Recent Advances in Hydrogels for the Diagnosis and Treatment of Dry Eye Disease

Dry eye disease (DED) is a complex ocular surface disorder occurring when the tears cannot provide sufficient lubrication for the eyes, which causes eye discomfort, damage to the eye tissues, or even significant loss of vision [1]. The prevalence of dry eye has been established to range from 14% to 33% of the general population, and 17% to 33% of the Asian population, giving rise to economic burdens to both the patient’s family and society [2,3]. According to the structure and function of the tear film, dry eye is clinically divided into two major types: reduced tear production and the increased evaporation of the tear film [4]. These conditions are not mutually exclusive; in fact, they often overlap. Patients with reduced tear production usually show a low Schirmer I test result, and patients with increased evaporation of the tear film show a tear film break-up time (TFBUT) that is reduced. Ocular surface damage and elevated tear film osmolarity can occur in both forms [5]. Recent studies found that the pathophysiology of DED is complex, and dry eye is a multifactorial and self-perpetuating inflammatory disease [6]. Both intrinsic factors, such as female gender, aging, Asian ethnicity, Sjögren’s syndrome, and systemic diseases, and extrinsic factors, such as the extensive use of cell phones and computers, environmental pollution, smoking, drug use, local inflammation of the eye, eye surgery, and contact lens wearing, can contribute to instable tear film [7] and increased tear osmolarity. Consequently, the stress signaling pathways are activated and inflammation is initiated [8].

It is necessary to distinguish dry eyes from eye infections and allergies through accurate diagnosis. If epitheliotoxic antibodies or antiallergic drugs are prescribed on the basis of an incorrect diagnosis, the symptoms of dry eyes may worsen [5]. The clinically available tests are summarized in Table 1. Tear osmolarity, which is superior to almost all other DED tests, is considered a reliable diagnostic test for detecting dry eye [9,10]. Tear secretion and the tear film break-up time, corneal staining score, conjunctival staining score, tear osmolarity, and questionnaire score are other clinically available methods for diagnosing dry eye [11,12]. Although these tests are routine and necessary for diagnostics in the detection of dry eye disease, it is difficult to obtain high specificity and high sensitivity simultaneously. Moreover, due to the multifactorial pathogenesis of dry eye, it is difficult to standardize the diagnosis of dry eye. The determination of the physiological characteristics and biomarkers of tears, including the pH (H₃O⁺/OH⁻) [13], electrolytes (Na⁺, Cl⁻) [13], lysozyme [14], lactoferrin [14,15], interleukin proteins (IL-1α, IL-1β, and IL-17) [16], tumor necrotic factor (TNFα) [17], interferon gamma (IFNγ) [18], matrix metalloproteinase-9 (MMP-9) [19], and mucins [20], can provide a more critical determination of DED. These tests, however, are limited by the need for specialized equipment, poor environmental stability of protein assay kits, or the use of expensive molecular detection reagents (i.e., antibodies). Therefore, there is an urgent demand for faster, more affordable, and easy-to-use biosensors that can be used to diagnose dry eyes.

Based on the symptoms and the clinical exam findings, DED is classified into mild, moderate, and severe levels. The treatment of dry eyes depends on the pathophysiology and severity level. Clinically, drugs for the treatment of DED include (I) lubricating agents, such as artificial tears and sodium hyaluronate eye drops; (II) anti-inflammatory drugs, such as glucocorticoids, cyclosporine A, and non-steroidal anti-inflammatory drugs; (III) sex hormones; (IV) secretagogues, such as pilocarpine eye drops; and (V) autologous serum eye drops [5,21,22]. Given its noninvasiveness and ease of administration, the topical administration of eye drops is the most common early treatment method for dry eyes. However, due to the complex structure of the eye surface, rapid clearance caused by tear dilution and the lacrimal drainage system leads to a low bioavailability, short retention time, and, subsequently, low efficacy [23]. An increased dose is often adopted to address this problem, which unfortunately increases the risk of systemic side effects due to the conjunctival absorption of drug molecules by the blood through the nasolacrimal system [24]. Severe dry eyes can be treated by surgery, such as autologous gland duct transplantation, palpebral suture, amniotic membrane transplantation, and submandibular and labial gland transplantation [25,26]. Therefore, the early cure of dry eyes through control-released drugs is promising.

