on the purpose of the use of biomaterials. For example, hydrogels used for controlled release of materials must be biocompatible, biodegradable, and informal [24] 3.2. Synthetic hydrogel Three-dimensional swelling networks of covalently or ionically Cross-linked hydrophilic homopolymers, or copolymers hydrogels, are known as polymeric synthetic hydrogels. Synthetic hydrogels, Such as poly (hydroxyethyl methacrylate) or PHEMA, polyethylene Glycol (PEG) hydrogels, and polyacrylic acid (PAA), are produced By polymerization of different synthetic monomers [25] 4. Properties of hydrogel 4.1. Swelling properties Hydrogels are materials that, when submerged in water, expand retain a significant volume of water inside their structure Without dissolving. The distinctive feature of hydrogels is swelling, which is contingent upon many environmental conditions, Including temperature, pH, and ionic strength [26]. Hydrogels’ swelling behavior is influenced by their Chemi-Cal structure since it contains both hydrophobic and hydrophilic Groups. In comparison to hydrogels with hydrophobic groups, those with more hydrophilic groups swell more. The expansion of Hydrogels is also influenced by pH and temperature. The ionization of hydrophilic groups, which fluctuate in response to pH changes, causes pH-sensitive hydrogels to expand [27] 4.2. Mechanical properties Compared to physical hydrogels, injectable chemical hydrogels. Have superior mechanical properties and longer stability. However, the preparation of chemical hydrogels using toxic crosslinking Agents may have an adverse effect on biocompatibility; in hydro-Gels, physical-chemical interactions are established and such toxic Initiators are avoided [28] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 442 Compression and tension analysis can be Performed by frequency-based testing using rheometry or by lim-Ited or unconfined local indentation using a probe. Hydrogels can Be mechanically analysed in two different methods. Frequency-Based sinusoidal testing frequently makes use of a rheometry. Grassi., et al. assessed the mechanical properties of calcium alginate hydrogel [29] 4.3. Biological properties Biocompatibility and non-toxicity, adequate mechanical quali-Ties, acceptable viscosity, stability, biodegradability, etc. are essen-Tial characteristics of injectable hydrogels for a range of medical Applications. The mechanical and biological properties of the hydrogel must match those of the tissue it substitutes and be appro-Priate [30] 5. Preparation method of Hydrogel 5.1. Microencapsulation Microencapsulation indicates the process of embedding cells in micro-sized hydrogels. Microgels of tens to hundreds of microns enable the direct injection of the stem cell-embedded microgels to the targeted tissue though a needle. As cells can be administered precisely in a minimally invasive fashion, operation and patient convenience can be greatly improved. Also, the delivery of cells via microgels can enhance cell retention at the local sites, at which they usually remain without cell uptake or entering the circulatory system in the body. Original attempts to encapsulate and deliver cells in microgels were made for allogenic or xenogenic beta pancreatic islet cell transplantation for diabetic patients [31,32,33,34] Hydrogels are the polymeric network capable of entrapping large amount of water though intermolecular cross linkage network. This ability of the hydrogels to form the complex cross linkages make them suitable in various field of science such as biomedical, biosensinganddrug delivery. The cross linkages depend upon the nature of the biopolymer used and the bioactive compound [35] Figure 6 Formation of hydrogel from biopolymer solution 5.2. Bulk polymerization For the synthesis of hydrogels, a variety of vinyl monomers Can be used. With one or more kinds of monomers, bulk Hydrogels may be made. Because of the large number of Monomers available, it is possible to make a hydrogel with The appropriate physical qualities for a particular application. Any hydrogel formulation typically contains a tiny amount of Cross-linking agents. Radiation, UV, or chemical catalysts are Commonly used to start the polymerization reaction.Bulk polymerization is the most straightforward method, Requiring only monomer and monomer-soluble initiators. The High concentration of monomer results in a high rate and Degree of polymerization. However, when the conversion Produces heat during polymerization, the viscosity of the Process increases significantly. Controlling the response at Low conversions can help to avoid these difficulties [36] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 443 Figure 7 Synthesis of hydrogel 6. Types of polysaccharide hydrogel 6.1. Alginate Alginate is a polysaccharide obtained from brown algae and has become increasingly popular due to its unique gelling, ion exchange, and stabilizing properties with aqueous solutions. The alginate is generally composed of β-d-mannuronic acid (m) and α-l-guluronic acid (g) connected by 1,4 linkages arranged in m, g units and also the combination of m g units [37] 6.2. Carrageenan The carrageenan is obtained from red seaweed (Rhodophyceae) containing repeating units of 3-linked-β-dglucopyranose (G-unit) and 4-linked-α-d-glucopyranose (D-unit) or 4-linked 3,6-anhydrogalactose (DA-unit) [38] The injection approach effectively creates hydrogel beads from anionic-carrageenan molecules in the presence of cationic cross-linking agents like metal ions, peptides, and proteins [39] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 444 6.2.1. Agar Agar, another seaweed-derived polysaccharide, comprises a diverse blend of agarose and agaropectin, leading to gelation. Agarose, known as a neutral polysaccharide, is composed of recurring units of agrobionts, involving alternating β-d-glucopyranosyl and 3,6-anhydro-α-l-glucopyranosyl groups. Agaropectin is a galectin mixture of a charged polysaccharide with sulphate groups, combines to form agar gel [40] 6.2.2. Chitin The sea shells are most abundant in production of the chitin as a byproduct. The unique biochemical attributes of biodegradability and biocompatibility uplift the scope of chitosan to be used in the food and pharmaceutical industries. Chitosan is considered one of the smarts, competent natural polymeric hydrogel materials for encapsulating bioactive compounds such as antioxidants, antimicrobials, and other nutraceuticals. The biocompatibility sustained release properties, and high encapsulation efficiency makes it one of the most wonderful hydrogels for drug release in different environments [41] 6.2.3. Hydrogels for drug delivery: Progress in clinical applications In recent years, there has been remarkable progress in the development of clinically applied hydrogels. Since 1960, the copolymers of 2-(HEMA) and ethylene methacrylate have been applied for their use in contact lens, urinary catheters, wound dressing and surgical gloves etc. [30] Other clinical Applications of hydrogels include the most exciting area of stem Cell encapsulation and their release for stem cell therapy. The Current technology uses liquid nitrogen for the effective transfer of stem cells, which requires a small time period for delivery That offers great challenges and is costly. One recent study by Carried out by Chen et al. [42] 6.2.4. Hydrogel for eyes Recently, the fabrication of drug delivery systems for the anterior and posterior segments of eyes has become the most challenging Aspect. The scope of implantable hydrogels for long term per Ocular delivery of various drugs has gained attention in recent Years. The most common limitation observed during the treatMent of anterior segments of the eyes viz., cornea, sclera, anterior Uvea and conjunctiva is the maintenance of an adequate Concentration of drug in the percorneal area. It was found that 75% of the ophthalmic solution is lost by nasolacrimal drainagebAnd the bioavailability of ocular drug is low [43] 6.2.5. Hydrogel for small intestine The small intestine is a very important part of the gastrointes-Tinal tract responsible for the digestion of major classes of Nutrients viz., proteins, lipids and carbohydrates. The sensitive Environment of the gastrointestinal tract, toxicity and adverse Side effects of the present drug delivery prompted researchers to Develop effective drug delivery with low toxicity and oral Administration. Hydrogels based DDS have drawn the attention of researchers owing to increased efficacy, lower toxicity and Higher exibility of dosing schedule and higher patient comfort.Biopolymers like alginate [44] Chitosan and other biopolymeric based hydrogels have fullled the need for a protective payload, which does not get Degraded by the intestinal peptidases. In context with this, the Chitosan based hydrogels for the delivery of insulin (for diabetes Mellitus) and 5urouracil (for colon carcinomas) have shown Promising results [45] 6.2.6. Hydrogel for Skin The tissue regeneration technology using hydrogels has Emerged as a boon in skin regeneration. Hydrogels are conStructed in such a manner that they promote the formation of new blood vessels and skin. Lot of literature is available Depicting the use of hydrogels in wound healing applicaTions.