Therapeutic applications of contact lens-based drug delivery systems in ophthalmic diseases

Abstract

Traditional ophthalmic drugs, such as eye drops, gels and ointments, are accompanied by many problems, including low bioavailability and potential drug side effects. Innovative ophthalmic drug delivery systems have been proposed to overcome the limitations associated with traditional formulations. Recently, contact lens-based drug delivery systems have gained popularity owing to their advantages of sustained drug delivery, prolonged drug retention, improved bioavailability, and few drug side effects. Various methods have been successfully applied to drug-loaded contact lenses and prolonged the drug release time, such as chemical crosslinking, material embedding, molecular imprinting, colloidal nanoparticles, vitamin E modification, drug polymer film/coating, ion ligand polymerization systems, and supercritical fluid technology. Contact lens-based drug delivery systems play an important role in the treatment of multifarious ophthalmic diseases. This review discusses the latest developments in drug-loaded contact lenses for the treatment of ophthalmic diseases, including preparation methods, application in ophthalmic diseases and future prospects.

Keywords:

• Drug delivery
• contact lens
• ophthalmic diseases
• polymer material

1. Introduction

Due to special anatomical and physiological factors, eyes are prone to various diseases such as keratitis, cataract, glaucoma and retinopathy, which endanger the health of patients and affect their quality of life. Currently, vision impairment due to ophthalmic diseases is the primary cause of disability worldwide. By 2015, 34.3 million blind people, 24.3 million people with severe visual impairment, and 214 million with moderate visual impairment were reported worldwide (Stevens et al., 2013). Therefore, the active prevention and treatment of ophthalmic diseases is crucial.

Topical drug delivery is the most widely preferred route of drug administration to treat ophthalmic diseases such as keratitis, conjunctivitis, dry eye disease, glaucoma, uveitis and so on. To date, there are multifarious forms of traditional ophthalmic drugs, and approximately 90% of drugs are administered in the form of eye drops (Patel et al., 2013). Owing to the complicated structure of eye, lipophilicity of corneal epithelium, defense mechanisms, bonding of drug with proteins contained in tears, enzymolysis, and metabolism, traditional ophthalmic drugs have disadvantages such as low bioavailability and potential drug side effects. In addition, many patients (especially elderly patients) have difficulties in correctly instilling the eye drops, which can reduce the efficiency of the drug and even lead to potential contamination of a chronically used bottle. All these factors limit their development (Table 1) (Stone et al., 2009; Hennessy et al., 2010; Toda et al., 2011; Ali et al., 2016; Awwad et al., 2017; Mutlu et al., 2019; Akhter et al., 2022).

Table 1. Characteristics of different forms of traditional ophthalmic drugs.

Topical ophthalmic drugs	Advantages	Disadvantages
Drops (solutions, suspensions, emulsions)	simple preparation, low price and convenient use	low bioavailability, short ocular surface residence time, high potential side effects, and large fluctuations in drug concentration
Ointments	longer ocular surface residence time, higher absorption and utilization rate (compare with eye drops)	slow efficacy, blurred vision and low comfort
Gels	long contact time with cornea, less dose and frequency of use	blurred vision and low comfort
Periocular injection (subconjunctival, peribulbar, retrobulbar injection)	delivery drug to the anterior or posterior ocular tissues	pain and scarring; drug deposition; bleeding or optic nerve injury; compromised by ocular static and dynamic barriers
Intravitreal injection	no eye barriers effect, delivery drug to the posterior ocular tissues and directly work to the lesion site	intraocular infection, coagulation, retinal detachment, lens damage and drug toxicity

To overcome the limitations of traditional ophthalmic drugs, researchers are committed to developing innovative drug formulations with long residence times and high bioavailability. New formulations and improved methods have been continuously developed such as viscosity or permeation enhancers, cyclodextrins, nanoparticles, nanosuspensions, liposomes, dendrimers, polymeric gels, punctal plugs, iontophoresis and so on (Yellepeddi et al., 2015; Gote et al., 2019; Jumelle et al., 2020; Perez et al., 2020; Singh et al., 2020; Xu et al., 2021). Although these measures have achieved initial results eventually, they cannot completely avoid all defects of traditional ophthalmic drugs and also face their own challenges in preparation, quality control and application (Baranowski et al., 2014). Therefore, there is an urgent need to develop new drug delivery forms that could maintain pharmacokinetics and pharmacodynamics at least comparable to eye drops, and possess the characteristic of better bioavailability, high safety, good biocompatibility and fewer side effects. Also, this method should preferably provide extended drug release at a therapeutic rate. These factors make drug-loaded contact lenses an obvious choice.

Drug-loaded contact lenses, as new drug delivery tools that use different techniques to load ophthalmic drugs into contact lenses, have attracted considerable attention. Particularly, drug-loaded contact lenses can overcome the problem of incorrectly instilling eyedrops, and also can continuously release drugs from lens to tear film, prolong drug retention time on the ocular surface and improve bioavailability. In the past few years, the development of drug-loaded contact lenses has progressed rapidly, and the contact lens-based drug delivery systems have been proved to play an important role in preventing of keratitis, glaucoma, dry eye, color blindness, corneal injury, keratoconus, ocular scar, retinopathy, and other ophthalmic diseases (Figure 1) (White et al., 2011; Ciolino et al., 2014; Huang et al., 2016; Salih et al., 2021; Zhao et al., 2021a; Mun et al., 2022). To the best of our knowledge, there are no comprehensive and systematic review articles on the role of drug-loaded contact lenses in different ophthalmic diseases. Hence, we summarized the new progress of drug-loaded contact lenses with novel designs in different ophthalmic diseases.

Figure 1. Application of novel contact lenses in ophthalmic diseases.

2. Novel methods for preparing drug-loaded contact lenses

Until now, immersion method is the simplest way to prepare drug-loaded contact lenses. Nonetheless, owing to the influence of water content of the contact lens and molecular solubility of the drug, this method has disadvantages of low drug loading and fast release speed (Soluri et al., 2012). To improve the drug loading capacity and prolong the drug release, many innovations have been made in the lens production process, such as molecular imprinting, polymer nanoparticles, vitamin E barriers, drug polymer film/coating, ionic interactions, supercritical fluid technology, and so on (Table 2) (Bengani & Chauhan, 2013; Nasr et al., 2016; Maulvi et al., 2016a; Torres-Luna et al., 2019a; Varela-Garcia et al., 2020; Franco & De Marco, 2021; Li et al., 2021a).

