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Abstract

Oral ulcers are painful inflammatory lesions of the oral mucosa that cause substantial difficulty in eating and speech, ultimately affecting health-related quality of life. Generally, conventional treatments such as corticosteroids, antiseptics and analgesics have limitations of poor mucosal retention, short salivary clearance half-lives, no site specific targeting and therefore potential adverse systemic effects. Over the past decade, green synthesized and functionalized hydrogel films have been regarded as potential transmucosal drug delivery systems for local therapy of oral ulcer. The high biocompatibility, mucoadhesion, hydration capacity and controlled drug release features of these hydrogel platforms improve the localized therapeutic effect and residence time at ulcer sites. The addition of natural polymers, plant-based compounds, and nanoparticles synthesised in an environmentally friendly way improves anti-inflammatory, antioxidant, antimicrobial activity, as well as the healing process itself. The characteristics of pH-responsive behaviour, enzyme-sensitive release and nano-particle incorporation together with the specific functionalization strategies comprising ligand-mediated targeting (that can also be related to active targeting), which facilitate this form of delivery in a quantitatively desirable manner within the dynamic oral environment. In addition, eco-friendly fabrication methods contribute to the sustainable and safer development of different pharmaceuticals via green chemistry principles. Comprehensively discussing the pathophysiology of oral ulcers, limitations associated with conventional therapies and various hydrogel fabrication methods along with green synthesis strategies, functionalization approaches, characterization techniques, biological evaluations and future perspectives. In conclusion, green-functionalized hydrogel films constitute an eco-friendly multifunctional and sustainable platform for modern targeted repairs of oral ulcers.

Keywords

Oral ulcers; Hydrogel films; Green synthesis; Transmucosal drug delivery; Mucoadhesive systems; Functionalized nanoparticles

Introduction

Oral ulcers are one of the most common lesions found on the oral mucosa that is defined as disruption of local epithelial covering, inflammation, and pain with possible impact on nutrition, speech and life quality. These lesions can result from various etiologies, such as mechanical trauma (such as biting the cheek), microbial infections, nutritional deficiencies, systemic diseases and immune system dysregulation, the most frequent of these clinical manifestations type will be recurrent aphthous stomatitis. The former is characterized by a compromise in epithelial healing and the latter can be attributed to exaggerated inflammatory reaction and microbial assault at the site of inflammation. Although the oral cavity has several therapeutic options, effective management still remains challenging since the dynamic oral environment facilitates fast drug clearance from or limited retention capacity of medications at the local site [1]. Conventional treatment options are mainly based on topical corticosteroids, analgesics, antiseptics and antimicrobials. While these strategies may alleviate symptoms, they have several drawbacks including but not limited to low tissue targeting, rapid residence time, mucosal irritation and long-term systemic side effects upon continuous use. In addition, the increasing incidence of antimicrobial resistance and non-cooperation of patients requires the advancement of new drug delivery systems that could provide a localised, sustained and targeted therapeutic effect [2]. Hydrogel based films can be a potential candidate for oral transmucosal drug delivery in this context. These systems are formed by polymeric networks with high hydrophilicity that can absorb large quantities of water, thus maintaining the physiological humidity favorable for wound repair. The mucoadhesive properties allow prolonged retention of the polymer at ulcer sites, providing enhanced bioavailability and therapeutic efficacy. In addition, these polymer films provide precise control of stimulus-controlled drug release at the molecular level and can thus precisely modulate and fine-tune therapeutic outcomes [3]. The recent progress towards green synthesis has a notable impact of the design and development of hydrogel-based drug delivery systems. Green strategies focus only on the application of natural polymers, plant-sourced extracts and green crosslinking approaches with a consequent reduction in hazardous chemicals and environmental impacts. Importantly, these natural agents usually have inherent pharmacological effects like anti-inflammatory, antioxidant, and antimicrobial actions that synergistically promote the healing of ulcers. Furthermore, the embedding of green-generated nanomaterials in hydrogel films allows producing multi-functional systems characterized by improved targeting function and therapeutic effect [4]. Herein, a brief overview of the recent advances, mechanisms, and formulations for targeting oral ulcer on green-synthesized and functionalized hydrogel films are reported.

Figure 1. Graphical representation of oral ulcer pathophysiology and targeted therapy using green-synthesized hydrogel films, highlighting inflammation, oxidative stress, and enhanced healing via controlled, mucoadhesive drug delivery (Created with BioRender.com).

