Glaucoma is a degenerative disease of the optic nerve characterized by changes in the optic nerve and damage to the visual field, caused by various underlying factors [1]. It has now emerged as the leading cause of irreversible blindness worldwide ^[2][3][4][2,3,4]. The term “irreversible blindness” indicates that once glaucoma damages or blinds a patient’s visual function, current technology cannot fully restore their vision to its previous level. Globally, glaucoma primarily affects individuals over the age of 40, encompassing approximately 3.54% of the total population. Alarmingly, it is projected that the number of individuals afflicted by glaucomatous blindness will reach 118.8 million by 2040 ^[3][5][6][3,5,6]. This condition not only significantly impacts an individual’s quality of life but also imposes substantial personal and socio-economic burdens [7]. As a result, glaucoma is poised to become a critical public health issue in the coming decades, demanding heightened attention and awareness [8].

The biological basis of glaucoma has not been completely figured out, and the factors contributing to its occurrence and development are not fully understood, thereby limiting clinical treatment options [5]. In recent years, long-term clinical trials completed by researchers have provided convincing evidence linking intraocular pressure (IOP) to retinal ganglion cell death, indicating that reducing IOP can effectively prevent the progression of early and late glaucoma ^[9][10][11][9,10,11]. Consequently, researchers consider reducing IOP as the primary and most effective method for glaucoma treatment [6]. The main goal of glaucoma treatment is to delay the progression of the disease and preserve the quality of life of patients. Clinicians believe that achieving the target IOP level can effectively slow down the advancement of glaucoma and prevent further functional impairment. The determination of the target IOP level for a specific eye depends on factors such as the patient’s IOP, the extent of fundus damage, and visual field impairment ^[9][12][9,12]. It is essential to achieve the target IOP level with the minimum number of drugs, minimal adverse reactions, and optimal patient compliance. Glaucoma treatment mainly involves the use of drugs or surgery to reduce high IOP in patients, with non-surgical drug treatment being the primary approach employed at present ^{[2][13][14][15]}[2,13,14,15].

In recent years, the rapid development of drug encapsulating systems with polymers as carriers has been fueled by the significance of polymers as essential structural, functional, and intelligent materials, coupled with their excellent biocompatibility. A polymer drug delivery system is defined as a preparation or device that efficiently introduces therapeutic substances into a specific targeted location ^[16][24]. Numerous studies have demonstrated that polymer drug delivery systems can achieve continuous drug delivery to the eye, effectively enhancing the bioavailability and compliance of drugs ^{[17][18][19][20][21]}[25,26,27,28,29].

2. Polymer-Based Delivery Systems for Glaucoma Treatment

The primary objective of glaucoma drug treatment is to reduce intraocular pressure, requiring most patients to undergo long-term medication for its control. However, the treatment’s effectiveness is often hindered by the low bioavailability and poor compliance of drugs. Thus, the development of a drug delivery system that is capable of sustained release becomes crucial ^[10][22][10,30]. In clinical settings, glaucoma drugs can be categorized based on their mode of action. Some drugs, such as α-adrenergic agonists, β-receptor blockers, and carbonic anhydrase inhibitors, work by reducing aqueous humor production. Others, such as prostaglandins, rho kinase inhibitors, nitric oxides, and mitotic or cholinergic drugs, facilitate fluid discharge from the eye. The polymer self-assembling drug delivery system represents an advanced and versatile drug delivery technology. This system offers precise control over drug release rates and timing, making it a valuable tool for achieving highly controllable drug release properties. Moreover, polymers play a pivotal role in shielding drugs from physical and chemical degradation, enhancing drug stability, and preserving their potency. One of the key advantages of polymer self-assembling drug delivery systems is their ability to encapsulate drugs within polymeric nanoparticles. This encapsulation can significantly enhance drug bioavailability. Polymeric drug delivery systems offer a solution to overcome the multiple barriers presented by the eye, enabling enhanced drug attachment, permeability, and sustained release on the cornea. To achieve this, several key strategies can be employed in the design of polymeric drug delivery systems: (1) Choose polymeric materials known for their excellent biocompatibility and biodegradability. This not only enhances the safety profile of polymeric carriers but also ensures minimal adverse effects. (2) Enhance the affinity of the polymer carrier to the cornea through surface modifications. This step helps improve the interaction between the carrier and the corneal tissue. (3) Boost the drug’s corneal permeability by incorporating penetration enhancers into the formulation. These enhancers facilitate the drug’s ability to traverse the corneal barriers effectively. (4) Utilize appropriate drug encapsulation technologies to ensure efficient drug loading, thereby achieving controlled release and prolonged therapeutic effects. (5) Leverage nanotechnology to create drug delivery nanoparticles with high surface area and permeability, enhancing the drug’s penetration into the cornea. (6) Design environmentally responsive polymer carriers capable of achieving targeted drug release in response to various ocular environmental conditions. These strategies collectively aim to prolong drug residence time on the cornea, improve permeability, and mitigate systemic side effects, ultimately enhancing the effectiveness of ocular drug delivery.