Table 2. Summary of novel methods for preparing drug-loaded contact lenses and the application in ophthalmic diseases.

Ophthalmic diseases	Method	Active principle	Findings/Results	Reference
Bacterial keratitis	FRP	EGCG	Release drugs for 14 days and significantly reduce the adhesion of P. aeruginosa	Zhao et al., 2021a
	Coating	GMA	Against MRSA with killing efficacy >99.99%	Pillai et al., 2020
	Coating	Copper ions	Endows CLs with the ability to effectively inhibit biofilm formation	Liu et al., 2020
	Nanocoating	Zn-CuO	Endows CLs with significant antibacterial activity	Nahum et al., 2019
	MI	Polymyxin B, vancomycin	Effectively inhibit P. aeruginosa	Malakooti et al., 2015
	Coating	Melamine	Significantly reduce the incidence of P. aeruginosa keratitis in rabbit models	Dutta et al., 2013,2014,2016
	Coating	Mel4 peptide	Against major ocular pathogen such as P. aeruginosa and S. aureus	Dutta et al., 2018
	FRP	Antibacterial peptide, penicillin G	Reduce the growth of S. aureus and Escherichia coli	Gallagher et al., 2016
	DPF	Gentamicin sulfate, triclosan	Against Gram-positive bacteria and inhibit biofilm formation	Wang et al., 2016
	β-CD	Thiosemicarbazones	Effectively inhibit the growth of P. aeruginosa and S. aureus	Glisoni et al., 2013
	Membranes	Ciprofloxacin, tobramycin	Inhibit S. aureus and Escherichia coli during 48 h	Daza et al., 2020
	Nanocoating	Gallic acid	Presents high antibacterial efficiency against S. aureus	Hoyo et al., 2019
	Coating	Diclofenac	Reduce bacterial growth and extend the therapeutic period	Silva et al., 2020
	FRP	Sulfobetaine silane	Resist the adsorption of protein and lipid, and enhance antibacterial performance	Yeh et al., 2014
Fungal keratitis	NPs	Silver NPs, voriconazole	Improve fungal keratitis in 7 days	Huang et al., 2016
	Nanocoatings	Gallic acid, tobramycin	Showed significant antimycotic, biofilm inhibition and antifouling properties	Khan et al., 2021
	Vitamin E	Levofloxacin, chlorhexidine	Prolong release time of levofloxacin up to 100 h and chlorhexidine up to 170 h	Paradiso et al., 2016
	DPF	Econazole	Maintain 100% fungicidal rate within 3 weeks	Ciolino et al., 2011
Viral keratitis	MI	Acyclovir, valacyclovir	Release the drug in a sustained manner for 10 h	Varela-Garcia et al., 2020
AK	NPs	Fe3O4-PEG-Dy2O3 NPs	Effectively against Acanthamoeba sp.	Kusrini et al., 2021
	β-CD	Voriconazole, diclofenac	May treat AK	Morgan et al., 2020
NIK	DPF	Diclofenac sodium	Prolong drug release within therapeutic level up to 11 h	Carreira et al., 2014
	DPF	Vancomycin	Sustainably released for more than 8 h	Jeencham et al., 2020
Corneal wound healing	FRP	Rutin	Release rutin for 14 days and promote corneal would healing	Zhao et al., 2021b
	FRP	HA	Reduce ocular inflammatory symptoms in corneal healing model	Wei et al., 2022
	DPF	HA, silver	Prolong the retention time of HA and enhance corneal healing rate	Yin et al., 2021
	AIS	Electric stimulation	Stimulate corneal epithelial cells and accelerate wound healing	Wu et al., 2022
POD	DPF	Pirfenidone	Obviously increased the duration of pirfenidone	Wu et al., 2021a,2021b
DED	MI	HM	Release drug for up to 60 days and effectively combat DED	White et al., 2011
	NPs	Ceria NPs	Effectively remove reactive oxygen species and avoid DED	Choi et al., 2020
	NPs	HA	Release HA for up to 14 days and effectively treat DED	Akbari et al., 2021
	Coating	Graphene	Enhance dehydration protection effect	Choi & Park, 2017, Lee et al., 2017
Keratoconus, myopia	FRP	HA-RB conjugates	Enhance the permeability of RB and effectively achieve corneal collagen cross-linking	Mun et al., 2022
Ocular cystinosis	NPs	Gold NPs	Bind cystine to cure ocular cystinosis	Liu et al., 2021
	Vitamin E	Cysteamine, carbon black	Reduce transmittance about 50% and prolong the release of cysteine	Dixon & Chauhan, 2019
	Vitamin E	Cysteamine	Increases the release duration from 10 min to about 3 h	Hsu et al., 2013
Glaucoma	DPF	Latanoprost	Deliver a therapeutic amount of drug into the eye for at least one month	Ciolino et al., 2014
	NPs	TM	Extend drug release time from 1-2 hours to about 2-4 weeks	Jun et al.2012
	NPs	TM	Reduce intra ocular pressure for 192 h	Maulvi et al., 2016b
	DPF	Latanoprost	Sustained delivery of latanoprost by CLs is at least as effective as daily eye drops	Ciolino et al., 2016
	β-CD	Puerarin	CLs had better efficacy on lowering intraocular tension than eye drops	Hu et al., 2016
	MI	Bimatoprost	The release time of bimatoprost was prolonged	Yan et al., 2020
	MI	TM	Continuously release timolol maleate for glaucoma	Anirudhan et al., 2016
	FRP	TM	It’s an effective device for the enzyme-triggered delivery of timolol	Kim et al., 2014
	Blend film	Betaxolol hydrochloride	Prolong drug precorneal residence time and release drug for over 240 h	Zhu et al., 2018
	Nanocoatings	TM	Maintain the release of TM and provide an alternative dosage form for glaucoma	Mehta et al., 2019
	NPs, β-CD	Acetazolamide	Extend drug release time up to 3 h and simultaneously treat glaucoma and DED	Prakash & Dhesingh, 2017
	Vitamin E	TM, dorzolamide	Increased release time of both drugs to 2-days and show superior IOP reduction	Hsu et al., 2015
Uveitis	DPF	Dexamethasone	Inhibit corneal inflammation for 7 days and anterior uveitis for 5 days	Bengani et al., 2020
	MI	Bromfenac	Deliver bromfenac in vivo for 8 days	DiPasquale et al., 2022
Color vision deficiency	NPs	Gold NPs	Filter out optical wavelengths of specific colors, enhance color perception ability	Salih et al., 2021
	Metasurfaces	Metasurfaces	Shift back incorrectly perceived pigments closer to the original pigments	Karepov & Ellenbogen, 2020
	NPs	Polydimethylsiloxane	Offers a good color filter for color blindness correction	Roostaei & Hamidi, 2022
Diabetic-eye Complication	AIS	Photonic structure glucose sensor	Apply in quantitative glucose measurements at point-of-care settings	Elsherif et al., 2018
	FRP	Fresnel lens	Monitor glucose concentration and correct myopia or presbyopia	Elsherif et al., 2018
	FRP	Epalrestat	Continuously release epalrestat to prevent lens opacification	Alvarez-Rivera et al., 2018
	DPF	Dexamethasone	Inhibit retinal vascular leakage in the rabbit model of diabetic retinopathy	Ross et al., 2019