Overview of Oral Ulcers

Oral ulcers are localised breakdown of the mucosal surface resulting in inflammation and pain. These can occur due to trauma, infection, systemic disease, and immune dysregulation etc. Complex mutual interactions between inflammatory mediators, oxidative stress and microbial colonization are involved in the pathogenesis. Ulcers typically appear as red lesions covered with a fibrin exudate and cause a burning sensation with eating or speaking. In particular, delayed healing and recurrence are still the main issues that need to be addressed, and we should apply advanced therapeutic strategies promoting rapid tissue regeneration in combination with suppressing secondary infections [5].

Limitations of Conventional Therapies

Oral ulcers are usually managed conventionally using topical corticosteroids, antiseptics, analgesics and antimicrobial agents [6]. These therapies ameliorate clinical signs, but they do not directly target the underlying pathophysiology and can be associated with adverse effects, including mucosal irritation, opportunistic infections, and systemic absorption. Therapeutic efficacy is additionally limited by the frequency of dosing and poor retention of drug at the ulcer site [7]. Even worse, synthetic drugs may be non-targeted because they act on both specific and nonspecific sites, resulting in lower patient compliance. The development of drug resistance and recurrence of lesions also raises the need for high-performance localized and safe therapeutic systems, which exhibit more advantages than systematic approaches [8]. The delivery of drugs more typically requires either the targeting or localisation of delivery in a specific area. Localized drug delivery system is well required for this purpose to limit the action site of the oral ulcer while maintaining sustained drug release in site specific manner. The rapid clearance of injected drugs from the oral cavity because of the dynamic oral environment (salivary flow and mechanical forces) is a critical problem that leads to unsuccessful treatment due to an insufficient concentration of drug in site [9]. The localization-oriented delivery platforms can increase drug concentration at the lesion site, reduce systemic exposure and frequency of dosing. Targeted systems can also be designed with the capacity to respond to external stimulation such as pH or enzymatic activity, setting the stage for presentation in controlled and sustained release of a therapeutic agent [10]. These methods promote better therapeutic results, as well as increased patient compliance and limited side effects.

Emergence of Hydrogel-Based Films

Hydrogel based films have gained popularity as potential drug delivery platforms for oral transmucosal route of administration in view of their high water content, flexibility and biocompatibility. These systems create a barrier of protection over ulcerated tissue allowing for a moist healing environment while permitting controlled release of drugs [11]. Their mucoadhesive characteristics improve the residence time at the site of application, thus enhancing therapeutic performance. Furthermore, various bioactive agents such as drugs, nanoparticles and phytochemicals can be loaded into these hydrogel films [12]. Through material science advances, scientists have been able to create hydrogels that are not only more responsive but also stronger with improved targeted delivery.

Green Synthesis and its Role in Current Drug Delivery

In contemporary drug delivery, embracing sustainability, safety and environmental compatibility; green synthesis is catching up with great attention. For hydrogel film development, green strategies use natural biopolymers, plant extracts, and environmentally friendly crosslinking agents to minimize toxic chemicals and lessen environmental burden [13]. Most of these biologically sourced elements are often inherent with biological activities such as anti-oxidative and anti-inflammatory properties, therefore promoting the overall therapeutic activity of a formulation. Additionally, green synthesis helps incorporate biogenic nanoparticles and thus creates multifunctional delivery systems of drugs. This strategy is consistent with the current regulatory and societal demand for biocompatible, sustainable and economically viable drug delivery technologies [14].

Pathophysiology of Oral Ulcers

Oral ulceration is a multifactorial pathological process characterized by disruption of the epithelium, infiltration of inflammatory cells and delayed tissue regeneration. The underlying pathophysiology is regulated by a complex interplay of immune dysregulation, oxidative stress and local environmental factors. Upon tissue injury, pro-inflammatory mediators are released causing vasodilation, recruiting leukocytes and cellular injury. Compromised integrity of both mucosal membranes also paves a way for microbial colonization and subsequently worsens inflammation. Delayed wound healing occurs because the balance between tissue destruction and repair is altered. These mechanisms may help find a precise therapeutic system to modulate inflammatory response, support wound healing process and reduce recurrence of oral ulcer [15].

Types (Aphthous, Traumatic, Infectious, Drug-Induced)

Oral ulcers can be classified (by etiology) into aphthous, traumatic, infectious and drug-induced types. Aphthous ulcers are recurrent idiopathic lesions commonly linked with immune dysregulation and genetic predilection. Traumatic ulcers are due either to mechanical trauma or chemical irritation, defective stress-response mechanisms, or thermal injury to mucosa. Infectious ulcers due to bacterial, viral, or fungal pathogens are all associated with infectious agents such as herpes simplex virus. Drug- and Medicine-Induced Ulcers includes ulcers corresponding to adverse effects of drugs, such as the nonsteroidal anti-inflammatory drugs or chemotherapeutic agents. This type is characterized by a specific set of clinical features and underlying mechanisms which therefore requires specific therapeutic approaches for a successful treatment [16].