Hydrogels are highly hydrophilic materials with a three-dimensional polymer network, which swell rapidly in water and maintain a large volume of water without dissolving this swelling state [27]. A wide range of natural, semisynthetic, and synthetic polymers can be used as starting materials for hydrogels [28]. Chitosan, hyaluronic acid (HA), carbopol, sodium alginic acid, poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), acrylic polymers, and siloxanes are representative polymers for synthetic gel-forming materials [29,30,31,32,33,34]. Drug-loading platforms, such as nanoliposomes and solid nanoparticles, can be incorporated into hydrogels for disease treatment [35,36]. The methods used for preparing hydrogels include chemical cross-linking (covalent bond) and physical cross-linking (non-covalent bond) [37]. Chemical cross-linking can lead to good mechanical strength in the hydrogels [38]. It is worth noting that, some small-molecule chemical crosslinkers and initiators are not environmentally friendly or are even toxic [39]. Physical cross-linking is usually achieved by means of electrostatic interaction, hydrophobic interaction, hydrogen bonding, etc., which can be reversible and rapidly rebuilt without any external factors [40].

The designed hydrogels can have good biocompatibility, excellent physical and mechanical properties, and long-term implant stability. Much emphasis has been placed on research on hydrogel as an ophthalmic biomaterial, and its main applications include long-term drug delivery on the ocular surface [41], the sustained release of long-acting drugs in the eye [42], corneal injury repair [43], artificial vitreous [44], and so on. These hydrogels can be retained in the eyes for a long time, reducing the adverse reactions caused by the systemic absorption of the drug, and their tolerance is better than that of ointment. Importantly, hydrogels have been studied in drug delivery because they can hold many different substances in the crosslinked matrix. They range from hydrophobic and hydrophilic molecules to micromolecules and macromolecules. Polymer microgels and nanogels, as non-imprinted hydrogels capable of semi-selectively recognizing proteins, do not match antibodies in terms of selectivity. Still, they are highly adjustable, based on inexpensive materials, and environmentally robust, suggesting that they are favorable substances for treating ocular disease. Moreover, we can implant these biosensors into hydrogel contact lenses (CLs) to continuously monitor the tear status [45].

Hydrogels are emerging drug-delivery platforms which offer many advantages for diagnosing and treating DED. The good transparency and biocompatibility of hydrogels are prerequisites for their applications in the field of ophthalmology [46]. Hydrogels have great prospects for application in the improvement of corneal permeability, drug bioavailability, and the prolongation of the drug retention time on the ocular surface [47]. Moreover, hydrogels can be used as materials for contact lenses which can not only provide protection and hydration but also be designed as drug carriers to improve the bioavailability and prolong the retention time of drugs on the ocular surface. In addition to the protective and hydrating functions of hydrogel contact lenses, the drug-loaded hydrogel contact lenses can prolong the retention time of the drug on the ocular surface [48,49]. There is a highly controversial issue between dry eye treatment with CLs and dry eye patients. It is widely thought that dry eye is more common among CLs wearers. Interestingly, dry eye can be relieved and treated by adding some drugs to CLs, including rewetting agents or anti-inflammatory drugs [50,51].

The past decade has witnessed significant headway achieved in research on the etiology of dry eye, which has led to the emergence of many clinical therapeutic drugs, thus significantly improving the quality of life of patients with dry eye. The hydrogels used in ophthalmology include artificial tears, drug carriers, CLs, adhesives, etc. Here, we review the recent advances in the diagnosis and clinical treatment of dry eye with hydrogels.

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