FRP: free radical polymerization, EGCG: epigallocatechin gallate, GMA: glycidyl methacrylate, CLs: contact lenses, MI: molecular imprinting, DPF: drug-polymer film, β-CD: β-cyclodextrin, NPs: nanoparticles, AK: acanthamoeba keratitis, NIK: noninfectious keratitis, HA: hyaluronic acid, AIS: artificial intelligence sensors, POD: proliferative ocular diseases, DED: dry eye disease, HM: hydroxypropyl methylcellulose, RB: rose bengal, TM: timolol maleate.

2.1. Molecular imprinting

Molecular imprinting is a polymer synthesis technology that uses a template-mediated polymerization mechanism to synthesize macromolecular networks with tailored affinities, capacities, and selectivity for template molecules (White & Byrne, 2010). The drug is first polymerized with the functional monomer and then extracted after polymerization, leaving a high-affinity drug-recognition cavity in the polymer network. While reloading, drugs can bind with high-affinity cavities to increase the partition coefficient and interact with functional groups in the polymer network to reduce the diffusivity and prolong the release time (Lanier et al.,2020; Zhang et al., 2020). Currently, this technology is widely used to produce drug-loaded contact lenses with sustained release time. Tieppo et al. demonstrated that the residence time of ketotifen for imprinted lenses was 4 and 50 fold greater than non-imprinted lenses and eye drops, respectively (Tieppo et al., 2012). Omranipour et al. studied the binding and release characteristics of brimonidine imprinted soft contact lenses and found that all imprinted polymers had higher affinity for brimonidine than non-imprinted polymers, demonstrating the positive effect of the molecular imprinting technique on improving the capacity for drug loading and sustained release (Omranipour et al., 2015).

2.2. Polymer nanoparticles

In this technique, drugs are encapsulated with colloidal nanoparticles (polymer nanoparticles, nanoparticles, etc.) and then dispersed into the polymerization medium of unreacted monomers to prepare contact lenses (Maulvi et al., 2016a). In many cases, drug molecules need to diffuse out of the nanoparticles and travel through the lens matrix to reach tear film, which generate low diffusion and long release time (Jung & Chauhan, 2012). Besides, drug-loaded nanoparticles can enhance drug efficacy by preventing drug interactions with polymer mixtures and avoiding drug metabolism caused by enzymes like lysosomes in tears (Maulvi et al., 2016a). Many studies have shown that nanoparticle-loaded hydrogels could be used for extended-delivery drugs. Nasr et al. studied the effects of nanoparticles loading on drug release and found that the hydrogel embedded with nanoparticles can release the drug for a period of 12 days (Nasr et al., 2016). In addition, studies about the effects of gold nanoparticles on the loading and delivery of drugs in contact lenses have confirmed that gold nanoparticles can increase drug uptake from soaking solution and improved the release kinetics without affecting the critical properties of contact lenses for therapeutic application (Maulvi et al., 2019; Li et al., 2021b). Drug-loaded nanocontact lenses have successfully achieved controlled and sustained drug delivery, which is a promising approach to treat ophthalmic diseases (Rodrigues et al., 2020; Khan et al., 2021; Kusrini et al., 2021; Liu et al., 2021; Maulvi et al., 2021; Li et al., 2021a).

2.3. Vitamin E barrier

Vitamin E barrier is a measure to reduce drug delivery rate and extend the release time by setting barriers on the drug transport path. Vitamin E can extend drug-release time through different mechanisms. Hydrophilic drug molecules can be forced to diffuse out of the lens through tortuous pathways, whereas hydrophobic drug molecules can be dissolved at high concentrations (Paradiso et al., 2016; Sekar & Chauhan, 2019; Liu et al., 2022). As reported, adding vitamin E to the lenses preserves visible light transmission and other properties. Vitamin E integration does not affect latanoprost transport and can make the bioavailability of bimatoprost greater than 50% (Sekar & Chauhan, 2019). Rad et al. found that when contact lenses were soaked in vitamin E solutions, the water content was significantly reduced, the betamethasone loading capacity enhanced, and the release rate decreased. What’s more, they also found applying vitamin E loading solutions, with 0.1 and 0.2 g/mL concentrations, could effectively enhance cipro release time from 2 hours (in a non-vitamin E–loaded lens) to 14 to 17 and 30 to 33 days, respectively (Rad et al., 2016; Rad & Mohajeri, 2017). Moreover, the strong antioxidant properties of vitamin E can improve the stability of combined drugs, protect the cornea from UV radiation, and inhibit the process underlying conditions such as cataracts and age-related macular degeneration (Palazzo et al., 2020; Tanito, 2021; Edwards et al., 2022). The advantages of vitamin E in prolonging drug release time without affecting important properties of lens and the strong antioxidant properties are beneficial for the development of drug delivery contact lenses.