Molecular Mechanisms and Inflammatory Pathways

The contribution of molecular pathogenesis of oral ulcer has been associated with activated inflammation pathway and release of inflammatory cytokines like tumor necrosis factor-α, interleukin-1β and interleukin-6 (Table 1). These mediators in turn induce leukocyte infiltration, oxidative stress and epithelial cell apoptosis, causing tissue injury. Central to this is activation of transcription factors that, in particular NF-κB, mediate the inflammatory response [17]. It also aggravates injury by generating imbalance between reactive oxygen species and antioxidant defenses. Impaired tissue repair due to differential growth factors and extracellular matrix remodeling. The molecular pathways that are documented to regulate inflammation and the healing process at different phases can be targeted by delivering precise therapeutic systems which may lead to novel adjunctive treatment [18].

Table 1.  Molecular Mechanisms and Inflammatory Pathways in Oral Ulcers

Component

Key Factors Involved

Mechanism of Action

Pathological Outcome

Therapeutic Implication

Pro-inflammatory Cytokines [17]

TNF-α, IL-1β, IL-6

Stimulate immune response and recruit leukocytes

Increased inflammation and tissue damage

Targeting cytokines reduces inflammation and pain

Transcription Factors [18]

NF-κB

Regulates expression of inflammatory genes

Amplification of inflammatory cascade

Inhibition helps control chronic inflammation

Leukocyte Infiltration [19]

Neutrophils, macrophages

Migration to ulcer site and release of enzymes

Tissue destruction and delayed healing

Modulation reduces excessive immune response

Oxidative Stress [20]

Reactive oxygen species (ROS)

Imbalance between ROS and antioxidants

Cellular damage and apoptosis

Antioxidants help restore cellular balance

Epithelial Cell Apoptosis [21]

Caspase activation, inflammatory mediators

Programmed cell death of mucosal cells

Ulcer formation and delayed regeneration

Cytoprotective agents promote healing

Growth Factor Dysregulation [22]

VEGF, TGF-β

Impaired signaling for tissue repair

Reduced angiogenesis and regeneration

Growth factor modulation enhances healing

Microbial Involvement and Secondary Infections

The presence of microflora plays an important role in the development and extent of oral mucosal damage. The open ulcer surface creates a perfect hotspot for opportunistic pathogens, such as bacteria and fungi, causing secondary infections [23]. These pathogens can generate toxins and enzymes that worsen tissue injury and impede healing. Moreover, biofilm formation is a bacterial virulence factor that intensifies the resistance of pathogens towards traditional therapeutics. Interactions between host immune responses and microbial components can also amplify inflammation. Hence, sufficient management of oral ulcerations involves a therapeutic agent that not only exhibits antimicrobial activity along with anti-inflammatory and regenerative properties to control infection and facilitate rapid mucosal healing [24].

Challenges in Healing and Recurrence

Factors contributing to insufficient healing of oral ulcers are unique physiological conditions within the oral cavity such as permanent salivary flow, mechanical stress and microenvironment due to microbial load. These factors lead to rapid clearance of drugs and additional tissue stimulation, causing the healing process takes a longer time. Furthermore, pre-existing systemic diseases, malnutrition and immune system dysfunctions may also limit tissue regeneration and make patients more prone to recurrence [25]. Traditional drugs often lead to imperfect recovery due to loss of longer term medicinal activity. Moreover, repeat occurrences of some ulcer types further complicate the management and underscore the need for more advanced drug delivery systems characterized by prolonged retention at the site of action with controlled release to optimize their therapeutic efficiency [26].

Transmucosal drug delivery systems based on hydrogel films

Hydrogel films are the next innovative transmucosal platforms developed to directly transport therapeutic agents to the site of action, the oral mucosa. Due to these properties, their polymeric network allows close contact with ulcerated tissue and mediated localized sustained release of drug. Such systems are capable of increasing the retention of the drug and protecting lesions against external irritating agents while allowing for increased therapeutical efficiency from within the oral cavity [27].

