Scaffolds have a crucial function in ex vivo tissue engineering methods for various organs, offering numerous advantages in the creation and transplantation of organs. First, they enable a greater quantity of viable cells to be transplanted, which is vital for fully restoring organ function. Scaffolds offer an ideal framework for diverse cells to coalesce and thrive within a controlled microenvironment. Second, scaffolds aid the process by offering surfaces where different cell types can flourish, directing their growth to precise locations for functional outcomes. Additionally, the meticulously selected physical and chemical attributes of biomaterials, including factors like strength and degradation rates, can be customized to boost specific functions of the emerging tissues, such as in the context of the lacrimal gland.

The introduction of organ-on-a-chip technology brought about the use of three-dimensional (3D) methods, incorporating microfluidics and bioengineering, to replicate in vivo conditions [113]. An instance of this technology in the field of ophthalmology is the creation of a human blinking eye-on-a-chip [114]. In this model, 3D shell scaffolds are utilized to create corneal curvatures. These scaffolds are infused with primary human keratocytes and placed between a microfluid channel and a circular chamber. Epithelial cells are then strategically positioned on the scaffold using a color-coded method, employing green fluorescence in the center and red fluorescence along the periphery of the scaffold surface. Additionally, 3D-printed eyelids, designed to simulate natural blinking, are mechanically activated, enabling the replication of tear-film spreading and hydration of the ocular surface.

The creation of scaffolds through different methods, the use of appropriate biomaterials, and thorough biological evaluations of relevant parameters are viable options. Both 2D and 3D culturing techniques continue to be valuable for assessing various in vitro and in vivo cultures, considering functional parameters. This approach can lead to the development of an effective ex vivo manufacturing process and enable post-implantation assessments, potentially eliminating ocular surface disorders associated with DES [115].

Nanosystems have been extensively studied in medicine, including their use in treating eye conditions [116]. Their complex, nanoscale structure shows significant promise in improving ocular drug delivery through the controlled release of different bioactive substances. Furthermore, these nanosystems have an enhanced ability to infiltrate and pass through ocular tissues, simultaneously protecting bioactive molecules from degradation [117]. A key benefit of employing nanosystems in delivering drugs to the eyes lies in their mucoadhesive properties. This characteristic boosts their ability to stick to the ocular surface, preventing the drugs from being washed away by the eye’s natural defense mechanisms [118].

Different types of nanosystems, including nanoparticles (NPs), nanoemulsions, lipid nanocapsules, and nanoemulsions, have been investigated for transporting drugs such as epigallocatechin gallate (EGCG), cyclosporine, dexamethasone, amfenac, and cyporin-N to the eye’s surface [119]. EGCG, an anti-inflammatory substance, was integrated into gelatin nanoparticles that are biocompatible and biodegradable, and these were further coated with HA [120]. The EGCG nanoparticle formulation exhibited enhanced penetration into human corneal epithelial cell cultures. When administered twice daily over a two-week period, these nanoparticle eye drops not only reinstated tear production but also repaired the impaired corneal epithelium in a rabbit model of DED. These effects surpassed those observed with standard EGCG eye drops. Additionally, a multifunctional therapeutic gold nanoparticle was developed, featuring a substantial surface area and combining anti-inflammatory (amfenac) and antioxidant (catechin) agents to address DED [121]. Poly(catechin) capped gold nanoparticles were designed to include the anti-inflammatory drug amfenac, effectively suppressing both DED-related inflammation and reactive oxygen species (ROS)-mediated processes within four days in the rabbit DED model induced by BAC. These nanoparticles have a loose polymeric matrix containing the drug, which is uniformly confined on the gold nanoparticles’ surface. This outperformed the effects of commercial cyclosporine eye drops.

In 2016, Liu and his team investigated an innovative mucoadhesive nanoparticle system. This system involved poly(D,L-lactide)-b-dextran (PLA-b-Dex) particles coated with phenylboronic acid (PBA) to prolong the retention of eye drops. This system was investigated with the inclusion of cyclosporine. Lipid nanocapsules (LNCs) are utilized for lipophilic drugs, with the lipid core providing enhanced nano-encapsulation of the drug. LNC eye drops containing CsA demonstrated quicker and more effective therapeutic outcomes in a rat model of DED, with improved TBUT (>8 s), a decreased corneal fluorescein score, and low expression of inflammatory cytokines, surpassing the effects of the commercial CsA emulsion (Restasis) [122]. Nanowafer (NW) is a drug delivery nanosystem consisting of small drug-containing nanoreservoirs arranged on a circular transparent disc [123].

