Chapter 1: Anatomy and Physiology of the Eye Free

The eye is a unique and specialized organ that supports vision. The structures of the eye allow for the generation of images from either reflected or emitted light. Briefly, light is focused and the subsequent images are converted by ocular cells to electrical impulses which are then transmitted to the brain, via the optic nerve, for processing. Visual function requires the coordination of a complex array of cellular components. As depicted in Figure 1.1, the eye, which is roughly spherical in shape, can be divided into the anterior and posterior segments, the dimensions of which are summarized in Table 1.1. While dimensions and structures vary slightly across mammalian species, the visual processes remain largely the same.

The tear film, depicted in Figure 1.2, consists of three layers: an inner mucin layer, a middle aqueous layer and an external lipid layer.¹  This tear film acts as a protective coating for the surface of the eye, providing a critical interface between the ocular structures and the outside environment. While only 3 micrometres in thickness, and containing only about 3 microliters of fluid in total, the tear film acts not only as a barrier, but also a smooth external lens by covering minor imperfections on the surface of the eye.²  The tear film is also responsible for nutrient and oxygen delivery to the tissues in the anterior segment of the eye and provides lubrication against mechanical forces like blinking and eye movement. The turnover of tears acts as a protective clearance mechanism through which waste and foreign materials can be washed from the corneal surface. In the tear film itself, there have been over 1500 distinct proteins reported, all of which work together to create an environment conducive of ophthalmic health and proper vision.³  These proteins are produced by the outermost epithelial layer of the cornea, as well as the eyelid and tissues surrounding the eye.

The innermost mucosal layer of the tear film is formed by the goblet, acinar, and epithelial cells, as well as the conjunctiva.⁴  The glycoprotein mucins are able to form hydrogen bonds with water in the aqueous layer of the tear film while their hydrophobic components interact with the non-polar outer epithelial layer of the cornea. The brush-like mucin structure can extend beyond the surface of the eye, while the hydrogen bonding of the mucosal layer allows the hydration of the mucin-covered cell layer.¹  This mucosal layer has been shown to increase the ability of the lacrimal functional unit to clear foreign debris and pathogens from the eye, demonstrating their roles in both the wettability of the ocular surface and the clearance mechanisms of the eye.¹ 

The aqueous layer of the tear film plays an important role in ocular oxygen and nutrient transport. The largely avascular nature of the eye requires unique transport mechanisms. Dissolved oxygen from the ambient environment and sugars, largely produced by the glands in the lacrimal functional unit, reach the ophthalmic tissues through the tear film. The lacrimal functional unit is responsible for the majority of the aqueous tear film production, as well as the maintenance of the concentration of electrolytes and proteins in this layer.⁵  The lipid layer of the tear film is largely produced by the meibomian glands, which exist under the lash line of the eyelids.⁶  This lipid film acts as a smooth outer surface, increasing optical clarity while preventing the aqueous tear fluid from evaporating from the surface of the eye and lubricating against shear forces like blinking that can damage the surface of the cornea.⁷ 

The tear film contains important proteins associated with wound healing of ophthalmic tissues, including various growth factors and antimicrobial agents like lysozyme and lactoferrin.²  The tear film also contains antioxidants, which scavenge free radicals in the eye, lowering oxidative stress and preventing ophthalmic tissue damage as a result of continuous exposure to environmental stressors and ultraviolet light. Proteins exist in all layers of the tear film, with hydrophilic protein structures remaining in the aqueous layer and hydrophobic proteins in the lipid layer and at the corneal surface.¹  Without maintaining the functional balance of the tear film, poor clearance of foreign materials and ophthalmic debris becomes a concern, leading to the potential for many ophthalmic conditions to develop. Dry eye disease is a common condition that relates to the improper equilibrium of the tear film, as the ability for the eye to maintain an outer lubricated layer is critical for nutrient delivery, preventing contaminants from entering the eye, and decreasing the shear forces associated with blinking.⁸ 

