Hydrogel-Based Drug Delivery: From Traditional Formulations to Advanced Applications

Background and Significance of Drug Delivery Systems

The efficacy of therapeutic agents often hinges on the method by which they are delivered. Traditional routes, including oral tablets and intravenous injections, can suffer from poor bioavailability, systemic side effects, and low patient adherence ^[1]. These drawbacks led to the emergence of controlled-release strategies designed to enhance drug efficacy and minimize unwanted toxicity. Early controlled-release systems focused on maintaining stable plasma drug concentrations over extended periods, but lacked the versatility to address diverse physiological barriers and patient-specific needs. Hydrogels have since become major players in this arena. Their high-water content and porous, networked structures allow for significant drug loading alongside tunable release profiles ^[2]. Research efforts over the past few decades have broadened the scope of hydrogel applications, encompassing stimuli-triggered drug release, tissue engineering scaffolds, and multifunctional therapeutic platforms.

Definition and Basic Concepts of Hydrogels

Hydrogels are crosslinked polymeric networks that retain large amounts of water without dissolving. These networks can be formed via physical or chemical crosslinking, resulting in materials that exhibit elasticity, permeability to small molecules, and compatibility with biological tissues. Natural hydrogels (e.g., alginate, chitosan) tend to be highly biocompatible but can face reproducibility and mechanical stability issues. Conversely, synthetic hydrogels (e.g., polyethylene glycol), polyacrylate) offer greater control over structure and performance but may require additional steps to ensure safety and biological acceptance^[3].

Scope of the Review

This review encompasses both foundational knowledge and advanced concepts in hydrogel-based drug delivery. It traces the history of hydrogel formulations from their early inception to contemporary innovations. It helps to explores the core chemistry, swelling behavior, and degradation profiles essential for rational hydrogel design. It got categorizes hydrogels by source, crosslinking type, and stimuli-responsiveness, while it helps to elucidates key drug release mechanisms. It addresses the traditional hydrogel systems, and it gives highlights of cutting-edge technologies like smart and nano-engineered hydrogels. It helps to examines applications in oncology, wound healing, ocular delivery, and more. Finally, the article discuss safety, regulatory considerations, challenges, and future perspectives. The review concludes that with a summary of current trends and anticipated directions for hydrogel-based therapeutics.

Evolution Of Hydrogel-Based Formulations

Early Development

The concept of hydrogels gained momentum in the 1960s, particularly through the work of Wichterle and Lim on soft contact lenses. Their pioneering contributions showcased the advantages of polymer networks capable of absorbing water while maintaining dimensional stability. These early hydrogels saw quick adoption in ophthalmic products and wound dressings, primarily due to their ability to keep surfaces hydrated^[4].

Progress in Drug Delivery

While the initial focus was on biomedical devices, the potential of hydrogels as drug carriers soon became evident. First-generation hydrogel-based drug delivery systems enabled sustained release over extended durations but offered limited adaptability to patient-specific conditions or targeting. Nevertheless, these early successes laid a foundation for the more sophisticated applications that would follow^[5].

Evolution into Modern Platforms

As polymer chemistry evolved, so did hydrogel formulations. Breakthroughs in chemical crosslinking, polymer blending, and nanotechnology paved the way for new functionalities and release profiles. The introduction of stimuli-responsive features—such as pH and temperature sensitivity—allowed for on-demand drug release in specific biological environments. The evolution of hydrogels is summarized in Figure 1. This evolution signaled the transition from relatively simple, passively releasing hydrogels to complex, interactive systems integral to personalized medicine strategies^[6].

Fundamentals Of Hydrogel Chemistry and Structure

Network Formation

Hydrogels arise from polymer chains that are crosslinked either physically (hydrogen bonding, ionic interactions, or hydrophobic forces) or chemically (covalent bonds formed via polymerization or functional group reactions)^[7]. Physical crosslinking often yields reversible gels responsive to environmental shifts, while chemical crosslinking produces more stable networks. Choice of polymer (natural, synthetic, or hybrid) influences mechanical strength, degradability, and biocompatibility.

Swelling Behavior

A hydrogel’s swelling capacity underpins its drug-release characteristics and mechanical properties^[8]. Swelling is modulated by polymer composition, crosslink density, and external factors like pH or ionic strength as shown in Figure 2.^[9]. Higher crosslink density typically reduces the degree of swelling, restricting diffusion pathways for larger molecules. In contrast, loosely crosslinked networks enable higher swelling but can compromise mechanical stability.

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250430163326-4.png" target="_blank"><img alt="Swelling Behavior of Hydrogels.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250430163326-4.png" width="150">
        </a>
Fig – 2: Swelling Behavior of Hydrogels

Mechanical and Rheological Properties

Mechanical demands differ among applications—e.g., injectable hydrogels need lower viscosity and quick gelation, while tissue engineering scaffolds may require higher stiffness.By adjusting the crosslink density, polymer chain length, and blending techniques,flexibility and strength can be balanced.Rheological studies give light on flow characteristics, elasticity, and gelation kinetics—all of which are crucial for clinical usability and product development^[10].