Restasis, a 0.05% CsA emulsion, was the first CsA formulation approved by the Food and Drug Administration (FDA) for the treatment of DED in 2003 [124]. Safety assessments in Phase III trials revealed that Restasis was associated with sensations of burning, foreign body presence, and stinging in 25% of patients. These effects were attributed to the use of a high total drug dosage [125]. In 2003, TJ Cyporin, a 0.05% cyclosporine A nanoemulsion, received approval for treating DED in South Korea. A study conducted by Kang and colleagues compared its effectiveness with Restasis in patients with primary Sjögren syndrome. Cyporin-N exhibited a significant improvement in TBUT after 12 weeks, while Restasis did not show the same improvement. Both treatments effectively reduced inflammation in Sjögren’s syndrome patients, with no notable difference in the reduction of inflammatory cytokines between the two groups. Additionally, in 2018, the US FDA approved Cequa^® (manufactured by Sun Pharma, Mumbai, India), a preservative-free 0.09% nanomicellar formulation of cyclosporine A, for the treatment of DED in adult patients [126]. Nanosized hydrogels, known as nanogels, have been widely utilized in ophthalmic applications, mainly due to their prolonged ocular retention and low viscosity [127]. In a rabbit model of DED, administering nanogel eye drops twice daily provided faster and more efficient relief for dry eyes compared to the commercially available highly viscous Vidisic gel containing 0.2% poly(acrylic) acid. Dendrimers, a unique category of nanosystems, are complex, branched molecules with diverse functional groups and intricate polymeric structures. Catechins are known for their anti-inflammatory, antibacterial, and anticancer properties. A nanocomplex consisting of PEG and catechin significantly increased tear production in a mouse model of DED while also reducing fluorescein and corneal irregularity scores [128]. Table 3 summarizes the outcomes from various studies exploring nanosystems for treating DED.

Hydrogels, made of absorbent hydrophilic polymers, maintain their 3D structure while absorbing water. They are formed from natural, semisynthetic, or synthetic polymers like HA and poly (acrylic acid). Hydrogels offer controlled drug release, biocompatibility, and the ability to carry diverse drugs, making them promising for ocular surface disease treatment [131].

Several hydrogel products for DED treatment are available in the market, such as Hylo^®gel (URSAPHARM, Saarbrücken, Germany), Vidisic^® gel (Bausch and Lomb, Rochester, NY, USA), GelTears^® (Bausch and Lomb, Rochester), Viscotears^® (Novartis, Basel, Switzerland), and Clinitas gel^® (Altacor, Reading, UK). Some products are in clinical trials, including VisuXL^® gel (VISUfarmaSpA, Rome, Italy), and bovine basic fibroblast growth factor (bFGF) gel (Zhuhai Yisheng Biological Pharmaceutical Co., Ltd., Zhuhai, China). Recent patents for DED treatment involve innovative hydrogel formulations like multi-arm PEG insert with CsA/Dex, PNIPAAm and butyl acrylate plug, guar gum, PVA, and boric acid drop containing diquafosol sodium [132,133,134].

Hydrogels containing HA have been explored in a few rabbit DED models. Soft hydrogels are well-tolerated on the ocular surfaces of rats, rabbits, and dogs [131]. In a clinical trial, canines suffering from DED and previously treated with artificial tears and cyclosporine exhibited alleviated clinical symptoms in more than 65% of instances, even if they had not responded to cyclosporine treatment initially. Thermo-responsive hydrogels have attracted considerable attention in the realm of hydrogel-based drug delivery systems due to their ability to change their physical form in response to external factors such as temperature, pH, and ionic strength [135]. Another study utilized crosslinked modified HA to create a hydrogel with higher viscosity and elastic modulus compared to non-crosslinked HA solutions. This hydrogel improved TBUT in rabbits and was found to alleviate dry eye symptoms in dogs in a preliminary clinical study, outperforming commercial HA tears in terms of symptom relief [136].

Researchers have studied hydrogels as plugs for the lacrimal drainage system in models of DED. In a rabbit DED model, a thermosensitive hydroxybutyl chitosan (HBC) hydrogel plug demonstrated notable enhancements in tear volume and decreased outflow [137]. This gel was safe and well-tolerated in both animal and human evaluations. Additionally, a novel mini eye patch containing palladium-coated gold nanorod hydrogel was developed to stimulate lacrimal tear secretion using visible light energy. The eye patch was proven safe and effective in improving tear-related parameters in healthy volunteers [138]. However, its impact on DED patients remains to be explored. Table 4 summarizes the outcomes from different studies exploring hydrogels for treating DED.

