Dry eye is defined as a multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis and accompanied by ocular symptoms, including instability, tear film hyperosmolarity, inflammation, an ocular surface and sensorineural abnormalities
[42]. It is a disorder of the ocular surface, affecting millions of people worldwide, with varying degrees in severity ranging from simple discomfort to pain or fluctuating vision
[43]. Dry eye is associated with several names, including keratoconjunctivitis sicca (KCS); dry eye syndrome (DES); dry eye disease (DED) or dysfunctional tear syndrome (STD). KCS is the traditional name that involves the drying and inflammation of the ocular surface. DES or DED is the most widely recognized term
[44][45].
Aetiologias of DED are often classified as environmental, aqueous tear deficient or evaporative
[43][46]. A problem in lipid secretion, mucins or water or an increase in tear film evaporation can cause a DED, which often has a multifactorial origin
[43][47]. DED is usually related to other pathologies and may be triggered by the environment, be a side effect of a drug and its prevalence increases with age. Dry eye is classified according to risk factors and pathophysiology characteristics to improve diagnosis and treatment. Dry eye diagnosis is complex, due to the lack of consistent results from current clinical trials, as well as individual variability and the subjective nature of symptoms
[43]. DED can be episodic or chronic. Patients often complain of eye irritation and occasional blurred vision, but if patients with chronic DED are not treated, symptoms may persist and cause eye damage without impairing vision. Cornea or conjunctiva erosion are rare complications. The treatment of DED reduces symptoms and prevents eye damage; furthermore, artificial tears are the most used treatment for this condition, regardless of disease severity
[46].
2.4. Inlays
The history of ophthalmic inlays begins in the 1940s, when Barraquer introduced the idea of correcting corneal refraction through an implant to increase cornea curvature
[48]. Barraquer proved that no existing material could be used due to their lack of biocompatibility (corneal inflammation, nutritional deprivation, lack of precision in refractive correction). The use of living corneal tissue did not prove to be a viable alternative due to difficult surgical procedures
[48][49].
The discovery of hydrogels deepened the concept of the intracorneal inlay
[9]. It was Dohlman, in the late 1960s, who first described the use of a hydrophilic hydrogel polymer to permit nutritional flow. Inlay migration, epithelial growth at the interface and crystal formation represent some of the most common complications. The shapes were limited by the materials and available equipment used to modify surfaces.
Inlays continued to be improved with the emergence of new biocompatible materials and were more tolerated. Femtosecond lasers developed at the end of 1990s made obtaining more accurate stromal pouches possible; therefore, a better centralization of the intracorneal inlay and a better estimation of the implementation depth were achieved
[9].
Presbyopia is a progressive decrease in the amplitude of accommodation, related with age, which is responsible for a reduction in near visual acuity. Presbyopia is a growing problem in view of an aging global population and increasingly, patients desire spectacle-free solutions to address this condition. This loss in accommodation amplitude is due to the aging of the zonula, capsule, lens and ciliary bodies. The lens becomes thicker and stiffer, the capsule increases in thickness and decreases in elasticity, and the zonula becomes more fragile and rigid; therefore, the ciliary body remains in a contracted position because of elasticity loss in the lens. Non-invasive methods to correct presbyopia include corrective lenses and contact lenses, however, these do not restore the accommodation process. Surgical methods can reduce visual acuity and quality of vision. Deploying inlays is technically easy and incurs less risk than an intraocular procedure
[9].
2.5. Vitreous Substitutes
The vitreous body, also called the vitreous or vitreous humor, fills the posterior space of the eye, between the lens and the retina. It occupies more than two thirds of the eye volume. It is a clear gel, highly transparent, inhomogeneous and consists of several parts with different densities and biochemical compositions
[19][50][51]. The vitreous is composed of water, proteins (mainly collagen), GAG (hyaluronic acid, chondroitin sulfate and heparan), metabolites (glucose and lactic acid), ascorbic acid, amino acid, fatty acid, prostaglandin, cells (hyalocytes, fibrocytes/fibroblasts and macrophages) and enzymes
[19][51][52][53].
The viscoelastic properties of the vitreous are due to collagen fibers, while the hyaluronic acid provides it with shock-absorbing properties. This protects the structures and tissue of the eye, maintaining the shape of the eyeball and keeping the lens and retina in place
[19][50]. The vitreous has four main functions, which are as follows: a structural function, it supports the eye growth, volume and elasticity; an optical function while maintaining transparency and improving accommodation; a barrier function, forming a barrier to biochemical substances; and a nutritional role in providing nutrients and for metabolism
[52].
At birth, the vitreous body is completely gelatinous, with age, the vitreous body gradually liquefies. It is this liquefaction of the vitreous that plays a role in posterior vitreous detachment (PVD), corresponding to vitreous cortex detachment of the retina
[19][51].
An ideal vitreous substitute should be (i) non-toxic and biocompatible with eye tissues, (ii) clear and transparent with a refractive index and density similar to natural glass, (iii) must remain transparent without opacifying after the operation, (iv) an effective buffering agent, (v) allow for the transfer of metabolites, proteins and solutes, (vi) if possible non-absorbable and not biodegradable, (vii) hydrophilic and not soluble in water, (viii) injectable in a small needle, (ix) retain its properties after injection, (x) can be preserved and sterilized without the loss of properties mentioned above. The ideal vitreous substitute does not yet exist and remains a goal to be achieved
[19][51].
