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Pharmacologic Vitreolysis

Raja Narayanan Baruch D. Kuppermann

The importance of vitreous in the pathogenesis of various retinal disorders has been well recognized, and currently vitreous can only be dealt with surgically. Anomalous posterior vitreous detachment (PVD), which is a condition where the vitreous liquefies without vitreoretinal dehiscence (1), can worsen diabetic retinopathy and cause retinal tears, detachment, macular pucker, macular hole, or vitreous hemorrhage (2). Vitreous hemorrhage is a major cause of vision loss. The most common cause of vitreous hemorrhage is diabetic retinopathy, which can also lead to tractional retinal detachment (3). Various enzymes have been investigated to dissolve the vitreous hemorrhage or modify the structural characteristics of the vitreous to allow diffusion of blood out of the visual axis. Enzymatic vitreolysis has several advantages over conventional surgery, including the ability to treat the hemorrhage earlier, in an office setting, and with lower costs. With pharmacologic vitreolysis, complications of surgery such as cataract, endophthalmitis, retinal hemorrhage, tear or detachment, and anesthesia-related complications can be avoided. A number of vitreolytic enzymes have been investigated, including hyaluronidase, plasmin, dispase, tissue plasminogen activator, and chondroitinase, with varying effects. Such pharmacologic therapies rely upon a good understanding of the biochemical composition and organization of the vitreous.

Ultrastructural studies have shown that the adult human vitreous contains fine, parallel fibers of collagen coursing in an anteroposterior direction (4, 5). Although several agents have been investigated in animal models, only a few have been employed in humans. Autologous plasmin enzyme (APE) has been used in some patients but has never been subjected to the rigors of a controlled clinical trial. Chondroitinase and hyaluronidase have been tested in clinical trials, but the former never entered Phase II testing. Hyaluronidase (Vitrase) failed a Phase III U.S. Food and Drug Administration (FDA) trial conducted in the United States. The Vitrase clinical trial results will be discussed in more detail later in this chapter.

HYALURONAN

Hyaluronan is a major macromolecule of the vitreous (5). Hyaluronan is a long, unbranched polymer of repeating disaccharide (glucuronic acid β [1,3]-N-acetylglucosamine) moieties linked by β 1–4 bonds. It is a linear, left-handed, threefold helix with a rise per disaccharide on the helix axis of 0.98 nm. The sodium salt of hyaluronan has a molecular weight of 3 to 4.5 × 10⁶ in the normal human vitreous. Hyaluronan is not normally a free polymer in vivo, but it is covalently linked to a protein core to form a proteoglycan. Hyaluronan plays a pivotal role in stabilizing the vitreous gel.

COLLAGEN

Studies have shown that the vitreous contains collagen type II, a hybrid of types V/XI, and type IX collagen in a molar ratio of 75:10:15, respectively (6). Vitreous collagens are organized into fibrils with types V/XI residing in the core, type II collagen surrounding the core, and type IX collagen on the surface of the fibril. The fibrils are 7 to 28 nm in diameter, but their length in situ is unknown.

SUPRAMOLECULAR ORGANIZATION

Vitreous is a dilute meshwork of collagen fibrils interspersed with extensive arrays of hyaluronan molecules. The collagen fibrils provide a scaffoldlike structure that is “inflated” by the hydrophilic hyaluronan. If collagen is removed, the remaining hyaluronan forms a viscous solution. However, if hyaluronan is removed, the gel shrinks but is not destroyed. Electrostatic binding occurs between the negatively charged hyaluronan and the positively charged collagen in the vitreous (7).

Studies have shown that the chondroitin sulfate chains of type IX collagen bridge between adjacent collagen fibrils in a ladderlike configuration spacing them apart (8). Such spacing is necessary for vitreous transparency, because keeping vitreous collagen fibrils separated by at least one wavelength of incident light minimizes light scattering, allowing the unhindered transmission of light to the retina for photoreception. Bishop (6) proposed that the leucine-rich repeat protein opticin is the predominant structural protein responsible for short-range spacing of collagen fibrils.

Numerous changes occur in the structure of the vitreous with age. There is a significant decrease in the gel volume and an increase in the liquid volume of the human vitreous. Derangement of the normal hyaluronan/collagen association results in the simultaneous formation of liquid vitreous and aggregation of collagen fibrils into bundles of parallel fibrils seen macroscopically as large fibers (9). In the posterior vitreous, such age-related changes form large pockets of liquid vitreous.

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