Delivering drugs using contact lenses (CL) has numerous benefits, including prolonged drug release, enhanced drug absorption, improved patient adherence, and greater comfort [142]. Advancements in CL materials and better patient education have resolved initial concerns, making CL more comfortable and increasing global adoption in the past decade [143]. Soft CL for delivering drugs to the eyes was first introduced in the 1960s. However, notable advancements in biomaterials from the 2000s onward have sparked increased research into CL drug delivery. Hydrogels and silicone hydrogels are the main materials employed in creating these lenses. Drug-releasing CL releases drugs that fall into two categories: lubricants and anti-inflammatory drugs. Various techniques, such as soaking, molecular imprinting, ring implantation, and incorporating nanocarriers and functional molecules, are used to load these drugs into the lenses (Figure 4b).

Researchers have investigated the use of CL as a delivery method for lubricants and anti-inflammatory drugs. Studies have successfully achieved sustained drug release over extended periods, ranging from 48 h to 15 days, in an in vitro experiment. Maulvi and colleagues (2015) investigated two methods of loading HA into hydrogel CL: soaking and direct entrapment during polymerization. Soaking allowed HA release for up to 48 h, while the entrapment method achieved a prolonged release lasting up to 264 h at therapeutic levels in vitro. These hydrogels were non-toxic and, with the direct entrapment method, demonstrated prolonged HA release for 15 days in the precorneal area of rabbits. Additionally, ring implants not only prolonged the presence of HA and maintained its continuous release onto the eye surface but also decreased corneal epithelial damage and reinstated tear volume in a BAC-DED rabbit model when compared to untreated eyes [144]. To enhance the sustained release, chitosan nanoparticles loaded with HA were integrated into ring-shaped poly(vinyl) alcohol hydrogels that were implanted in CL and that were able to release HA for 14 days [145].

In a recent study, a porous carrier loaded with CsA was created utilizing a supercritical fluid method and incorporated into a hydroxyethyl methacrylate (HEMA) hydrogel CL. This resulted in an initial rise in CsA concentration, followed by sustained release lasting 48 h. Its application resulted in elevated tear volume and extended TBUT, along with decreased corneal staining scores in the rabbit DED model in contrast to 0.05% CsA eye drops, balanced salt solution (BSS), and soft contact lenses. Additionally, CsA-CL significantly lowered pro-inflammatory cytokine IL-1β levels compared to BSS-soft CL groups [146]. The inclusion of vitamin E in CL prolonged the dexamethasone release significantly [147]. When loaded with 30% vitamin E, the release time was extended to 7–9 days. For p-HEMA hydrogel lenses, CsA was released for one day, while for silicone hydrogel lenses, the release continued for two weeks. [148]. Table 5 summarizes the results from different studies using various drug-eluting contact lenses for treating DED, and Table 6 summarizes the pros and cons of the most commonly used contact lenses for treating DED.

The objective of managing dry eye is to alleviate symptoms, enhance the eye’s surface, enhance vision, and tackle root causes. Various therapies, including drug delivery through contact lenses, have been proposed to manage the complex nature of DED. CsA can be incorporated into contact lenses for treating dry eyes. Compared to corticosteroids, CsA offers advantages such as reversible effects, minimal systemic absorption, and no notable side effects. These pharmacokinetic benefits are crucial for the prolonged treatment of chronic conditions like dry eye [153].

In a study conducted by Mun and colleagues in 2019, they showed that the liberation of CsA from CL significantly enhanced the treatment of DED in rabbit eyes. To induce DED, they administered 3-concanavalin A injections to rabbits and discovered that the contact lens facilitated consistent CsA release for a duration of 7 days. The effectiveness of the treatment was confirmed through corneal immunofluorescence staining, focusing on MMP9, a marker for DED [154]. In a study conducted by Desai and colleagues in 2022, they observed a decrease in MMP9 intensity in the right eyes treated with CsA/C-HA micelle contact lenses and eye drops compared to the control group in the left eyes. Moreover, rabbits exhibited swift recovery from DED when using a graphene contact lens loaded with CsA, ensuring a continuous high concentration of CsA in the corneal fluid [155].

A biosensor is a diagnostic tool that utilizes a biological element and a physicochemical indicator to detect a specific chemical substance [156,157]. It employs biological components like enzymes, antibodies, cell receptors, etc. to interact with the target analyte. The biosensor works through various mechanisms, such as piezoelectric, electrochemiluminescence, optical, and electrochemical, to measure and quantify the analyte. The results are displayed simply through a connected reader [71]. The human eye holds essential chemical, physical, and biological information relevant to human health. This aspect has become a focal point for the advancement of soft electronic systems employed in diagnosing different eye ailments and other organ-related disorders. Wearable and pliable medical devices such as CL can take on pivotal tasks in the diagnosis and management of ocular diseases [158].