The various vitreous substitutes available today make it possible to replace the mechanical role of the vitreous, but they are toxic in the long run. They can be classified into the following broad categories: gas (air, sulfur hexafluoride (SF6)), perfluoropropane (C3F8); liquid (physiological solution, perfluorocarbon fluids (PFCL), semi-fluorinated alkanes (SFA), natural and semi-synthetic polymers namely hyaluronic acid and chitosan, silicone oil; and experimental substitutes.
Currently, silicone oil (OS) is the only substance used for long-term vitreous replacement despite some clinical complications
[51].
Regarding experimental substitutes, these correspond to the search for a substance with the same molecular structure than the vitreous, as well as the same chemical and physiological properties. These are mainly synthetic polymers, especially hydrogels that can be divided into hydrogels and smart hydrogels. They seem to be promising materials because they have excellent transparency, biocompatibility and can absorb viscoelastic shocks, thus mimicking the behavior of natural vitreous
[19].
Hydrogels and smart hydrogels seem to be good candidates as long-term vitreous substitutes once they show excellent transparency and good biocompatibility. They can act as viscoelastic shock-absorbing materials, thereby closely mimicking the behaviour of the natural vitreous body. Hydrogels are networks of polymer chains that contain 99.9% water, they are hydrophilic and not flowable, they swell in aqueous solutions without being solved, can be injected in an aqueous form forming a gel in situ
[54]. However, many issues, such as retinal toxicity, increased intraocular pressure, and the formation of opacities still need to be addressed. Fragmentation and changes in viscoelastic properties and resiliency after injection through a small-gauge needle have also been found in some types of hydrogels.
Smart hydrogels are a relatively new class of stimuli-sensitive hydrogels. They possess the common properties of conventional hydrogels, and they can respond to a variety of signals, including PH, temperature, light, pressure, electric fields, and chemicals
[50][51][52][53]. These interactions lead to better gelation, drug diffusion, and gel expansion. However, there is still insufficient information about its toxicity or inflammatory action. These materials are still in the experimental phase, as certain complications are still not well understood. Generally, smart hydrogels appear promising, but research on their use is still at an early experimental stage, and their effects on long-term toxicity are unknown
[5].
Recent research in vitreous substitutes mostly include cross-linked hydrogels; these materials show an enhanced retention time in the eye and are capable of acting as a tamponade agent. New developments in existing hydrogel-based vitreous substitutes have been reported. A study conducted by Leone et al. reported PVA hydrogels synthesis through cross-linking with non-toxic trisodium trimetaphosphate (STMP), resulting in rheological properties similar to the natural vitreous body. These properties were preserved after injection and in vitro cytotoxicity presented good results. In vivo studies to prove the long-term compatibility of this promising material have yet to be conducted
[55]. Swindle-Reilly et al. copolymerized acrylamide with bisacryloylcystamine, obtaining good mechanical properties similar to the natural vitreous humor with in vivo animal testing showing good biocompatibility. However, long-term testing is still needed
[56]. Tao et al. proposed a different cross-linking approach using two reactive PEG derivatives and tested it on rabbits. The obtained hydrogel was stable during the time of the in vivo rabbit study (9 months), the mechanical and optical properties were very similar to the natural vitreous body and no adverse reactions were found
[57].
Natural polymers for vitreous replacement have also been investigated with hyaluronic acid (HA) the most promising material. Schramm et al. compared two different HA hydrogels regarding their suitability as a vitreous substitute with different cross-linking methods (adipic dihydrazide (ADH) as well as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the photopolymerization of glycidyl methacrylate groups. During in vitro cell culture experiments, ADH/EDC cross-linked hydrogels induced mild cytotoxicity, whereas photopolymerized HA gels presented no toxicity. During 6 weeks of in vivo testing, the photopolymerized gels showed appropriate biocompatibility
[58]. However, another study found no toxic effects with similar ADH cross-linked HA hydrogels not only in vitro but also in vivo
[59].
2.6. Tissue Engineering
Tissue engineering evolved from biomaterials development and is based on the combination of scaffolds, cells, and biologically active molecules to promote the development of functional tissues. The goal of tissue engineering is to assemble functional constructs that restore, maintain, or improve damaged tissues or whole organs. The approach was conceived to address the critical gap between the growing number of patients on the waiting list for organ transplantation and the limited number of donated organs available
[23].
The general process of tissue engineering is based on the implantation of living cells in a scaffold specially designed to promote tissue replacement and regeneration
[22][23] as is schematized in
Figure 1. It is therefore considered as the next step in the development of biomaterials. Regenerative medicine relies on interdisciplinary research and applications based on repair, replacement or the regeneration of cells, tissues or organs to restore impaired functions. However, adult humans have only a limited capacity for spontaneous regeneration. Induced regeneration has been reported in conjunctiva and cornea.
Figure 1. Tissue engineering applied to cell and tissue manufacture and delivery. Cells are collected and harvested in order to perform expansion and differentiation. Cells and bioengineered scaffolds are then assembled to be able to be transplanted on the patient.
Tissue engineering in the eye has been reported mainly in the anterior segment (cornea and conjunctiva) and significant progress has been made in cell therapies to treat degenerative diseases of the retina. Ocular regenerative therapies are a new tool to treat several blinding disorders, namely corneal disease, cataract, glaucoma, retinitis pigmentosa, and age-related macular degeneration. Several transplantable products, delivered as cell suspensions or as preformed 3D scaffolds combining cells and natural or artificial substrates, are being studied. Bioengineering approaches with advance cell product manufacturing are being developed, thereby enhancing stem cell-based medicine
[60].