2.1. Eye Drops

Eye drop administration is the most convenient method to deliver ocular surface drugs for treating glaucoma with ocular hypertension. However, blinking, tear flushing, and the complex anatomical structure of the tear film and cornea reduce the bioavailability of drugs, leading to poor drug compliance ^[23][38]. To address these issues, the design strategy for eye drops should focus on increasing the residence time of drugs in the cornea, enhancing bioavailability, improving therapeutic effects, and ensuring good histocompatibility to enhance drug compliance ^[24][39]. During the process of physiological blinking, ocular shear force and tear wash are generated, which enables polymers or pseudoplastic fluids with appropriate viscosity to maintain higher drug concentrations on the ocular surface. Mucins present on the ocular surface attach to the tear film surface and carry a negative charge. This makes it more likely that positively charged eye drops and drug carriers will remain on the ocular surface. The design strategy for eye drops should involve selecting an appropriate polymer with good biocompatibility, adjusting the polymer carrier’s structure to endow it with appropriate viscosity and positive charge, and ensuring efficient drug loading capabilities. These modifications are conducive to increasing drug retention time in the cornea, thus improving bioavailability. Moreover, the sustained release of drugs further enhances medication compliance and ultimately improves the therapeutic effect ^[25][40]. Increasing the viscosity of eye drops is a straightforward approach to extend the retention time of drugs on the ocular surface, thereby enhancing their bioavailability ^[26][19]. At present, one of the methods to achieve higher viscosity is by using polymer thickeners, such as hyaluronic acid, polyvinyl alcohol, cyclodextrin, and others ^[27][41].  Enhancing adhesion to the mucin layer is an effective means to increase the retention time of drugs in the cornea. Researchers have predominantly chosen polymer chitosan with cationic groups due to the negative electrical characteristics of the mucin layer ^[28][44]. Mohan et al. developed chitosan micelles capable of interacting with mucins on the corneal surface by polymer self-assembly, loaded with the IOP lowering drug brinzolamide, with a micelle particle diameter of 74.32 ± 1.46 nm, resulting in improved corneal permeability ^[29][45]. The particle size of the polymer carrier in eye drops plays a crucial role in drug delivery efficiency. The scope of nanomedicine encompasses dimensions ranging from 1 to 1000 nm ^[30][50]. This dimension range is crucial because drugs are loaded into nanoparticles at the nanoscale, offering several advantages. These advantages include improved drug pharmacokinetics, and pharmacodynamics, reduced non-specific toxicity, lower immuno-genicity, and enhanced biocompatibility. Ultimately, these benefits contribute to the overall therapeutic efficacy of drugs ^[31][32][51,52]. Nanoscale drug delivery systems hold significant potential in the treatment of glaucoma ^[33][53]. 