[46,47] The devel-opment of hydrogel nanocomposites has led to a breakthroughin biomedical applications for skin. Incorporation of various nanoparticles [48] the linear incision and the full thickness wound healIng models are employed to evaluate the in vivo healing activity of These gels. The histopathologic examination showed enhanced Cutaneous wound repair. The rejoining of cut wounds by glue Made up of gelatin and keratin has been found to be suitable for Wet tissue approximations. The present glues in the market have Some promising challenges, like toxicity, low adhesiveness and High cost. The latest engineered gelatin and keratin glue Prepared by Thirupathi et al. [49] 6.2.7. Hydrogel for lungs Respiratory diseases have a high morbidity and mortality and are Thus excellent candidates for the novel nanotechnology-based Diagnostic and treatment strategies. [50,51] Presently both hydro-Phobic and hydrophilic polymeric materials based on crosslinked Hydrogels, such as a poly (lactic-co-glycolic acid) (PLGA) chain Converted World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 445 into particles and dispersion of polymerized poly (butylcyanoacrylate) particles, have been used in lung delivery. Very common problem faced by lungs and in thoracic functions is Air leak. The study by Otani et al [52] put forward the sealing effect gelatin–poly (L-glutamic acid) hydrogel glue on lung air leaks. These hydrogels showed a signi cant sealing effect in comparison to the earlier used brin glue. The bonding strength of this glue was higher than the brin glue. It is suggested that in comparison to the non-swellable particles the swellable particlesb“hydrogel nanoparticles” (HN) have the capacity to limit the phagocytic engulfment by alveolar macrophages and clearance from the lungs. For instance, degradability characteristics showed a longer-term release of a therapeutic agent [53] 6.2.8. Hydrogel for tuberculosis Tuberculosis (TB), a disease caused by Mycobacterium tubercu-Losis (M. tb) acts as an oppressor to mankind and dates back tobAntiquity. Even a er many decades it is scourging human life and is still disinclined to renounce its grip. It ranks as the Second leading cause of death from infectious diseases world-Wide, a er the human immunode ciency virus (HIV). As per the WHO Global Tuberculosis Report 2012, the latest estimates Included almost 9 million new cases in 2011 and 1.4 million TB Deaths (990 000 among HIV negative people and 430 000 HIV-Associated TB deaths). The short biological half-life of existingAnti tubercular drugs (ATDs) and patient non-compliance112 has Raised the need for the development of new drug delivering Strategies to ensure the enhanced bioavailability and reduced Toxicity over a long period of therapeutic intervention (6–9Months). The controlled drug delivery system will not only Improve patient compliance by reducing the dosage frequency, but may also help in relieving the burden of the drug-resistant Mutants and potential toxicity. This would be a major milestone in overcoming the shortcomings of an effective ATD therapy. In Recent research various drug vehicles including liposomes [54] 6.2.9. Hydrogel for brain The systematic administration of drugs to the BBB is Quite restricted due to its physiological features. Thus, 98% of The newly synthesized drugs fail to cross this crucial barrier. An Extremely low number of drugs are coming into the market due To the complex nature of CNS delivery [55] microspheres of PLGA con-Taining camptothecin increased the survival period in the rat Model for malignant gliomas. Thus, a long-term sustained Release from PLGA microspheres was achieved.The most commonly used local delivery requires the intra-Cerebroventricular implantation of a catheter/mini pump System. This implantation resulted in brain tissue damage and Is prone to severe infections. Recent research suggested “epi-Cortical delivery” as a better option for the release of drugs Causing minimal tissue damage. Wang et al[56] 7. Evaluation of Hydrogel 7.1. Percentage Transmittance Transparency of micro emulsion Formulation was determined by measuring percentage Transmittance through U.V. Spectrophotometer at 638 nm with distilled water taken as blank and three replicates were Performed for each sample [57] 7.2. pH determination The apparent pH of all micro emulsions was determined at 25°C by immersing the electrode directly into the micro emulsion using a digital pH meter [58] 7.3. Refractive index Refractive indexes of the prepared micro-Emulsions were determined at 25°C by Abbe’s refractometer By placing one drop of micro emulsion on the slide [59] 7.4. Viscosity measurement The viscosity of the prepared micro-Emulsion was measured at 25°C at 60 rpm by LV spindle no. 63 using a Brookfield viscometer [60] Determination of Drug Content The drug content of the Micro emulsion formulation was determined by dissolving 1 Ml (equivalent to 10 mg drug) of the formulation in 10ml of Methanol. After suitable dilutions with methanol, absorbance Was determined using the UV World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 438–449 446 spectrophotometer keeping Blank micro emulsion as control at wavelength 250 nm and Three replicates were performed for each sample [61] 7.5. Drug solubility study Valsartan was added in excess to the Optimized microemulsion formulation as well as each Individual ingredient of the formulation. After continuous Stirring for 4 hours at room temperature, samples were Withdrawn and centrifuged for 10 minutes. The amount of Drug soluble in optimized formulation as well as each Individual ingredient of the formulation was calculated by Subtracting the drug in the sediment from the total amount of Drug added. The solubility of drug in microemulsion was Compared with respect to its individual ingredients [62] 7.6. Advantages of Hydrogels • Posse’s high degree of flexibility similar to natural Tissues. • Bio compatible, bio degradable and that is why they Can be injected. • Applied locally so by passing first pass metabolism • Sustained and prolonged action in comparison to Conventional drug delivery systems • Decreased dose of administration. • Decreased side-effects. • Improved drug utilization. • Improved patient compliance. Drug targeting to specific site like colon. Protection of mucosa from irritating drugs. Drug loss is prevented by extensive first pass Metabolism. Lower daily cost to patient due to fewer dosage units Are required by the patient in therapy. 7.7. Limitations of hydrogels In addition to all the merits related to hydrogels, there Are some demerits or limitations as well. However, the Number of advantages of the hydrogels as carriers for drugs Relatively high as compared to the demerits. Most of these Limitations can be overcome but some substantial challenges Remain to exist with the hydrogels. The main drawback of the hydrogels is that they are expensive. The loading of drug In the hydrogels is a complex process and requires skilled Labor and mechanical devices for manufacturing. They are Very fragile, so they careful handling. The sterilization of the Hydrogels is a complicated process. The concentration of the Cross-linkers in the hydrogels is vital as a high concentration May lead to toxicity [63] 7.8. Future prospects The remarkable versatility of hydrogels in inducing alterations or serving various scientific purposes has proven to be a highly efficient technology. The biocompatibility of hydrogels, particularly those derived from polysaccharides, holds significant potential for applications in regenerative medicine, tissue engineering, food testing, smart packaging, biosensing and targeted drug delivery. The utilization of a 3D bio-printing approach for crafting intricate designs, particularly for organ transplants, stands out as a promising aspect of hydrogel technology. Additionally, the development of environmentally friendly materials to replace conventional napkins and diapers reflects a practical method toward sustainability. Designing high-tensile materials through polysaccharide hydrogels could contribute to advancements in orthopedic technology. The amalgamation of biocompatibility, precision, and efficient encapsulation renders hydrogels as encouraging structures for their design in drug delivery [64] 8. Conclusion Hydrogel formulations enhanced by advanced technologies offer highly tunable, biocompatible platforms for controlled and sustained drug delivery. Smart (stimuli-responsive) hydrogels can precisely respond to environmental cues like pH, temperature or ultrasound, improving release specificity. Hybrid hydrogels—integrating nanomaterials—boost mechanical strength, loading capacity, and multifunctionality. Injectable hydrogels enable minimally invasive delivery and in situ formation at target sites. Advanced fabrication methods (e.g., 3D-printing, AI-driven design) optimize structure, predict behavior, and accelerate development. These innovations significantly reduce systemic toxicity and maximize therapeutic efficacy. Despite progress, challenges like scalability, reproducibility, and long-term stability remain to be addressed. Overall, modern hydrogel systems represent a versatile and promising frontier in personalized and precision medicine.