Light enters the eye through the cornea, which is the transparent front window of the eye. In a healthy eye, the cornea is an entirely avascular structure. With a diameter ranging between 10.5 and 12.5 mm,⁹  the cornea serves as both a protective barrier as well as performing a significant refractive function, providing ∼80% of the focusing power of the eye.¹⁰  It has a refractive index of approximately 1.34 and is composed of 5 structurally distinct layers.¹¹  Covering the anterior surface of the cornea are 5–6 layers of tightly packed corneal epithelial cells. This tightly packed uniformity serves a protective role and is critical in maintaining corneal health. The epithelial basement membrane, or Bowman’s layer, is composed mainly of collagen, and is thought to represent a transition between the stromal and epithelial layers, while maintaining corneal shape. Incapable of regeneration, damage to Bowman’s membrane can lead to scar formation, decreasing visual transparency for that section of the visual field.¹²  The stroma, comprising approximately 90% of the corneal thickness, is made up mainly of hydrated collagen, consisting of 80% water by weight, with interspersed keratocytes that synthesize collagens, glycosaminoglycans and matrix metalloproteinases that produce and repair the collagen matrix, as well as producing other components. Stromal function requires a consistent level of hydration to maintain function, otherwise it can cause the onset of a condition known as corneal edema.¹³  Descemet’s membrane, the basement membrane of the corneal endothelium, is composed mainly of type IV and type VIII collagen. Descemet’s membrane has the important function of maintaining stromal hydration, controlling water flow to the aqueous layer, while providing nutrients to the keratocytes.¹⁴  The corneal endothelium has a distinctive hexagonal shape, although the exact morphology does not remain consistent throughout the aging process, as cell density decreases with age. Corneal endothelial cells do not undergo mitosis, accounting for this decrease in cell density with age or injury. Due to the lack of proliferation of these cells, there is a risk of corneal edema if the cellular density drops to about 20 percent of the density at birth. This condition is associated with a limited ability for the endothelium to control the hydration of the stroma, which, in turn, will swell.¹⁵  The corneal structure is dense in nerves, which extend through the layers of the cornea to the posterior of the eye: a feature that is important for protection. Corneal transparency is an important attribute of the ocular anatomy.¹⁶  To maintain this transparency, a combination of factors must be accounted for, including the organization of the collagen in the stromal layer, the maintenance of hydration due to the endothelial pump, the presence of glycosaminoglycans, which reduce light scattering, and the lack of blood vessels in the eye.¹⁷  The structure and layers of the cornea are depicted in Figure 1.2.

The iris, responsible for controlling the amount of light that passes through to the retina by varying the size of the pupillary opening, is a vascularized, pigmented tissue between the anterior and posterior chambers of the eye.¹⁸  The ciliary body, also a vascularized pigmented tissue, consists of the ciliary processes and the ciliary muscle, and has two major functions: the production of aqueous humor and accommodation.¹⁸  The aqueous humor, a clear fluid with a composition similar to blood plasma, resides in the anterior segment. This fluid provides nutrients to the crystalline lens and the cornea, neither of which has a direct blood supply. This watery substance is constantly being produced by the ciliary body, thus requiring a consistent outflow pathway.¹⁹  Turnover of the aqueous humor and an outflow path to maintain intraocular pressure are provided by drainage through the porous trabecular meshwork of Schlemm’s canal. Typically, in the human, the intraocular pressure (IOP) is between 10 and 20 mmHg. Outflow through the Schlemm’s canal is pressure-dependent, meaning that when the intraocular pressure is higher, the trabecular meshwork allows the aqueous humor to flow from the eye more readily. While this is the main pressure regulator in the eye, some ophthalmic outflow also occurs through the uveoscleral pathway.²⁰  Aqueous outflow through this path is far more limited, as the transport through this tissue is passive, and the sclera is an elastomeric tissue with tight junctions. Improper pressure regulation in the eye is serious and can cause blindness if left untreated. If the intraocular pressure is too high, the patient can develop glaucoma. Glaucoma has the potential to lead to other ophthalmic conditions, as it places the eye under pressure, damaging the optic nerve and photosensitive cells in the retina.²¹  The two main ways of treating glaucoma are decreasing aqueous humor production or increasing outflow through the Schlemm’s canal.