2.4. Liposomes

Liposomes are composed of lipid bilayers with stable hydrophobic, hydrophilic or amphiphilic functions and good biodegradability, which are often used as drug delivery carriers. Owing to their special structure, hydrophilic drugs can be encapsulated in the aqueous center surrounded by hydrophilic head, while hydrophobic drugs can be anchored in the hydrophobic tail (Lanier et al., 2020). Liposome particles can break down and allow the drug to spread freely through the contact lens matrix before being released into tear film; they can also penetrate the lens and lipid layers of target cells before rupturing and releasing the encapsulated drug, which can prolong the drug release from contact lenses (Sercombe et al., 2015; Jain & Shastri, 2011). Danion et al. demonstrated that contact lenses bearing surface-immobilized layers of intact liposomes loaded with levofloxacin can provide a sustained release over 6 days, which showed antibacterial activity against Staphylococcus aureus (S. aureus) (Danion et al., 2007). In addition, ciprofloxacin released from the liposomes coated on the contact lenses can inhibit both Pseudomonas aeruginosa (P. aeruginosa) and S. aureus, and approximately 40% of ciprofloxacin was retained up to a period of 3 months at 4 °C (Jain & Shastri, 2011). The liposome system is highly specific for the sustained application of the drug.

2.5. Ionic interactions

Because ophthalmic drugs are mostly charged under physiological conditions, ionic interactions can be used to increase drug binding to the substrate. The hydrophobic interactions between ionic surfactants and gel polymers and the electrostatic interactions with drugs can lead to stronger adsorption. Ionic drugs can be adsorbed on surfactant-covered polymers to reduce the transport rate and prolong the release time. Torres-Luna et al. incorporated the microemulsion approach with a cationic surfactant in the fabrication of contact lenses and found that cationic surfactant and microemulsions at low cetalkonium chloride weight percentage could prolong the release time (Torres-Luna et al., 2019b). The partition coefficient of the drug exponentially increased with surfactant loading in the gel, and drug release duration was increased from about 2 hours to 50 hours in 1-day ACUVUE contact lens (with 10% surfactant). Furthermore, ionic surfactants can increase wettability and reduce the adsorption of proteins without affecting the lens transparency (Bengani & Chauhan, 2013; Bengani et al., 2013). These advantages make ionic interactions effective for preparing drug-loaded contact lenses.

2.6. Supercritical fluid technology

Supercritical fluid technology is a way that uses supercritical solvents such as CO₂ to load/impregnate hydrophilic and hydrophobic drugs into contact lenses. Braga et al. investigated the loading of hydrophobic drug into soft contact lenses using a supercritical fluid-assisted molecular imprinting method. They found both the loading amount and sustained release time of drug were improved after the lens processed by supercritical fluid, and can be controlled by adjusting operating parameters including pressure, temperature and decompression rate (Braga et al., 2010, 2011; Yañez et al., 2011).

In summary, in addition to the above methods, free radical polymerization, drug polymer film/coating, β-cyclodextrin, and artificial intelligence sensors are also effective in improving drug loading and prolonging drug release time, and have been applied in drug-loaded contact lenses (García-Fernández et al., 2013; Phan et al., 2014a; Aouak et al., 2019; Hewitt et al., 2020; Li et al., 2020; Liu et al., 2020; Pillai et al., 2020; Zhao et al., 2021a, 2021b; Wong et al., 2022).

3. Novel contact lenses in ophthalmic diseases

3.1. Keratitis

Keratitis is a corneal inflammatory reaction caused by external pathogens or internal diseases that attack corneal tissue, and is often accompanied by symptoms such as eye pain, photophobia, and vision loss. In recent years, its incidence has been increasing yearly with the increase in vegetative ocular trauma, misuse of broad-spectrum antibiotics or hormones, improper use of contact lenses and extensive development of eye surgery (Kam et al., 2017; Das et al., 2020; Brown et al., 2021; Durand et al., 2021). Besides, new methods for the treatment of keratitis have been explored, among which drug-loaded contact lenses have been proved to have great potential for clinical application (Shi et al., 2013; Hui et al., 2014; Phan et al., 2014b; Qin et al., 2017; Dixon et al., 2018). New therapeutic contact lenses for different types of keratitis are described below.

3.1.1. Bacterial keratitis

Bacterial keratitis is a type of purulent keratitis caused by different species of bacteria, P. aeruginosa being among the most common and destructive. Keratitis caused by P. aeruginosa develops rapidly and can evolve into an acute suppurative ulcer within 24–48 hours, lead to vision loss and even eyeball removal if not treated promptly. Recently, the incidence has increased with the widespread use of contact lenses, but treatment options remain scarce and antibiotics lose their specificity due to microbial resistance. Therefore, new therapeutic targets are urgently needed to fill these treatment gaps (Sy et al., 2012; Vazirani et al., 2015; Fernandes et al., 2016; Ung & Chodosh, 2021; Gurnani & Kaur, 2022; Tuft et al., 2022).

New strategies for preparing antibacterial contact lenses, such as antimicrobial peptides, natural antimicrobial products, and antibacterial coatings/films, have been reported (Xiao et al., 2018; Nahum et al., 2019). Malakooti et al. demonstrated that the imprinted contact lenses loaded with polymyxin B and related antimicrobial peptides can effectively inhibit P. aeruginosa (Malakooti et al., 2015). Dutta and coworkers found that melimine-coated lenses can significantly reduce the incidence of P. aeruginosa keratitis in rabbit models (Dutta et al., 2013, 2014, 2016). Moreover, they also demonstrated that some silicone hydrogel contact lenses, which were plasma-coated with acrylic acid followed by Mel4 antimicrobial peptide immobilization by covalent coupling, had excellent bactericidal functions (Dutta et al., 2018). Besides, Gallagher et al. reported that contact lenses prepared with an antibacterial peptide hydrogel and penicillin G or poly-ε-lysine can reduce the growth of S. aureus and Escherichia coli (Gallagher et al., 2016). Therapeutic contact lenses containing antibacterial peptides offer a potential intervention strategy for the prevention of microbial infections.

