Anatomically, the eyes consist of two segments, anterior and posterior. The lens, which is a transparent structure responsible for refracting the light coming into the eye, is the border that separates these two parts [118]. The anterior segment includes the cornea, iris, ciliary body, conjunctiva, and anterior surface of the sclera. The choroid, retina, optic nerves, and the posterior surface of the sclera are located in the posterior segment. In both the anterior and posterior segments, the interstitial spaces are filled with aqueous humor and vitreous humor, respectively [13].

The anatomical structure of the eye can be classified independently of its segments, as well as according to the structural features of the layers that make it up. These layers are from outside to inside: Tunica fibrosa oculi (fibrous layer), tunica vasculosa oculi (vascular layer), and tunica interna oculi (neural layer). Tunica fibrosa oculi, the fibrous layer of the eye, consists of the cornea, conjunctiva, and sclera. This layer, which does not contain lymph and blood vessels, surrounds the eyeball from the outside [119]. The cornea is a thin and transparent tissue consisting of five layers (corneal epithelium, Bowman’s membrane, stroma, Descemet’s membrane, and the endothelial layer). The conjunctiva is a mucosal membrane [13]. The sclera is a fibrous tissue consisting of five layers (Tenon’s capsule, episclera, scleral spur, limbus, and posterior sclera) [120], just like the cornea. The tunica vasculosa oculi, located just below the tunica fibrosa oculi, is also known as the uvea. This layer consists of the choroid, ciliary body, and iris. Thanks to the vessels it contains, the blood circulation in the eye tissues and the production of aqueous humor are carried out by the tissues in this layer [13,119]. The tunica interna oculi is the inner layer where the light is transformed into a neural impulse and transmitted to the brain [121].

Since the eye is a vital organ in contact with the external environment, it must maintain its integrity. For this reason, it contains natural anatomical and physiological barriers. All ocular tissues, vessels, and fluids are the natural barriers of the eye. These barriers are the tear film, cornea, conjunctiva, sclera, blood–aqueous humor (iris–ciliary body), lens, and blood–retina barrier [122,123,124]. These barriers, whose main task is protecting the eye from foreign fluids and objects, also act as drug rate-limiting steps. They reduce the penetration of drugs into ocular tissues and their bioavailability. Since each of these barriers has different structures from the others, they also perform rate-restriction functions on drugs with different properties.

The tear film covers the surface of the cornea and conjunctiva. It is the primary protective structure against ocular problems of chemical, mechanical, bacterial, or viral origin. Likewise, it forms the largest barrier among drugs applied topically to the eye [120,125]. Topically applied drugs are usually applied to an area called the cul-de-sac with a volume of 7–10 µL [126]. However, the application dose of any drug is 20–50 µL on average [127]. Due to this sudden increase in the volume of the area, topical drugs such as drops and emulsions applied topically are removed from the eye by nasolacrimal drainage and added to the systemic circulation [123,128]. Around 80% of a topically applied conventional drug is eliminated due to the tear film and nasolacrimal drainage [129].

The cornea acts as an important barrier to conventional topical drugs in the anterior segment of the eye [130]. The epithelium, stroma, and endothelium, which are parts of the cornea, are tissue formations of different polarities. Depending on the arrangement of the cells in the epithelial layer, there is a high shunt resistance and is considered a tight tissue [122]. These tight junctions give the epithelium a lipophilic character. Stroma, conversely, has a highly hydrophilic character due to the collagen fibers in its structure. Therefore, while the epithelium prevents the passage of hydrophilic drugs, the stroma acts as a barrier to the passage of lipophilic drugs. In the endothelium, the innermost layer of the cornea, molecules of up to 70 kDa can pass through passive transport [123,124,130].

The conjunctiva acts as a barrier through the numerous capillaries and lymphatic structures in its structure. It dilutes applied drugs with the blood or lymphatic circulation. There are epithelial cells in the conjunctiva as well as in the cornea. These epithelial cells have a shunt resistance, although not as much as in the corneal epithelium. Points of this resistance are considered tight structures and act as barriers to drugs. The conjunctiva acts as the main barrier for drugs not administered via the corneal route. Compared to the cornea, the conjunctiva is a hydrophilic tissue and more suitable for passing large molecules. For this reason, the direct conjunctival application of ocular drugs is being studied by reducing corneal application to increase the absorption of larger bio-organic molecules such as proteins and peptides. However, considering that most of the drugs used in the clinic are lipophilic and small molecules, it is seen that corneal application will not lose its importance [120,122,130].