Definition and Classification of Hydrogels

Hydrogels are three-dimensional hydrophilic polymeric networks that can swelling in aqueous media and can hold large amounts of water or biological fluids. They are categorized by origin (natural, synthetic), crosslinking mechanism (physical or chemical), and responsiveness (stimuli-responsive or conventional). Their multi-functional tunability allows their potential for applications in various biomedical and drug delivery fields [28][29].

Film-Forming Hydrogel Systems

Film-forming hydrogel systems are thin and flexible matrices delivery designed specifically for mucus surfaces. These systems are hybrids that incorporate the swelling of hydrogels with some structural properties so that drugs can be uniformly distributed and remain in contact at the site of action for extended periods. These films are usually produced by solvent casting and sophisticated fabrication strategies for regulated treatment supply [30][31].

Mucoadhesion and Drug Release Mechanism

Hydrogel films have reported mechanisms of mucoadhesion including hydrogen bonding, electrostatic interactions and polymer chain interpenetration with mucin glycoproteins. It is this adhesion which helps on enhancing its residence time at the site of application. Mechanism of delivery is based on diffusion, swelling and polymer degradation which lead to sustained and localized drug release from the device at the target mucosal tissue [32].

Advantages over Conventional Dosage Forms

Hydrogel films present numerous advantages compared to traditional formulations, such as improved site-specific delivery, prolonged duration in the desired location, and less frequent dosing. They act as a physical barrier over the ulcerated tissue, while also keeping the area moist and allowing it to heal. Moreover, these systems reduce systemic exposure while improving compliance and comfort with the application [33].

Green Synthetic Methodologies in Hydrogel Synthesis

Green synthesis is the promising approach for developing hydrogels based on environmentally benign processes, sustainable bio-based compatible components and minimizing toxicity making it a step forward for green manufacturing of pharmaceuticals. This strategy combines natural polymers and plant-derived bioactives with green synthesis protocols to generate biocompatible/sustainable, multifunctional drug delivery systems [34]. In the management of oral ulcers, hydrogel films derived from green synthesis provide enhanced clinical advantages due to their inherent anti-inflammatory and antimicrobial functions. These systems reduce the risk of exposure to hazardous chemicals and energy consumption, improving safety and regulatory acceptance. This intersection of green chemistry and advanced biomaterials thus allows for the creation of cost-effective, sustainable, and patient-friendly systems reaching targeted transmucosal delivery of pharmaceuticals [35].

Principles of Green Chemistry in Pharmaceutical Sciences

Pharmaceutical sciences is one of the fields for applying green chemistry principles to minimize environmental ramifications as well as ensuring product safety and efficacy. These include the use of renewables as raw materials, no toxic reagents used, energy-efficient processes, and minimizing waste. In hydrogel synthesis, this means replacing synthetic crosslinkers and solvents with biocompatible substitutes [36]. Green principles also promote atom economy and safer reaction conditions, thus leading to the increased sustainability of chemical processes. Such principles are especially useful in oral drug delivery systems that require high biocompatibility due to direct contact with mucosa. These approaches help in the formulation of safe, environmentally friendly and industrially acceptable hydrogel-based systems [37].

Natural Polymer-based Hydrogel Films

Green hydrogel films have their base in natural polymers, due to their biodegradable and biocompatible nature and a wide range of structural possibilities. Chitosan, alginate, gelatin and cellulose derivatives are examples of polymers often employed for the treatment of oral ulcers. Chitosan possesses wound healing, mucoadhesive and antimicrobial properties to improve mucosal retention and localised drug delivery [38]. Hydrated networks such as those formed by alginate and gelatin also provide the needed hydrated environment to facilitate tissue regeneration. Mechanical strength and stability is provided by cellulose derivatives. These polymers have functional groups that allow crosslinking and the transformation into stimuli-responsive systems to induce controlled drug release. Since they are biocompatible with intrinsic bioactivity, hydrogels are very promising for forwardable transmucosal drug delivery applications [39].

Plant-Mediated Crosslinking and Functionalization

Plant-mediated crosslinking and functionalization is a recent and eco-friendly advancement of hydrogel design by using plant-derived phytochemicals such as polyphenols, flavonoids, tannins and polysaccharides as natural crosslinkers (Table 2). They bind through hydrogen bonding and ionic interactions with polymer networks which eliminates toxic synthetic crosslinkers while improving biocompatibility [40]. Moreover, plant extracts offer bioactive substances used for their antioxidant, anti-inflammatory, antimicrobial and immunomodulatory properties. Such dual functionalization not only enriches structural stability but also therapeutic potency. These multifunctional hydrogels also play an active role in promoting tissue regeneration and combating infections, rendering them ideal candidates for oral ulcer treatment without the lack of safety concerns, sustainability issues, and enhanced clinical performance [41][42].