2.2. Hydrogels

Hydrogels, which are formed by the crosslink and self-assembly of polymers or low molecular weight molecules, with hydrophilic functional groups that can bind a large number of water molecules, making them ideal drug carriers with flexible characteristics similar to living biological tissues. In the treatment of glaucoma, reducing the frequency of medication to achieve therapeutic effects is a common approach to improve patient compliance. Due to their unique structure and properties, eye hydrogels have the potential to replace conventional eye drops, offering promising benefits ^[34][35][35,57]. In the design of hydrogels for glaucoma treatment, researchers have focused on developing ocular environmentally responsive gels that respond to factors such as temperature, pH, and ions. Key parameters, including in situ gel-forming ability, drug encapsulation and release, ocular biocompatibility, and biodegradation, are carefully considered when selecting suitable polymer hydrogel systems. These chosen systems can construct ocular hydrogel drug-loading systems with environmental responsiveness, in situ gel-forming ability, high drug loading, effective drug delivery, long-term drug release, and good biocompatibility, ultimately enhancing the bioavailability of drugs and patient compliance ^{[17][36][37][38]}[25,31,58,59]. Ophthalmic thermosensitive hydrogels are widely used, with physiological temperature serving as a response factor for in-situ gel formation ^[39][60]. Typically, ocular thermosensitive hydrogels are composed of biocompatible polymers. Upon contact with the eye, these hydrogels swiftly transition into a gel state, extending their retention time within the eye and ensuring long-lasting adhesion. Khallaf et al. developed a thermosensitive in-situ gel using poloxamer 407 and adhesive hydroxypropyl methylcellulose, loaded with a fasudil complex with phospholipid. In a solution, surfactant molecules undergo self-assembly to create micellar structures once the polyoxyethylene poloxopropylene block copolymer Poloxamer 407 reaches the Critical Micelle Concentration value. This formulation improved the bioavailability of the drug and significantly reduced intraocular pressure in a rabbit glaucoma model ^[40][54].  Ocular pH-responsive hydrogels utilize the ocular pH as a key factor for in situ gel formation. These pH-sensitive hydrogels exhibit responsiveness to pH due to the presence of acidic or basic groups within the polymer network that can undergo ionization. For example, a common polymer like Carbopol^® 934P contains carboxyl groups that play a pivotal role in the polymer’s self-loading process. Allam et al. successfully prepared a pH-responsive in situ gel by loading betaxolol with Carbopol^® 934P and hydroxyethyl cellulose. This gel exhibited high viscosity and adhesion, leading to improved drug retention and bioavailability in the eye. In glaucoma rabbit eyes, the relative bioavailability of the drug with this gel compared to free betalol eye drops was as high as 254.7% ^[41][67].  To enhance the bioavailability and compliance of drugs, researchers have developed a dual environmental-responsive ocular hydrogel drug loading platform through a self-assembling cross-linking strategy. Rawat et al. created a temperature/ion-responsive in situ gel for the adrenergic antagonist nebivolol (NEB). The gel employed poloxamers (poloxamer-407 and poloxamer-188) as a thermoresponsive component and kappa-carrageenan as an ion-sensitive component. The optimized dual-responsive in situ gel exhibited desired flow characteristics at room temperature and rapidly underwent a sol-gel transition in the presence of simulated tear fluid (STF) at physiological temperature. The dual-responsive in situ gel achieved a sustained-release rate of 86% over 24 h, and it was well-tolerated in the eye, effectively treating glaucoma.

2.3. Contact Lenses

Contact lenses offer the advantage of easy wear and direct contact with the tear film on the ocular surface. With drug loading capabilities, they serve as an alternative to traditional eye drop administration, making them an attractive drug delivery system for glaucoma treatment requiring long-term effective drug delivery to maintain normal intraocular pressure. Studies have reported that contact lens drug delivery systems can extend drug release for several days or even months ^[34][42][43][35,37,75]. When designing contact lens drug loading systems, the drug addition and loading method influence the transparency, swelling, and adhesion of the lenses. Common drug loading methods include soaking drug loading, molecular imprinting technique, and direct loading of drug colloidal particles. Choosing an appropriate drug loading method can improve the long-term effective drug release, bioavailability, and compliance ^[44][76]. The immersion drug loading method for contact lenses is a feasible and simple approach. For instance, Costa et al. successfully impregnated two anti-glaucoma drugs (acetazolamide and TM) into commercial silicon-based polymer hydrogel contact lenses (Balafilcon A) using intermittent supercritical solvent impregnation, obtaining a favorable drug release performance ^[45][77].

3. Summary

Glaucoma causes irreversible blindness and significantly impacts patients’ health and quality of life, resulting in a considerable economic burden on both individuals and society. Currently, the main treatment method to alleviate glaucoma’s progression involves drug therapy to reduce high IOP. However, due to the multiple barriers of the eyes, achieving effective treatment and patient compliance with drug therapy has become a major challenge. Urgent action is needed to develop more efficient and patient-friendly solutions.

Eye drops are a more widely accepted treatment option for the public, but they currently suffer from issues such as low drug utilization and poor compliance with frequent administration, leading to suboptimal therapeutic outcomes for glaucoma. Hydrogels and contact lenses loaded with intraocular-pressure-lowering drugs have emerged as the primary alternatives to traditional eye drops in glaucoma treatment. Compared to hydrogels with single ocular environmental response factors, hydrogels with multiple responses offer more advantages in improving drug bioavailability and compliance. However, this undoubtedly increases the complexity of hydrogel materials. Therefore, it is necessary to optimize the materials based on the relationship between the structure and properties of responsive polymers, allowing less content of the drug hydrogel carrier to achieve better response performance. Polymer drug delivery systems face challenges in treating glaucoma, and cross-linking technology or self-assembly strategies offer effective solutions for their design. Cross-linking technology and self-assembly strategies are excellent approaches for enhancing polymer drug delivery systems in glaucoma treatment. Cross-linking generates a robust biological network structure that can efficiently load and release drugs, improving targeting and bioavailability. Additionally, nanoparticles can self-assemble, incorporating various functionalities such as magnetic properties. This self-assembly feature opens up the possibility of precise drug delivery through the use of magnetic fields, which can guide the carrier to the intended target location. This approach has found extensive application in the treatment of cancer-related diseases and offers innovative avenues for addressing glaucoma.