Antibacterial coatings/films or antimicrobial drugs also show excellent application value in inhibiting bacterial keratitis. Contact lenses with poly(dimethyl siloxane)-gentamicin sulfate or poly(dimethyl siloxane)-triclosan blend films exhibit good bactericidal and sufficient biofilm inhibition against gram-positive bacteria (Wang et al., 2016). Thiosemicarbazone-loaded pHEMA-co-β-cyclodextrin contact lens can effectively inhibit the growth of P. aeruginosa and S. aureus (Glisoni et al., 2013). Polyvinyl alcohol (PVA)/anionic collagen membranes as carriers of ciprofloxacin hydrochloride can inhibit bacterial activity and reduce inflammation in canine corneal ulcers (Daza et al., 2020). Furthermore, a multifunctional coating containing ZnO nanoparticles, chitosan, and gallic acid can be engineered on contact lens in a one-step sonochemical process, exhibiting high antibacterial efficiency and effectively combating S. aureus (Hoyo et al., 2019). Pillai et al. recently found that the contact lenses with antibacterial coating prepared by ozone activation or thermal polymerization showed antibacterial activity against methicillin-resistant S. aureus bacteria with a killing efficacy >99.99% (Pillai et al., 2020). Zhao et al. prepared epigallocatechin gallate-loaded starch hydrogel contact lens by free radical polymerization and demonstrated that they can sustainably release drugs for 14 days and significantly reduce the adhesion of P. aeruginosa (Zhao et al., 2021a). Moreover, Silva et al. designed a layer-by-layer coating using chitosan, sodium alginate, sodium hyaluronate, and genipin, which can endow contact lenses with ability to regulate the release of the anti-inflammatory diclofenac sodium salt, decreasing the initial burst and inhibiting bacterial growth (Silva et al., 2020).

In general, reducing the deposition of proteins and lipids is also important to prevent microbial adhesion and inhibit biofilm formation. Yeh and coworkers developed a stable superhydrophilic zwitterionic interface on polydimethylsiloxane elastomer by covalent silanization of sulfobetaine silane. The zwitterionic silane endows contact lenses with the ability to resist the nonspecific adsorption of proteins and lipids, potentially enhancing the antibacterial performance (Yeh et al., 2014). Additionally, Liu et al. confirmed that the contact lenses modified by zwitterionic and antimicrobial metal-phenolic networks can effectively prevent the adhesion of proteins, inhibit biofilm formation, and reduce many eye problems caused by bacterial colonization (Liu et al., 2020).

3.1.2. Fungal keratitis

Fungal keratitis is an infectious corneal disease caused by pathogenic fungi. It has a slow onset and long course, and corneal ulcer can appear within a few days of onset. Unfortunately, even if the diagnosis is clear and medication is administered timely, the disease cannot be completely controlled and often requires surgical treatment (Niu et al., 2020; Brown et al., 2021). In this context, contact lenses, as ideal drug delivery systems, have attracted the interest of researchers in developing antifungal products. In the early exploration, the contact lens could maintain a 100% fungicidal rate within 21 days by adding econazole-impregnated poly(lactic-co-glycolic) acid films (Ciolino et al., 2011). Moreover, chlorhexidine-loaded contact lenses can extend the drug-release time to 170 hours after modification with vitamin E (Paradiso et al., 2016). Although initial explorations have shown promising results, new preparation strategies compatible with a wide range of drugs should be used to prepare antifungal contact lenses for practical applications (Phan et al., 2014).

Huang et al. used quaternized chitosan, graphene oxide, silver nanoparticles and voriconazole to manufacture a hybrid hydrogel contact lens with antibacterial and antifungal properties. This drug delivery system significantly improved fungal keratitis in 7 days in a fungus-infected mouse model, exhibiting potential for the rapid and effective treatment of fungal keratitis (Huang et al., 2016). Additionally, Khan and coworkers developed a surface-modified multifunctional contact lens using a simple and efficient sonochemical approach. The surfaces were modified by applying multifunctional nanocoating comprising tobramycin, gallic acid, and phytomolecules-coated zinc oxide nanoparticles, which allowed the lenses to exhibit remarkable anti-pollution properties. Interestingly, the antifouling features improved the patient comfort level and enhanced the antimicrobial potential of the lenses by inhibiting the adhesion of proteins, lipids and platelets. This design provides a solution for simultaneously addressing the wettability, antifouling and antimicrobial requirements of contact lenses (Khan et al., 2021).

3.1.3. Viral keratitis

Viral keratitis is a common ophthalmic disease caused by various viruses, among which herpesviruses are the predominant etiologic agent (Koganti et al., 2021). So far, the treatment mainly relies on antiviral eye drops, and novel drug delivery systems are being developed due to eye barriers prevent drugs penetration (Polat et al., 2022). Varela-Garcia et al. recently fabricated contact lenses with an affinity for acyclovir and valaciclovir using molecular imprinting techniques and used computational models to screen hydrogel functional monomers suitable for interacting with these drugs. Results clearly suggest that valaciclovir had a stronger electrostatic interaction with methacrylic acid than acyclovir, which increasing the drug loading amount. Moreover, this kind of contact lens could release valaciclovir for 10 hours and shows great potential for the treatment of viral keratitis (Varela-Garcia et al., 2020).

3.1.4. Acanthamoeba keratitis

Acanthamoeba keratitis (AK) is a serious inflammation caused by Acanthamoeba sp., which is often contracted following corneal trauma, improper use of contact lenses, corneal transplantation, or contact with contaminated water. In general, AK can cause severe eye pain, inflammation, epithelial or stromal defects, and even vision loss if not diagnosed early and promptly treated (Fanselow et al., 2021). Until now, avoiding the risk factors and diagnosing the disease early are the most effective ways to combat AK, and there is an urgent need to develop novel methods to preventing AK (Morgan et al., 2020). A recent study detailed the development and testing of dysprosium-based nanoparticles for treating AK. Dysprosium-based nanoparticles, particularly Fe₃O₄-PEG-Dy₂O₃ nanocomposites, showed considerable antiamoebic cytotoxicity against Acanthamoeba sp. even after seven days of incubation. This kind of dysprosium-based nanocontact lens is a promising method for preventing AK (Kusrini et al., 2021).