The crystalline lens sits in the posterior chamber, behind the iris and the pupil. The centre of the lens consists of a nucleus which is surrounded by lens fibre cells. These cells synthesize crystallin proteins, which maintain the refractive index of the lens at approximately 1.42. The lens is a three-dimensional ellipsoid shape, with the purpose of fine-tuning the image that has been mainly focused with the cornea.²²  The outer ring of the lens is surrounded by the ciliary body, which contains muscle fibres involved with the focusing power of the lens. Accommodation is the ability to change the focus of the lens to allow for visualization of both near and distant objects. The ability of the natural crystalline lens to accommodate decreases with age.²³  When the ciliary muscle contracts, the zonule fibres relax their natural state of tension on the lens periphery which changes the focal length of the lens.²²  Presbyopia is a vision condition associated with an aging population caused by an increased rigidity in the lens as it ages. This lack of elasticity limits the ability for the lens to be manipulated and focus on objects, specifically close-up. Ultraviolet light can cause oxidative damage to the proteins and irreplaceable cells within the lens. Clear lens epithelial cells are present in the anterior capsule of the healthy lens, while no cells are present at the posterior. During cataract formation, non-transparent epithelial cells layer the lens capsule, limiting vision through their opacity.²⁵ 

The vitreous humor is an aqueous, transparent gel that accounts for the majority of the volume of the eye, filling the space between the lens and the retina. The main components of the vitreous humor are collagens II, IV, V and VI, with collagen II being the most prevalent.²⁵  The most abundant type of cells present in the vitreous of a developed eye are hyalocytes. Hyalocytes are responsible for producing the extracellular matrix, including hyaluronic acid and glycosaminoglycans, which are both found in high concentrations and are responsible for maintaining the gel structure within the vitreous.^24,26  The vitreous humor is non-vascular and receives nutrients from the ciliary body and the retina.

The most prominent structure at the posterior of the eye is the neural retina. The retina is up to 10 layers thick (see Figure 1.3.) and is responsible for phototransduction of light stimuli to electrical impulses that are transmitted to the brain via the optic nerve. The retina is complex in structure, consisting of numerous, intricately stratified cell types.²⁷  These cells emerge in a fixed, overlapping, chronological order, with the ganglion cells followed by horizontal cells, cone photoreceptors, amacrine cells, rod photoreceptors, bipolar cells, and finally the non-neuronal Müller glia organized into nuclear and plexiform layers.²⁸  The choroid is the vascular layer behind the retina, supplying oxygen and nutrients to the cellular layers of the retina.²⁹  The retinal pigmented epithelial cells (RPE) form a tight-junction epithelial layer immediately apical to the choroid.³⁰  The pigmented nature of these cells means that the absorption of light is among its primary functions. Critical to retinal health, the RPE layer also must provide efficient defense against free radicals, light energy and photo-oxidative exposure. The tight junctions of the RPE layer also play a role in maintaining the blood–retinal barrier and the immune privilege of the eye.³¹  Two types of photoreceptors, rods and cones, sit next to the RPE layer. The cones are concentrated in the macula, the central region of the retina, while the rods are more dominant in the peripheral retina. Cones are responsible for central vision, as well as for daytime vision; rods play a greater role in peripheral and dim-light vision.³² 

The National Eye Institute in the United States has estimated that there are currently 1.3 million Americans who are considered blind (visual acuity <20/200) and another 2.9 million Americans that are living with low vision, defined as best corrected visual acuity <20/40.³³  This number is expected to increase 72% by 2030. Internationally, the World Health Organization estimates that there are more than 1.3 billion people living with some kind of visual impairment, with 36 million of these people characterized as blind.³⁴ 

The vast majority of vision issues occur in patients older than 50. In the United States, age-related diseases, including cataract, glaucoma, and age-related macular degeneration, account for almost 80% of all cases of vision-associated disorders.³³  Diabetic retinopathy, the main vision issue of the working age population, accounts for the other 20% of cases. The economic burden of vision issues in the US alone has been estimated at more than $139 billion. Correctable and more common vision issues, including myopia, hyperopia, astigmatism and presbyopia, arise from refractive errors. Myopia, more commonly known as nearsightedness, in which the patient cannot focus on an object in the distance, has reached epidemic proportions in children, particularly in the Far East.^35,36  This is thought to be partly the result of screen time and a lack of outdoor play in children. Hyperopia, or far sightedness, occurs when one can focus on objects in the distance but not on objects that are close.³⁷  A schematic of image formation in the myopic and hyperopic eye is shown in Figure 1.4. Presbyopia, a condition of aging, occurs as a result of the loss of accommodation in the lens. It typically becomes symptomatic between the ages of 40 and 50 and results in the need for reading glasses to allow for focusing on near objects.³⁸  Astigmatism, estimated to affect as many as 30% of Americans, occurs when the cornea is no longer spherical.³⁹ 