The sclera has a hydrophilic character due to the collagen fibers in its structure. For this reason, it acts as a barrier for lipophilic drugs. However, small-sized lipophilic drugs also show scleral permeability similar to hydrophilic drugs. In addition, the size of the molecules and the positive charge are other parameters that reduce the passage through the sclera [124,131].

The iris and ciliary body, the tissues of the tunica vasculosa bulbi form the blood–aqueous barrier (BAB). This barrier is also known as the anterior blood–eye barrier [124]. The ciliary body produces aqueous humor, which stabilizes intraocular pressure. On the other hand, the dense capillaries in this layer contain tight junctions. These tight junctions, the epithelial cells of the iris, and the barrier formed by aqueous humor are highly restrictive for hydrophilic drugs. Small molecules and lipophilic drugs can easily pass the BAB and enter the systemic circulation via the uvea. An inflammation that may occur in this barrier disrupts the integrity of the barrier. This causes the amount of drug passing to the anterior region of the eye to not be controlled [122,124,131,132,133].

The lens is the eye’s tissue, consisting of 65% water and the remainder predominantly proteins. It is distinctly different from other eye tissues with its protein content. The lens is a tissue in which active and passive transport, depending on Na⁺, are effective. It mainly affects the passage of drug molecules for this reason [122,131].

The blood–retinal barrier (BRB) is formed by the combination of several factors. Primarily, retinal pigment epithelial cells have Na⁺, K⁺-ATPase pumps that ensure the balance of Na⁺ and K⁺ ions in the eye. On the other hand, the capillaries in their structure have tight connection points. The passage of drug molecules through these tight junctions is the second rate-limiting step. At the same time, molecules that can pass through these capillaries quickly enter the systemic circulation, which reduces the number of drugs in the target area, thus reducing the bioavailability. Finally, the ganglion cells in the retina are nerve cells and form a barrier similar to the cerebrospinal barrier. The BRB acts as a barrier for the passage of proteinaceous and small hydrophilic molecules while allowing the passage of lipophilic molecules. However, these lipophilic molecules are also rapidly distributed and eliminated due to intense systemic circulation [120,122,124,131].

Increasing the ocular bioavailability of a drug to be applied to the eye can only be achieved by overcoming all of these barriers and delivering the drug to the target tissue. Two ways are followed for this purpose. One of them is the application of the drug to the eye in different routes. These routes of administration are classified as topical, periocular (subconjunctival, transscleral, and intravitreal), and systemic [120,124]. Although these different routes, which are actively used today, seem to have solved the problem of low ocular bioavailability, they contain risks as they can cause serious complications such as blindness. For this reason, the second way to increase ocular bioavailability is the development of drug delivery systems [118].

Conventional dosage forms applied to the eye are solutions, suspensions, ointments, and gels [134,135]. Today, 90% of the drugs on the market fall into this group. These dosage forms usually target the anterior segment of the eye and may have little effect on a possible disease in the posterior segment [136]. On the other hand, they have very low bioavailability due to ocular barriers. Due to their low bioavailability, their dosing frequency during the day is high, which reduces patient compliance. In addition, the fact that gels and ointments cause blurred vision is another factor that reduces patient compliance [137]. To prevent all of these negativities, drug delivery systems targeting certain eye tissues are being developed.

Drug delivery systems are produced by using a suitable polymer/surfactant/lipid, have micro or nano size, and are developed to deliver the loaded drug to the target tissue [138]. Since they target the drug to the tissue where the effect is desired, they allow the use of active pharmaceutical ingredients (API) at lower doses. Thus, a decrease in the rate of side effects may occur. In addition, drug releases can be extended thanks to the polymer/surfactant/lipid used in their preparation. Thus, the dosing frequency can be reduced and patient compliance can be increased [139,140,141]. There are different delivery systems developed for ocular drug targeting. Micro and nanoparticles, micro and nanoemulsions, nanosuspensions, micelles, liposomes, solid lipid nanoparticles, dendrimers, cubosomes, discosomes, niosomes, spanlastics, bilosomes, hydrogels, implants, inserts, lenses, and nanofibers are among the carrier systems developed [118]. While some of these carrier systems have turned into commercial products, some have remained in experimental studies. The most well-known commercial products are Ocusert^® (an ocular insert containing pilocarpine) [142], Xelpros^® (a pilocarpine-containing micellar system) [143], Modusik-A Ofteno^®, Papilock Mini^®, and Cequa^® (which are micellar systems containing cyclosporine A) [144,145].