3.1.5. Noninfectious keratitis

Recently, with extensive progress in eye surgery and corneal transplantation, the incidence of noninfectious keratitis has increased. In this context, development of drug-loaded contact lenses for the prevention and treatment of postoperative inflammation has important clinical significance (Kaczmarek et al., 2014; Behl et al., 2016). Carreira et al. prepared a vancomycin-loaded film using chitosan, PVA, and glyoxal to prevent inflammation after keratoprosthesis. The excellent transparency, biosafety, and sustained release effect of the film enable the production of vancomycin-eluted contact lenses (Carreira et al., 2014). What’s more, Jeencham et al. successfully developed chitosan and regenerated silk fibroin-blended films, which can be loaded with the anti-inflammatory agent diclofenac sodium to prepare daily disposable therapeutic contact lenses. The results demonstrated that the incorporation of regenerated silk fibroins increased the amorphous portion of the films and prolonged the drug release. This type of therapeutic contact lens can reduce the side effects of drugs and prevent postoperative inflammation (Jeencham et al., 2020).

3.2. Corneal wound healing

Dry eye, corneal dystrophy, ocular trauma, limbal stem cell deficiency, and other factors can cause imperfect corneal wound healing, which results in serious complications such as infection, ulcer, and even perforation if not treated promptly. At present, autologous serum, drug-eluting bandages, and amniotic membrane transplantation remain the main therapeutic methods (Sandri et al., 2016; Dhillon et al., 2020). To develop a safe and effective method, Zhao and coworkers fabricated a rutin-encapsulated gelatin hydrogel contact lens that could release rutin for 14 days and could significantly promote corneal wound healing in rabbits (Zhao et al., 2021b). Wei et al. successfully reduced ocular inflammation and facilitated epithelial healing by adding hyaluronic acid (HA) and Pluronic®F127 into contact lenses (Wei et al., 2022). Besides, Yin et al. covalently bonded HA with bovine serum albumin/silver (BSA/Ag) porous films via chemical crosslinking and evaluated the therapeutic potential of this complex in an alkali burn-induced corneal injury mouse model. Results proved that the BSA/Ag/HA films had high potential in fabricating contact lenses, exhibiting the capacity to relieve inflammation and improve the rate of corneal healing (Yin et al., 2021). Since electric stimulation for corneal wound healing could imitate the natural wound-healing mechanism of the endogenous electric field to facilitate epithelial repair. Wu and colleagues developed a wireless-powered electrical bandage contact lens, which powered by wireless power transfer and can create an electric field on the corneal surface to stimulate corneal epithelial cells and accelerate wound healing. Furthermore, the wireless electrical stimulation circuit employed a flower-shaped layout design that could be compactly integrated on a bandage contact lens without blocking vision. Hence, the wireless and wearable device is promising for the treatment of corneal injuries (Wu et al., 2022).

3.3. Proliferative ocular diseases

The eye is an important information collector, whose function depends on the integrity of refractive media. However, proliferative ocular diseases, such as scarring after glaucoma filtration surgery, proliferative vitreoretinopathy, and alkali burns, can affect the function of refractive media and cause certain visual impairments. Pirfenidone (PFD), as a safe and effective innovative broad-spectrum antifibrotic drug, can inhibit proliferative ocular diseases by regulating matrix metalloproteinases, transforming growth factors, and collagen (Zhong et al., 2011; Yang et al., 2016; Khanum et al., 2017; Diaz-Palomera et al., 2022). A study conducted by Wu et al. investigated the efficiency of drug delivery in PFD-loaded contact lenses that prepared by embedding an insert of PFD and PVA into two layers of silicone elastomer. Results demonstrated that the contact lens could prolong the residence time of PFD in tears and aqueous humor by five times, while the drug loaded was only one-tenth of that used in eye drops. Furthermore, the addition of PVA makes the lens equipped with higher oxygen permeability and lower protein adsorption characteristics. PFD-PVA-loaded contact lens is a promising drug delivery system for inhibiting proliferative ocular diseases (Wu et al., 2021a, 2021b).

3.4. Dry eye disease

Dry eye disease (DED) is a chronic illness characterized by symptoms of ocular discomfort and visual dysfunction, which result from abnormal tear quantity, quality, or fluid dynamics. At present, reducing tear evaporation, improving the function of related glands, applying eye drops, and removing inducements play an important role in the treatment of DED. For removing inducements, a study found that contact lenses embedded with ceria nanoparticles can effectively remove reactive oxygen species and avoid DED in high H₂O₂ environment (Choi et al., 2020). Moreover, scleral lenses can retain drugs during prolonged periods due to their tear film reservoir (Lim et al., 2009; Ciralsky et al., 2015; Polania-Baron et al., 2021), and have become a viable option to relieve the symptoms of dry eye syndrome (Bavinger et al., 2015; La Porta Weber et al., 2016; Marty et al., 2022). To alleviate ocular symptoms, White et al. fabricated a hydroxypropyl methylcellulose-loaded contact lens using molecular imprinting technology, which can continuously release hydroxypropyl methylcellulose for up to 60 days and effectively combat DED caused by contact lens (White et al., 2011). Besides, Akbari and coworkers prepared HA-loaded chitosan nanoparticles via ionic gelation and then embedded them into a PVA hydrogel implant ring to obtain therapeutic contact lenses. The results demonstrated that the lens could release HA for up to 14 days and effectively treat DED (Akbari et al., 2021). To reduce tear evaporation, graphene has been used to prepare contact lenses due to the mass impermeability of pristine graphene lattice (Choi & Park, 2017). Lee et al. first demonstrated the dehydration protection of graphene-coated contact lenses by monitoring the change of water evaporation rate from the vial capped with contact lens (Lee et al., 2017). In general, drug-loaded contact lenses are the most convenient platform for relieving DED symptoms.