Degradation and Biocompatibility

Many hydrogel systems are designed to degrade in vivo to avoid post-treatment removal. Degradation can occur via hydrolysis or enzymatic pathways, yielding soluble byproducts ideally excreted without toxicity. Biocompatibility hinges on ensuring the absence of harmful residues, minimal immune response, and proper mechanical integration within tissues ^[11].

Drug Loading Methods

The drug incorporation approach—physical entrapment, covalent conjugation, or post-gelation loading—impacts release profiles and therapeutic efficacy ^[12]. Physical entrapment mixes drug and polymer prior to gelation, risking initial burst release if not managed carefully. Covalent linkage can reduce burst effects, but demands compatible reactive groups. Post-loading infiltration allows controlled diffusion into formed gels, useful for temperature- or pH-sensitive therapeutics^[13]. A comparative representation of drug loading methods for optimal release is given in Figure 3.

Classification Of Hydrogels for Drug Delivery

By Source

• Natural Polymers: Examples include alginate, chitosan, and collagen, prized for inherent biocompatibility and biodegradability but subject to potential variability and weaker mechanics.
• Synthetic Polymers: PEG, PVA, or poly(acrylic acid) allow greater customization of network architecture and mechanical features.
• Hybrid Systems: Combine natural and synthetic elements, merging robust mechanical attributes with favorable biological interactions.

By Network Formation

• Physical Crosslinking: Reversible bonds formed via electrostatic or hydrogen bonding.
• Chemical Crosslinking: Covalent linkages that yield more durable scaffolds but may require additional purification to remove unreacted compounds^[14].

By Stimuli Responsiveness

• pH-Responsive: Ideal for GI or tumor applications where pH differs from systemic levels.
• Thermo-Responsive: Gelation near physiological temperature, enabling in situ formation for minimally invasive administration ^[15].
• Light-Responsive: Photo-triggered changes in network structure allow precise spatiotemporal control^[16].
• Enzyme or Multi-Stimuli: Achieve highly targeted release by responding to complex biochemical cues.

By Crosslinking Density and Swelling

Microgels (micrometer scale) and macrogels (larger 3D structures) differ in crosslink density and mesh size, influencing drug diffusion and mechanical stability. Loosely crosslinked networks swell more but can be prone to rapid drug release; tighter networks constrain swelling but may hinder larger drug molecules^[17]. The classification of hydrogels is given in figure 4 and the key criteria for the classification of hydrogels is given in Table 1.

Table 1: Key Classification Criteria for Hydrogels

Mechanisms Of Drug Release from Hydrogels

Diffusion-Controlled Release

Drug diffusion in hydrogels is often guided by Fick’s law, especially when the network remains intact. The polymer matrix serves as a rate-limiting barrier, with mesh size and polymer–drug interactions influencing the release rate. Non-Fickian or anomalous diffusion arises when swelling or polymer relaxation significantly contributes to the release kinetics^[18].

Swelling-Controlled Release

In swelling-controlled systems, the hydrogel’s expansion in aqueous media regulates drug liberation. As water permeates the network, it increases mesh size, facilitating drug egress. Mathematical models like the Peppas–Sahlin equation describe situations where both diffusion and network relaxation are important^[19].

Chemically Controlled Release

Some hydrogels gradually erode through hydrolysis or enzymatic cleavage, releasing the embedded drug. Prodrugs can also be covalently tethered to the polymer backbone for targeted release upon bond cleavage. This approach is particularly useful when precise control over temporal or site-specific dosing is essential.

Stimuli-Induced Release

“Smart” hydrogels can alter their swelling or degrade upon exposure to triggers like pH, temperature, light, or magnetic fields. This property enables on-demand release in response to changes in the local environment (e.g., acidic tumor milieu) or external signals (e.g., LED illumination in dermatology). These hydrogels are designed to react to specific stimuli, such as changes in pH, temperature, light exposure, or magnetic fields^[20]. Stimuli-responsive mechanisms enhance therapeutic specificity and minimize off-target effects.

Traditional Hydrogel Formulations: Sustained And Controlled Release

Conventional Systems and Their Drawbacks

Early hydrogel-based technologies improved upon conventional dosage forms by offering extended drug release. Examples include:

• Oral Hydrogels: Designed to swell in the GI tract, resulting in slow, sustained delivery.
• Transdermal Patches: Hydrogel matrices delivering analgesics or hormones with reduced skin irritation^[21].

Although successful, these systems largely lacked dynamic responsiveness. The release profile was often governed by passive diffusion and limited by the inability to target specific tissues or quickly adapt to physiological changes.

Case Studies

• Contact Lens Devices: Hydrogels for ocular drug delivery offered continuous dosing of anti-inflammatory or anti-glaucoma medications.
• Wound Dressings: Hydrogel-based dressings maintained moisture and, in some formulations, released antimicrobials or growth factors for improved healing.