Table 2.  Plant-Mediated Crosslinking and Functionalization in Green Hydrogel Films

Aspect

Description

Mechanism Involved

Functional Outcome

Relevance to Oral Ulcer Therapy

Phytochemical-Based Crosslinking [39]

Use of plant-derived compounds such as polyphenols, flavonoids, tannins, and polysaccharides

Formation of hydrogen bonds and ionic interactions with polymer chains

Stabilization of hydrogel network without toxic crosslinkers

Enhances biocompatibility and safety for mucosal application

Elimination of Synthetic Crosslinkers [40]

Replacement of chemicals like glutaraldehyde with natural agents

Reduction of cytotoxic residues and chemical toxicity

Improved biological compatibility and reduced adverse effects

Suitable for sensitive oral mucosal tissues

Bioactive Functionalization [41]

Incorporation of plant extracts into hydrogel matrix

Release of phytochemicals with antioxidant, anti-inflammatory, and antimicrobial effects

Multifunctional therapeutic action

Promotes healing and prevents secondary infections

Sustainability and Safety [42]

Use of renewable plant resources

Eco-friendly synthesis with minimal environmental impact

Safer and greener formulation approach

Aligns with regulatory and environmental requirem

Eco-Friendly Solvents and Processing Techniques

One of the most important elements facilitating green hydrogel fabrication is biological solvents/process. Better alternatives to organic solvents are water and bio-based solvents because of lower toxicity and environmental hazard. When just simple techniques such as solvent casting, freeze-drying, and microwave-assisted synthesis can produce hydrogels with high efficiency and consume very little energy [43]. Moreover, the use of enzymatic crosslinking and methods based on radiation are also cleaner than traditional chemical processes. These methodologies not only make the product safer, but more scalable and reproducible as well. Non-toxic solvents, which are crucial for mucosal compatibility in oral drug delivery, allows eco-friendly processing as a key aspect of sustainable hydrogel development [44].

Sustainable Manufacturing Strategies

Various sustainable manufacturing strategies such as resource-efficient, scalable, and low-impact hydrogel production systems are discussed. This comprises of usage of renewable feedstock, energy efficient processes and waste reduction techniques. Utilizing process optimization, including Quality by Design (QbD) approaches to ensure consistent product quality with minimum variability [45]. Moreover, the combination of green synthesis with advanced technologies like nanotechnology and automation improves the manufacturing process. Furthermore, principles of life cycle assessment and eco-design enforce the need for sustainable development. Such approaches are essential to enable the translation of green nanohydrogels systems from laboratory research into practical protein-based therapeutics at an industrial scale and will ultimately support the use of such proteins in future wide-scale clinical applications related to oral ulcers treatment [46].

Functionalization Strategies for Targeted Therapy

The therapeutic performance of hydrogel films for treating localized oral ulcer disease is significantly improved with functionalization strategies, leading to enhanced specificity, responsiveness and drug delivery efficiency (Table 3). Surface modification methods add functional groups capable to increase the mucoadhesion, wettability and interaction with mucosal tissues increasing residence time for longer periods and improving drug release [47]. The specificity of ligands provides the ability to induce selective targeting with molecules including folate, peptides or antibodies which are expressively in inflammatory and vulnerable tissues so that drugs can reach their target considerably accurate while diminishing negative off-target effects. Introduction: Stimuli-responsive hydrogels especially pH-sensitive ones which undergo smart swelling or shrinkage take advantage of the change in microenvironment of ulcerated tissues for controlled and site- specific drug release. Enzyme-responsive systems take this further by having a controlled release of therapeutic agents proximal to sites where levels of particular enzymes (e.g. matrix metalloproteinases) are elevated [48]. Moreover, its use in hydrogel films facilitated drug stabilization, penetration and sustained release through the incorporation of nanoparticles exerts antimicrobial and anti-inflammatory effects. Together, these functionalization strategies offer to design a sophisticated detailed advanced multi-functional hydrogel system that will prove effective against the complex pathophysiology of oral ulcers and held major improvements in therapeutic efficacy facilitating the evolution of precision and targeted drug delivery-tailored strategies [49].