Cataract, the leading cause of low vision in the US, refers to the clouding or opacification of the lens, typically as a result of aging. However, cataracts can also emerge from trauma or injury, congenital formation, or can result from underlying pathologies or medications. Cataracts are highly treatable, affecting more than 20.5 million patients in the US over the age of 40. More than 2 million surgeries, involving the replacement of the diseased lens with an artificial intraocular lens, are performed annually.⁴⁰  The success rate is typically more than 90%, with posterior capsule opacification (PCO) being the most common complication. PCO can be effectively treated with a surgical laser procedure.⁴¹ 

Glaucoma, including primary open angle glaucoma, angle closure glaucoma and congenital glaucoma, is typically characterized by increased intraocular pressure, changes in the optic nerve head, specifically increased cupping, and/or loss of visual field. Vision loss is ultimately the result of the death of retinal neurons and as such is not reversible.²¹  Typically, the treatment strategy is initially pharmacological with a goal of lowering the IOP. However, if the IOP cannot be managed pharmacologically, laser treatment or surgery to implant a glaucoma shunt or stent is performed. Laser trabeculoplasty treatments have a goal of creating space in the trabecular meshwork to facilitate aqueous humor outflow. A glaucoma shunt consists of a plate that resides in the subconjunctival space and a tube that is placed in the anterior chamber of the eye. The shunt lowers IOP by creating an outflow pathway through which aqueous humor drains through a sieve into the surrounding tissues where it is absorbed.⁴² 

Age-related macular degeneration (AMD) is the most common cause of blindness in the aged population.^43,44  Dry AMD, the most common form, accounts for approximately 90% of all cases and is characterized by the presence of small yellow deposits known as drusen which accumulate in the retinal pigmented epithelial cells adjacent to the macula.⁴⁵  People with late-stage dry AMD, also called geographic atrophy, did not have any available treatment options until the FDA approval of two complement cascade inhibitors, which target the innate immune system, in 2023.⁴⁶  Progression of the dry form to the wet form, which accounts for approximately 10% of all cases of AMD, leads to ∼90% of AMD-associated vision loss. Wet AMD is characterized by the growth of abnormal blood vessels, known as choroidal neovascularization (CNV), which originate in the choroid under the macula and invade the retinal tissue, leading to major cellular damage and central vision loss. Treatment for wet AMD involves monthly intravitreal injections of anti-VEGF molecules into the globe of the eye.⁴⁷ 

Diabetic retinopathy (DR) is the leading cause of blindness among the working-age population.⁴⁸  Affecting approximately 7.7 million Americans, a number which is projected to increase to 11.3 million Americans by 2030, DR is associated with both type 1 and type 2 diabetes. There are two types of DR – non-proliferative and proliferative. Non-proliferative DR is less severe, and leads to blurred vision as a result of the leakage of edema fluid from the blood vessels into the retina. Proliferative DR is usually more severe and results in neovascularization on the surface of the retina; these vessels can at times reach into the vitreous. These new, poorly formed vessels are leaky, leading to hemorrhage and profound vision loss.⁴⁹  As with AMD, approved treatments include injections of anti-VEGF drugs into the back of the eye or in some cases laser treatment of the hypoxic retina.

The National Institute of Biomedical Imaging and Biomedical Bioengineering describes biomaterials as “natural or synthetic and are used in medical applications to support, enhance, or replace damaged tissue or a biological function”.⁵¹  Because of the criticality of vision, biomaterials have a long history of use in ocular applications. Similar to materials used in other areas of the body, biocompatibility, stability, degradation, sterilizability, and manufacturability all must be considered. However, unique to materials to be used in ophthalmic applications, considerations around the optical properties must be taken into account. Optical properties are particularly critical for contact lens materials, corneal inlays or onlays and intraocular lenses. The materials must be transparent with refractive indices that are equal to or greater than the tissue that is being replaced. In some cases, UV-blocking agents are incorporated into these materials in order to protect the delicate retina from UV light exposure. In addition, any material used in the cornea, such as a contact lens or a corneal inlay, must have sufficient oxygen and nutrient permeability to allow for the maintenance of corneal health, due to the lack of vascularization of this tissue.