Nanofibers have also been used in ocular drug targeting since the first years they were designed as drug delivery systems. Thanks to the materials used in their preparation, they increase the penetration and contact time of drugs with ocular tissues and show high biocompatibility. In addition, their extended-release profile also reduces the dosing frequency [146,147]. However, the features that make nanofibers distinctly superior to other drug delivery systems are that they have a large surface area, high porosity, easily adjustable diameters, and can be combined with other drug delivery systems [15]. Having a large surface area enables the nanofibers to be loaded with more drugs than other drug delivery systems. These features, coupled with extended drug release profiles, allow for further reductions in dosing frequencies. For this reason, nanofibers stand out as a promising approach to the medical treatment of chronic ocular diseases. The fact that porous structures can be produced to be similar to ocular tissues further increases their biocompatibility compared to other carrier systems [148,149,150]. One of the most important features of drug delivery systems is that they are micro or nanosized. The diameter size of nanofibers could be adjusted much more easily than other carrier systems. Thus, the permeation of the drug with ocular tissues can be increased. The studies found that the carrier systems should be smaller than 100 nm to overcome the corneal barriers [151], and the scleral pore openings were between 20–80 nm [13]. Nanofibers can be easily produced in the appropriate diameter according to the target tissue. It also provides an important advantage in that it can be used in combination with other drug delivery systems (nanoparticle, dendrimer, etc.). In recent years, studies in the hydrogel form of nanofibers, which are generally converted into insert or implant form, have also been carried out. Although the drug has been proven to increase penetration and permeation with ocular tissues, it can cause blurred vision, irritation, and watery discharge. Despite these problems, nanofibers may be a viable option for a variety of ocular drug delivery systems [152]. To avoid these side effects and maximize the benefits of using nanofibers for ocular drug delivery, nanofiber properties such as size, surface charge, and polymer type and composition can be optimized, which can significantly affect their interaction with ocular tissues. By optimizing these properties, researchers can minimize the negative effects of nanofiber-based drug delivery systems while maintaining their effectiveness. Thus, the irritation potential of formulations can be reduced by reducing interactions with ocular tissues. In addition, nanofibers can be combined with other delivery systems such as hydrogels or liposomes to increase their performance and reduce their adverse effects. For example, nanofibers prepared with hydrogelizing polymers can provide a protective barrier by minimizing irritation and other side effects. In Table 1, nanofibers developed as an ocular drug delivery system are summarized (in alphabetical order).

Many tissues in the living body cannot regenerate after injury. Even with surgical intervention on these damaged tissues, the tissue cannot regain its former form and return to the former quality of life of the individual [179]. One of the methods developed to solve this problem is tissue engineering. Tissue engineering, also known as regenerative medicine, is the science that deals with the development or production of therapeutic stem cells, tissues, and artificial organs [180]. Tissue engineering is widely used in bone and nerve regeneration, cartilage repair, and cardiovascular and ocular tissue development. Although it may seem simple and feasible, it is a multidisciplinary field of study and contains various difficulties in each step of obtaining tissue from stem cells [109].

The extracellular matrix (ECM) is a heterogeneous, binding network of fibrous glycoproteins with micro- and nanosized pores [181]. It provides the physical scaffold and mechanical stability required for tissue morphogenesis and homeostasis. It is aimed at developing scaffolds similar to ECMs in tissue engineering [148,149,150]. Electrospinning is the widely used method in producing scaffolds produced using biodegradable materials to obtain micro or nanosized fibrous tissue.

The eye has a unique structure and is rich in epithelial cells and neural networks. However, the structural integrity of this organ, which is in contact with the outer surface, may be impaired due to chemical, radiation and burn injuries, and infections caused by contact lenses. Unfortunately, these structural problems can be permanent. For example, the cornea, the outermost transparent layer of the eye, has two main functions. The first is to protect the structures inside the eye, and the second is to refract the light coming from outside and focus it clearly on the retina [182]. Good vision largely depends on corneal epithelial regeneration by limbal epithelial cells [183]. However, structural problems due to environmental factors may lead to limbal stem cell deficiency, and in this case, the act of seeing may not be performed. Therefore, the development of ocular tissues is an important field of study for tissue engineering. It is a great advantage that many biodegradable polymers used in the production of scaffolds are also biocompatible with ocular tissues. Table 2 summarizes the ocular tissue engineering studies with nanofibers.

When the studies are examined, it is generally emphasized that nanofibers produced with different methods and different materials in ocular tissue engineering studies are highly biocompatible with eye tissue and suitable for adhesion and proliferation for different types of cells [184,185]. In addition, successful results have been obtained from anti-inflammatory gene expression studies [186,187]. In other studies, it has been concluded that the prepared nanofibers have better mechanical properties than the amniotic membrane [188]. In some in vivo studies, it has also been observed that cell-cultured nanofibers provide re-epithelialization in the eye [189,190].