Table 3.  Functionalization Strategies in Hydrogel Films for Targeted Oral Ulcer Therapy

Strategy

Modification Approach

Mechanism of Action

Therapeutic Advantage

Relevance to Oral Ulcers

Surface Modification [45]

Grafting, plasma treatment, chemical conjugation

Enhances mucoadhesion via hydrogen bonding and electrostatic interactions

Prolonged residence time, improved drug retention

Prevents rapid drug washout in saliva-rich oral environment

Ligand-Mediated Targeting [46]

Conjugation with folate, peptides, antibodies

Receptor-mediated binding and uptake at inflamed tissues

Increased specificity and reduced off-target effects

Targets inflamed mucosal cells expressing specific biomarkers

pH/Stimuli-Responsive Hydrogels [47]

Incorporation of smart polymers

Swelling or degradation triggered by pH or environmental changes

Controlled and site-specific drug release

Exploits acidic/inflammatory microenvironment of ulcers

Enzyme-Responsive Systems [48]

Enzyme-cleavable linkages within polymer matrix

Drug release triggered by enzymes (e.g., MMPs)

Condition-specific and adaptive drug delivery

Responds to elevated enzyme levels in ulcerated tissues

Nanoparticle-Embedded Hydrogels [49]

Incorporation of metallic/polymeric nanoparticles

Controlled drug release, enhanced penetration, antimicrobial action

Improved bioavailability and multifunctional therapy

Combats infection, enhances healing, and ensures sustained delivery

Role of Phytochemicals in Green Hydrogel Films

Phytochemicals are identified as essential therapeutic tools for improving the oromucosal activity of green synthesized-derived polymeric hydrogel films. Bioactive compounds (e.g., curcumin and flavonoids) with potent anti-inflammatory activity modulate key signaling pathways through suppression of pro-inflammatory cytokines as well as inhibition of NF-κB activation [50]. The addition of such antimicrobial herbal extracts enables more active control over bacterial species in the oral environment to an extent that it minimizes secondary infections and may help establish immediate conducive conditions for healing. Moreover, had high content of antioxidant phytochemicals scavenge reactive oxygen species decrease oxidative stress to restoration of tissue [51]. In addition, several plant-based constituents also promote wound healing by stimulating collagen synthesis and epithelialization. Above all, these natural agents can act in combination with conventional drugs to maximize treatment efficacy while lowering both dosages and side effects. Combination of phytochemicals in hydrogel matrices can be used not only for controlled and targeted drug delivery but also include multi-functional characteristics suitable for modern advanced eco-friendly oral ulcer healing systems [52].

Fabrication Techniques of Hydrogel Films

Hydrogel films are used widely in the field of drug delivery; however, fabrication techniques affect both the structure and function of these materials. Common methods for producing uniform, thin films with a defined composition include solvent casting [53]. Lyophilization or freeze-drying creates pore structures that increase swelling and drug diffusion. Sophisticated techniques featured electrospinning and 3D printing to allow for precise microarchitecture and drug distribution control [53]. Multilayered systems with release profiles can be fabricated through layer-by-layer assembly. Novel strategies for green fabrication with a focus on solvent-free processing methods, bio-based materials, and energy-efficient approaches without compromising high-performance and reproducible characteristics of hydrogel-based drug delivery systems have appeared in the literature [54].

Solvent Casting Method

Solvent casting method is a prevalent and simple approach to producing hydrogel films. Films are cast from dissolution of polymers and active agents in an appropriate solvent and dried. This approach provides accurate control of thickness, composition and drug loading appropriate for oral transmucosal use [55].

Freeze-Drying and Lyophilization

Routine lyophilization (or freeze-drying) involves freezing the hydrogel matrix followed by sublimation of solvent under low pressure. The process produces porous structures that greatly improve swelling capacity and drug transference ability. Such hydrogel systems could offer higher bioavailability and stability, which is especially advantageous when designing fast-hydrating and physically-crosslinked hydrogel systems [56].

Electrospinning and 3D Printing

Electrospinning is an electrostatic spinning method that creates highly surface area- and porosity-matched nanofibrous hydrogel films which allows for efficient drug incorporation with rapid drug release. On the other hand, with 3D printing technology where gelatin can be precisely fabricated at controlled geometry and drug distribution. Both strategies provide control over architecture, allowing for selective and customized drug delivery uses [57].

Layer-by-Layer Assembly

Layer-by-layer assembly consists of successive deposition of oppositely charged polymers, resulting in multilayered hydrogel films. This allows for precise control over factors such as film thickness, composition, and drug release profiles [58]. It is especially beneficial for multipurpose therapeutic agents and/or sustained or repeated drug delivery [59] of oral ulcer treatment.

Green Fabrication Innovations

Innovations in green fabrication involve the utilization of eco-friendly procedures such as water-based solvents, natural polymers and energy-efficient streaming techniques. These strategies help tackle toxic residues and ecological impact while ensuring product safety and potency. These sustainable methods are more desirable for producing biocompatible polymeric hydrogel films in the clinics [60].