3.5. Keratoconus and myopia

The corneal collagen layer weakens in certain diseases, such as myopia and keratoconus, and its mechanical properties also decline. Until now, corneal collagen cross-linking is often used to solve this problem, but it sometimes requires de-epithelialization, which can damage the eye (Saad et al., 2020; Shetty et al., 2020; Santodomingo-Rubido et al., 2022). A recent study showed that collagen cross-linking can be achieved by embedding flexible reservoirs of hyaluronate-rose bengal (HA-RB) conjugate in a contact lens. More specifically, the contact lens can receive signals using an ASIC chip and deliver the HA-RB conjugate to cornea on-demand via electrical signals. The combination of HA and RB enhances the permeability of RB and allows it to penetrate deep corneal layer without de-epithelialization. What’s more, loading HA-RB conjugate into contact lens can improve the delivery efficiency and prolong residence time of the conjugate on corneal surface, which is beneficial for achieving effective corneal collagen cross-linking (Mun et al., 2022). The smart contact lens is expected to be used for noninvasive biophotonic myopia vision correction or keratoconus treatment.

3.6. Ocular cystinosis

Cystinosis is a hereditary disease characterized by the accumulation of cystine crystals in various tissues and organs, eventually leading to progressive multiorgan damage and dysfunction. The disease always affects the kidneys and eyes first, and the accumulation of crystals in the eye often causes photophobia, blepharospasm, corneal scarring, retinopathy, cataract, and even blindness (Biswas et al., 2018; Castro-Balado et al., 2020). Cysteamine is currently the only effective drug for treating cystinosis, and new drug delivery systems are urgently needed. Dixon et al. designed a cysteamine-loaded contact lens containing 0.3% carbon black, which effectively alleviated photophobia symptoms by reducing transmittance by approximately 50% without changing the lens transparency. Additionally, vitamin E loading can reduce the accumulation of cystine crystals by prolonging the release time of cysteamine and providing additional protection by blocking UV radiation (Dixon & Chauhan, 2019; Hsu et al., 2013). Moreover, Liu et al. designed gold nanoparticle-loaded contact lenses by reverting gold precursor in the lenses. This method effectively avoids the loss and the instability or separation of gold nanoparticles in the traditional polymerization process. Owing to the high affinity between cystine and gold, this contact lens can bind cystine to cure ocular cystinosis (Liu et al., 2021).

3.7. Glaucoma

Glaucoma is a chronic eye disease caused by the progressive degeneration of retinal ganglion cells, which can lead to secondary optic atrophy, visual field loss, and even permanent blindness. Currently, the limited availability of glaucoma drugs has increased the need for novel anti-glaucoma drug delivery mechanisms with fewer toxic side effects (Aref, 2017; Carvalho et al., 2015). As reported, implanting timolol maleate-loaded ethyl cellulose nanoparticle-laden ring in hydrogel contact lenses continuously reduce the intra ocular pressure for eight days in a rabbit glaucoma model (Maulvi et al., 2016b). Besides, encapsulating a thin latanoprost-polymer film within the periphery of a hydrogel contact lens sustainably released drugs and effectively reduced intraocular pressure in glaucoma monkeys (Ciolino et al., 2016). Furthermore, contact lens loaded with latanoprost-poly(lactic-co-glycolic acid) film sustainably release drugs for one month (Ciolino et al., 2014). Jung & Chauhan investigated that timolol-loaded nanocontact lenses using diluents as polymeric modifiers extended drug-release time from 1–2 hour to approximately 2–4 weeks (Jung & Chauhan, 2012). Additionally, copolymerization and molecular imprinting technologies have also shown good results in glaucoma treatment (Anirudhan et al., 2016; Hu et al., 2016; Yan et al., 2020).

With continuous innovation in preparation technology, innovative drug-loaded contact lenses for treatment of glaucoma have been developed. Kim et al. wrapped diamond particles in polyethyleneimine and then cross-linked them with chitosan and timolol maleate to prepare lysozyme-dependent polysaccharide degradation-mediated diamond nanogel contact lenses, which provides a new platform for lysozyme-triggered delivery system (Kim et al., 2014). A study on the preparation of inner layer-embedded contact lenses by sandwich method combined with photopolymerization found that this PH-triggered controlled release system had good stability and could continuously release drugs for more than 10 days in rabbit models (Zhu et al., 2018). Mehta et al. used electrohydrodynamic atomization to engineer on-demand coatings for contact lenses. In this technique, poly(N-isopropylacrylamide) and polyvinylpyrrolidone polymers were utilized to encapsulate maleate and were electrically atomized to produce contact lens coatings. Borneol and chitosan were used to modulate the release of timolol maleate. This method provides an alternative formulation for glaucoma treatment (Mehta et al., 2019). Prakash designed a highly amorphous hydrophilic composite with β-cyclodextrin and acetazolamide using co-evaporation technology, and subsequently prepared a polymer film on the contact lens surface by combining it with the wet agent PVA. Results demonstrated that the contact lens simultaneously treated glaucoma and dry eye, and the polymer film extended drug-release time from 5 minutes to 3 hours (Prakash & Dhesingh, 2017). Hsu et al. added vitamin E to timolol and dorzolamide co-loaded contact lenses to explore the duration of drug release and the efficacy of the combination. The results suggested that vitamin E increased the release durations of both drugs to about 2-days and the lens showed superior IOP reduction with 3–4-fold lower drug payload compared to that of eye drops. In particular, a more important benefit of the lens was that the IOP reduction was maintained for about one week after the removal of contact lenses (Hsu et al., 2015). These results are encouraging and advance the development of drug delivery systems for glaucoma treatment.

3.8. Uveitis

Uveitis is a vision-threatening disease that can be caused by noninfectious or infectious etiologies. Owing to therapeutic drugs often need to penetrate the ocular surface tissue into the inner eye, and the required concentration and dose are very high, resulting in greater drug side effects and poor compliance (Sève et al., 2017). With the development of new materials, several approaches have been proposed for developing novel sustainable delivery systems. Bengani et al. encapsulated a ring-shaped dexamethasone-polymer film into the periphery of a methafilcon contact lens and evaluated its safety and efficacy by rabbit models of experimental anterior uveitis. Results showed that the lens had good biological safety and could sustained release dexamethasone for at least seven days, which effectively inhibited lipopolysaccharide-induced anterior uveitis for five days (Bengani et al.,2020). Similarly, DiPasquale and coworkers used a new macromolecular memory strategy to successfully load bromfenac into silico-hydrogel contact lenses that could sustainably be released for eight days in rabbits (DiPasquale et al., 2022). These studies highlight the great potential of drug-release lenses as a platform strategy and provide a new drop-free clinical strategy for uveitis treatment.