Barriers to Widespread Adoption

Manufacturing scale-up remains nontrivial. Ensuring consistency in polymer composition and crosslinking across large batches can be challenging. Moreover, certain hydrogels degrade or lose functionality with prolonged storage, complicating commercialization and regulatory approval.

Advanced Hydrogel-Based Drug Delivery Systems

Smart and Responsive Hydrogels

pH-Responsive Hydrogels exploit the acidic microenvironment of tumors or the varying pH in the GI tract, releasing drugs specifically at thes         e sites.
Temperature-Responsive Hydrogels—often leveraging PNIPAAm—undergo solution-to-gel transitions around body temperature, facilitating injectable in situ gelling.
Multi-Stimuli Responsive Designs combine multiple triggers, further refining control over drug release timing and location. Figure 6 demonstrates different types of smart hydrogels and table 2 summarizes the examples of stimuli responsive hydrogels.

Nano-Engineered Hydrogels (Nanogels)

Nanogels, sub-1000 nm hydrogel particles, can leverage the enhanced permeability and retention (EPR) effect in tumors, improving drug accumulation in diseased tissue. Fabrication techniques include emulsion polymerization and ionic gelation. Nanogels often exhibit better circulation times and targeted drug delivery capacity^[22].

Targeted Drug Delivery

By linking targeting ligands (e.g., antibodies or peptides) onto the hydrogel surface, site-specific interactions with receptor-bearing cells can be achieved. This active targeting approach can significantly elevate drug concentration at the desired site while minimizing systemic exposure.

Injectable and In Situ Forming Hydrogels

Injectable hydrogels simplify the administration process: a solution precursor is injected, transitioning into a gel upon experiencing physiological conditions. This approach is particularly attractive in tissue engineering, allowing hydrogel scaffolds to mold to irregular cavities and deliver growth factors or cells locally^[23].

Co-Delivery of Multiple Agents

Advanced hydrogel systems support the simultaneous release of small molecules, proteins, and nucleic acids. This co-delivery strategy can be critical in diseases like cancer, where combination regimens show improved therapeutic outcomes and reduced resistance. Designing hydrogel compartments that segregate different drugs can manage drug–drug interactions.

3D-Printed Hydrogel Systems

3D printing enables customized hydrogel constructs with precise architecture and drug-loading patterns. This customization is highly relevant for patient-specific implants or scaffolds in regenerative medicine^[24]. The technique allows layer-by-layer deposition, which helps control local drug concentrations and release kinetics. Some examples of selected advanced hydrogel formulations are given in table 3.

Table 3: Selected Advanced Hydrogel Formulations

Specific Therapeutic Applications

Cancer Therapy

Conventional chemotherapy is often associated with systemic toxicity and low tumor specificity^[25]. Hydrogels help localize chemotherapeutic agents at tumor sites, exploiting unique tumoral conditions like pH or enzyme overexpression for triggered release. Injectable formulations can be placed directly into or near the tumor to form a depot, maintaining high local drug concentrations.

Combination Treatments

In cancer, combination therapies—e.g., chemotherapy and immunotherapy—can be delivered via hydrogels to achieve synergistic effects^[26]. Co-encapsulation of drugs with different mechanisms can enhance overall efficacy while reducing exposure-related side effects.

Wound Healing and Tissue Regeneration

Hydrogel-based wound dressings keep the wound environment moist, promoting cell migration and nutrient exchange ^[27]. Incorporation of antimicrobial agents reduces infection risk, while encapsulated growth factors stimulate tissue repair ^[28]. In tissue engineering, biodegradable hydrogel scaffolds seeded with cells can regenerate damaged tissues with minimal surgical intervention ^[29].

Ophthalmic Delivery

Ocular drug delivery is complicated by tear turnover and limited corneal permeability ^[30]. Hydrogels in contact lenses enable extended-release therapies, improving efficacy over conventional eye drops. For posterior eye diseases (e.g., macular degeneration), injectable hydrogels can be placed in the vitreous cavity to deliver drugs over weeks or months.

Oral Drug Delivery

Oral hydrogels can protect acid-labile drugs in the stomach and release them in specific intestinal regions. Mucoadhesive properties extend gastric residence time, enhancing drug absorption. pH-responsive formulations can further refine release, targeting the colon or other GI segments^[31].

Transdermal and Topical Applications

Hydrogel patches are favored for transdermal delivery of analgesics, hormones, or nicotine, thanks to their comfortable adhesion and high water content. The hydrated matrix improves skin permeability while reducing irritation.

Neurological Disorders

Surmounting the blood–brain barrier (BBB) is a major obstacle in CNS drug delivery. Injectable hydrogels can be administered intracranially for localized release of therapeutics aimed at treating conditions like glioblastoma or Parkinson’s disease ^[32]. Certain enzyme-responsive hydrogels can degrade selectively in neural regions, tailoring drug delivery to pathological sites ^[33]. Therapeutic applications of hydrogels are summarized in table 4.

Table 4: Therapeutic Applications of Hydrogel-Based Delivery