Characterization of Hydrogel Films

The hydrogel films can be characterized to ensure that they are effective, stable and suitable in localized therapy of oral ulcer. Complete assessment comprises physicochemical, mechanical and biological qualities affecting drug liberation, mucoadhesion and therapeutic efficacy [61]. Physicochemical Parameters such as dose uniformity, hydration behavior, thickness, swelling index (SI), and folding endurance maintain structural integrity [62]. Mucoadhesive strength helps to determine and compare the ability of films stick onto mucosa ensuring that it stays at this site for longer, providing better drug delivery to the ulcer. Determination of drug content as well as uniformity ensures accurate dosing and formulation reproducibility. In vitro drug-release studies are designed to evaluate the diffusion and sustained release behavior of formulations under simulated physiological conditions [63]. SEM and AFM analyses of surface morphology offer information on porosity, roughness, and structural uniformity; DSC and XRD thermal analyses establish drug–polymer interactions, physical stability, and crystallinity that ultimately dictate overall formulation performance [64].

Biological Evaluation

The biological evaluation of hydrogel films intended for oral ulcer treatment is crucial to determine their safety, efficacy, and clinical utility. A summary of in vitro, ex vivo and in vivo studies is presented that evaluate demonstration of cytocompatibility, anti-inflammatory and antimicrobial activity, permeation behavior and efficacy in the acceleration of wound healing [65]. The biocompatibility is established by studying in vitro cytotoxicity, including MTT and live/dead assays, to guarantee that the formulation did not adversely affect on mucosal cells [66]. Anti-inflammatory and antimicrobial assays characterize the hydrogel's capacity to reduce inflammatory mediators and inhibiting an invasion of pathogenic microbes, which reduces the risk of secondary infections. Excised mucosal tissues, used to embark ex vivo permeation studies, can give important information pertaining drug absorption and retention and permeability in respect to their performance under physiological conditions [67]. Animal models of infection-based pathogenicity drive further characterization of therapeutic efficacy based on elicited outcomes such as reduced ulcer size, healing rate and histopathological alterations. Lastly, clinical perspectives consider safety, patients' compliance, regulatory subjection and also quickness of translational practice that indicates the hydrogel films as a promising candidate for oral ulcer management [68].

Specific Delivery of Medication in Oral Ulcers

These drug delivery systems are therefore critical for effective management of oral ulcers, as they provide localized action, prolonged residence time, and minimal systemic exposure during the course of treatment. Hydrogel films based on mucoadhesive and controlled-release approaches provide superior therapeutic performance over standard formulations [69]. Mucoadhesive polymers, that adhere to mucosal tissues by hydrogen bonding or electrostatic interactions with mucin at a polymer–tissue interface, provide retention of drugs at ulcerated sites and protection from salivary wash out and mechanical disruption. This leads a local persistence of the drug concentration and promotes healing [70]. Diffusion, swelling,and polymer degradation mechanisms enable controlled and sustained release, as well as stimuli-responsive hydro-gels for tailored, site-specific drug delivery. Such systems can provide therapeutic levels over longer periods and, thus, less frequent dosing. Moreover, localized delivery will limited the amount of drugs entering systemic circulation, reducing side effects and improving safety. Improved elasticity of hydrogel films enables flexibility, enhanced comfort and easier application of the films improves compliance and acceptability in patients leading to better adherence and higher success rates of therapy on oral ulcers [71].

Regulatory and Safety Considerations

Green-synthesized and functionalized hydrogel films as innovative formulations for the targeted and sustainable treatment of oral ulcers has multiple pharmacological effects for localized and controlled drug delivery. Fluorochlorophylls and oleogels offering phytochemicals, nanoparticles and stimuli-responsive components are used as hydrogel films to overcome the inflammation, microbial infection and oxidative stress caused due to oral ulcers [72]. Their mucoadhesive properties provide a longer duration of retention at the site, in turn increasing drug bioavailability and eliminating dosing frequency [8]. Functionalization strategies are also applied to enhance specificity and therapeutic potency while reducing systemic drug toxicity. Green fabrication techniques also foster sustainability and safety in the ecosystem. While there has been success, it also creates challenges around standardization, scalability and regulatory compliance. Ongoing research integrating nanotechnology, smart materials and Quality by Design principles will likely accelerate clinical translation. In summary, these new hydrogel platforms provide enormous promise in the vision of developing novel approaches towards safe, efficient and patient-compliant therapies for oral ulcer management [73].