3.9. Color vision deficiency

Color vision deficiency (CVD) is an incurable congenital eye disorder that limits patient’s abilities to distinguish specific colors. Patients with CVD often need to use color vision filters like chromogen filters, tinted glass/lens to enhance their color perception, which is considered unesthetic (Badawy et al., 2018; Sekar et al., 2019; Male et al., 2022). Recently, with the development of metasurfaces and nanoparticle technology, innovative contact lenses for CVD have emerged. Nanocomposite contact lenses targeting red-green CVD have been developed to improve color perception ability. In this design, the orientation of nanocomposites can be shifted by uniaxial drawing to filter out the optical wavelengths of specific colors that are difficult to distinguish for CVD patients (Salih et al., 2021). Besides, Karepov et al. embedded metasurfaces into contact lenses and simulated their effects on color perception by using conventional models of human color-sensitive photoreceptors. As results suggested, the metasurface-based contact lenses could shift incorrectly perceived pigments back better approximate the original pigments (Karepov & Ellenbogen, 2020). Further, Roostaei team prepared a 2D biocompatible and flexible plasmonic contact lens using polydimethylsiloxane based on the soft nano-lithography method, which offers a good color filter for CVD correction (Roostaei & Hamidi, 2022). Consequently, these studies demonstrate that novel contact lenses provide new ideas for CVD correction and other color filtration.

3.10. Diabetic-related eye complications

Diabetes is a chronic metabolic disease caused by genetic, environmental, living habits, and other factors, which can easily to induce various tissue complications. Among these, ocular complications, such as diabetic retinopathy and cataract, can affect people’s health and quality of life (Seewoodhary, 2021). Hence, continuous blood glucose monitoring is essential to eliminate the health risks and long-term complications associated with diabetes. However, traditional detection methods are mostly invasive and only provide point but not continuous glucose monitoring information.

Owing to the discovery of glucose in tears and the development of ophthalmic sensors, wearable contact lens biosensors for glucose monitoring have attracted the attention of researchers (Farandos et al., 2015; Zha et al., 2020; Dennyson Savariraj et al., 2021; Kar et al., 2022). Elsherif et al. developed a glucose-sensitive photonic microstructure sensor integrated with a contact lens for continuous glucose monitoring by using smartphone camera readouts (Elsherif et al., 2018). They also created a bifocal contact lens by attaching a hydrogel glucose sensor to a soft contact lens to monitor the glucose concentration and correct myopia and presbyopia. When tear glucose level is increased, the contact lens can respond rapidly to this change in the form of changes in the refractive index and groove depth of the Fresnel lens. Quantitative readouts can then be obtained from smartphones and photodetectors to reflect the blood glucose concentration by measuring the changes in optical power reflected from the bifocal contact lens (Elsherif et al., 2021).

In addition to blood glucose monitoring, the treatment of diabetes-related eye complications is also important for improving quality of life. Alvarez-Rivera et al. designed a contact lens for local prevention/treatment of diabetes-related ocular diseases by adding bioinspired functional groups and an aldose reductase inhibitor (epalrestat) to the hydrogel material. Under hyperglycemic conditions, the contact lenses continuously release epalrestat to prevent lens opacification (Alvarez-Rivera et al., 2018). Ross et al. prepared an innovative delivery system by encapsulating dexamethasone polymer films inside contact lenses to continuously deliver drugs to retina. In a rabbit model of diabetic retinopathy induced by intravitreal injection of vascular endothelial growth factor, this type of contact lens successfully inhibited retinal vascular leakage (Ross et al., 2019). In summary, these studies confirmed that the contact lens, as a minimally invasive diagnostic and drug delivery platform, is expected to play an important role in blood glucose monitoring and the treatment of diabetes-related ocular complications.

Although various technological innovations have extended drug-release time from contact lenses, several challenges in application limit the commercialization. For example, particle instability in nanoparticle-loaded contact lenses can occur during polymerization, sterilization, or storage. Highly cross-linked structure of molecularly imprinted hydrogels can affect optical and physical properties of contact lenses, and low water content will reduce the permeability of ions and oxygen. Besides, vitamin E barrier can affect the physical properties of contact lenses, reduce oxygen permeability and increase protein adsorption. Multilayer liposomes can reduce the permeability of oxygen and carbon dioxide. In a word, contact lens-based drug delivery systems in ophthalmic diseases needs to be further optimized and developed.

4. Conclusions

Contact lens-based drug delivery systems has been widely studied because of their advantages including sustained drug delivery, prolonged drug retention, improved bioavailability and few drug side effects. They are expected to be potential treatments for ophthalmic diseases. Despite series of technological innovations have been achieved in contact lens-based drug delivery systems, most of them are still limited to the laboratory level. Technological challenges such as optical and physical properties, manufacturing, sterilization, and storage, together with non-technological challenges including complications associated with long-term wear, public acceptance of the technology, market regulation and so on, should be overcome for scaling up contact lens-based drug delivery systems. In the future, we need to balance optimization for optical and physical properties with adequate drug loading and release, and solve the processing and storage issues to increase chances of successful commercialization. Besides, it is also necessary to incorporate drugs to reduce complications such as microbial keratitis, allergic conjunctivitis, and dry eye syndrome. These measurements will not only provide new strategies for clinically treating ophthalmic diseases and but also to some extent benefit commercialization of drug-loaded contact lenses.

Authors’ contributions

Lianghui Zhao: sorting out the references and writing original draft; Jike Song: drawing the figure and tables; Yongle Du and Cong Ren: consulting and sorting out the references; Bin Guo and Hongsheng Bi: conceiving and revising the manuscript. All authors have read and agreed to the published version of the manuscript, and that all authors agree to be accountable for all aspects of the work.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by the National Key Research and Development Project (2019YFC1710200), the Focus on Research and Development Plan in Shandong Province (2021LCZX09), and the Natural Science Foundation of Shandong Province (ZR2021LZY045 and ZR2020MH393). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.