Challenges and Limitations

However, there are several challenges to the widespread clinical and industrial application of green-synthesized and functionalized hydrogel films. However, performance and shelf-life can be limited through stability concerns including a susceptibility to moisture and degrading natural ingredients. Natural products offer problems with reproducibility due to quality variances between plants within a batch or from different batches. In addition, limited clinical evidence and regulatory challenges have crippled their translation into approved therapies. From an industrial feasibility perspective, this includes high production costs and often rather complicated scaling of green fabrication processes. Success in their commercialization and therapeutic uptake clinically often requires the resolution of these challenges through highly standardized protocols, innovative formulation approaches, and appropriate clinical validation.

Future Perspectives And Emerging Trends

Future outlooks regarding green synthesized hydrogel films focus on the design of smart systems that respond to oral stimuli for site-specific and controlled release. Integration with nanotechnology improving targeting, bioavailability and multi-function specially therapeutic activity. Personalized medicine approaches aim to customize formulations according to individual patient requirements as well as disease environments. With widespread use of advanced tools such as artificial intelligence and Quality by Design (QbD), systematic optimization can result in improved reproducibility and efficient scalability. Moreover, these novel systems may provide a clinical utility for other mucosal disorders. Altogether these emerging trends are expected to accelerate next-generation, patient-centric drug delivery solutions.

CONCLUSION

Green approaches to synthesis have redefined the hydrogel development paradigm by informing more sustainable yet sophisticated therapeutic function, as observed in oral ulcers. Adoption of green chemistry principles guarantees biocompatible materials, avoid potential toxic reagents, minimize environmental effects and assure improved clinical safety and acceptance. This versatility of natural polymers provides a suitable natural bioactive design scaffold for hydrogel film by having intrinsic antimicrobial, mucoadhesive and wound healing properties like in chitosan or alginate. In addition, plant-mediated crosslinking and functionalization bring additional therapeutic advantages by offering phytochemicals, allowing combined anti-inflammatory, antioxidant and immunomodulatory effects. The integration of green-synthesized nanomaterials significantly enhances the efficacy of hydrogel systems, which is responsible for their improved drug-delivery efficiency, targeting ability and antimicrobial activity. The controlled release allows local application and these hybrid systems successfully tackle the complex pathophysiology of oral ulcers. Nonetheless, key obstacles to commercialization emerge from reproducibility, scalability and regulation standardization issues. The combination of green synthesis with developing technologies including Quality by Design, artificial intelligence, and stimuli responsive materials is anticipated to remedy these limitations in the future. In conclusion, green synthetic hydrogel films contribute to sustainable, multifunctional approach for the next-generation oral ulcer treatment.

ACKNOWLEDGEMENT

The authors are thankful to the researchers and scholars for their published work on green-synthesized and functionalized hydrogel films in terms of targeted oral ulcer therapy, which has greatly assisted in developing this review article. The authors further acknowledge the financial assistance of online scientific databases, digital library and journal repository of The Assam Royal Global University which provided access to requisite research literature essential for finalisation of this review. The authors also mention that they received no funding for this work.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ABBREVIATIONS

OU: Oral Ulcer; RAU: Recurrent Aphthous Ulcer; TMDD: Transmucosal Drug Delivery; HGF: Hydrogel Film; GSNPs: Green-Synthesized Nanoparticles; QbD: Quality by Design; ROS: Reactive Oxygen Species; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; MMPs: Matrix Metalloproteinases; SEM: Scanning Electron Microscopy.

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Bipul Nath
Corresponding author

Department of Pharmacy, Royal School of Pharmacy, The Assam Royal Global University, Betkuchi, Guwahati, Assam-781035, INDIA.

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Rabina Kalita
Co-author

Department of Pharmacy, Royal School of Pharmacy, The Assam Royal Global University, Betkuchi, Guwahati, Assam-781035, INDIA.

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Mukta Agrawal
Co-author

Department of Pharmacy, Royal School of Pharmacy, The Assam Royal Global University, Betkuchi, Guwahati, Assam-781035, INDIA.

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Anushriya Talukdar
Co-author

Department of Pharmacy, Royal School of Pharmacy, The Assam Royal Global University, Betkuchi, Guwahati, Assam-781035, INDIA.

Rabina Kalita, Mukta Agrawal, Anushriya Talukdar, Bipul Nath*, Green-Synthesized and Functionalized Hydrogel Films for Targeted Oral Ulcer Treatment, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 6131-6150. https://doi.org/10.5281/zenodo.20352327

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