the vitreous body.69,75-77 The individual fibrils cannot be seen with the slit lamp, but the pattern of variations in their density and regularity can be seen. The density of this collagen fibril network differs throughout the vitreous.44

activity.2,71 The vitreous transmits and refracts light, aiding in focusing the rays on the retina. Minimal light scattering occurs in the vitreous because of its extremely low concentration of particles and the interfibrillar spacing ensured by the HA-collagen complex.

Hyaluronic Acid (hyaluronan)

The second major vitreal component, hyaluronic acid (HA), a glycosaminoglycan, is a long unbranched molecule coiled into a twisted network.72 This hydrophilic macromolecule is located in specific sites within the collagen fibril network and is believed to maintain the wide spacing between fibrils.60 The concentration of HA is highest in the posterior cortex and decreases centrally and anteriorly.68,78 The gel structure is a result of the interaction of collagen and HA. HA stabilizes the network formed by the collagen strands.

Hyalocytes

Vitreous cells, or hyalocytes, are located in a single, widely spaced layer in the cortex near the vitreal surface and parallel to it.60,72 Various functions have been attributed to these cells. Some investigators have determined that these cells synthesize HA.79-81 Others have found evidence that hyalocytes synthesize glycoproteins for the collagen fibrils.60,82 Still others indicate that hyalocytes have phagocytic properties.72,81,83 Apparently, hyalocytes can have different appearances depending on their activity at a given time.60 Cells located in the vitreous base are fibroblast-like when anterior to the ora serrata and macrophage-like when posterior to it.64

Fibroblasts present in the vitreous are located in the vitreous base near the ciliary body and near the optic disc. Although composing less than 10% of the cell population, fibroblasts may have been mistaken for hyalocytes in the past. It is believed that fibroblasts synthesize the collagen fibrils that run anteroposteriorly and are active in pathologic conditions.60

Other cells that have been identified as macrophages likely originate in the nearby retinal blood vessels.2,71

VITREAL FUNCTION

The vitreous body provides physical support holding the retina in place next to the choroid, the blood supply for the outer retina. (Neural retina and choroid are only connected to each other at the disc and the ora serrata.) The vitreous is a storage area for metabolites for the retina and lens and provides an avenue for the movement of these substances within the eye.41 The vitreous, because of its viscoelastic properties, acts as a “shock absorber,” protecting the fragile retinal tissue during rapid eye movements and strenuous physical

AGE-RELATED VITREAL CHANGES

In the infant the vitreous is a very homogeneous, gel-like body. With maturation, changes occur in which the gel volume decreases and the liquid volume increases; this is called vitreous liquefaction or vitreous synersis.60 By age 40 years, the vitreous is 80% gel and 20% ­liquid, and by 70 or 80 years it is 50% liquid,70 with most of the liquefaction occurring in the central vitreous.71 Both HA and collagen may be detrimentally affected by free radicals that cause conformational changes in the HA molecule and breakdown in collagen crosslinks. Subsequent displacement of collagen from the HA-collagen network influences the change from gel to liquid.46,84,85 As the dissolution of the HA-collagen complex occurs, the macromolecule moves out of the collagen network, causing the fibrils to coalesce into fibers and then into bands.85,86 The redistribution of collagen leaves spaces adjacent to these bundles, allowing pooling of liquid vitreous; these pockets are called lacunae. 68,86,87

Clinical Comment: Peripheral

Retinal Traction

With aging, the vitreous base adhesion extends further posteriorly, and the border approaches the equator.88,89 These changes can increase traction on peripheral retina and might contribute to the development of retinal tears and detachment.

Clinical Comment: Posterior Vitreal

Detachment

As the HA is displaced from the collagen network and as the fibrils coalesce into bundles, the bundles can

contract and apply traction to the vitreous and thus to the posterior retina. One of the most common abnormalities that occurs at the posterior retinal-vitreous interface is a posterior vitreal detachment caused by this traction. The vitreous usually detaches from the retinal internal limiting membrane at the peripapillary ring, forming a retrocortical space. If glial tissue is torn away with the vitreous, a circular condensation, Weiss’ ring (senile annular ring), may be visible within the vitreous.90 If liquid vitreous seeps into the retrocortical space through the prepapillary and premacular areas, a syneresis, or collapse, of the vitreous can follow because of the volume displacement.86,91

P H Y S I O L O G Y O F T H E V I T R E O U S

The vitreous was thought to merely passively interact and support surrounding tissues but a new understanding of the dynamic vitreous is developing. The cells in the cortex reamin largely quiescent because factors present in the vitreous prevent cell migration and proliferation. The interaction between HA and collagen fibrils contributes to the viscoelastic properties of the vitreous92,93 and influences the physical properties, i.e., the balance between gel and liquid, of the vitreous state.60 Most of the water in the vitreous is bound in the widely-spaced network of collagen and HA. A disruption in the HAcollagen complex can cause the collagen fibrils to aggregate into bundles, which may become large enough to be visible clinically, and reported by a patient as floaters.

While there is little metabolic activity within the vitreous and a slow degradation occurs with age, an intact vitreous gel may be quite important to ocular health; age-related degeneration of the vitreous gel and liquefaction accompanies several age-related ocular diseases, such as nuclear sclerotic cataract and neovascular diabetic retinopathy.94 Studies suggest a correlation between vitreous degeneration and the development of nuclear sclerotic cataract (NSC), inferring that an intact vitreous provides some protection against lens nuclear changes. A much higher incidence of NSC after vitrectomy was found in patients over 50 than in those younger.95,96 It may be that the younger lens is more resistant to cataractous changes or that the presence of anterior vitreous that is still adherent to posterior lens (it was not removed in the vitrectomy because of the stronger adhesion) provides some protection against NSC.

Nuclear sclerotic cataract is the result of oxidative changes within the lens nucleus. The vitreous has a high concentration of ascorbate (up to 40 times higher than blood plasma) and might have a role in the regulation of intraocular molecular oxygen.94 As oxygen diffuses into the vitreous from the retinal vessels, it is likely to be consumed by ascorbate before it reaches the lens and anterior segment, providing some protection from oxidative stress. The lens might therefore be exposed to a greater concentration of oxygen after vitrectomy. Vitreous­ gel has a higher concentration of ascorbate and consumes oxygen at a faster rate than liquid vitreous.97 Vitreous loss due to liquefaction or vitrectomy can be linked to disease processes in which excessive oxygen causes oxidative stress and tissue damage.

Another hypothesis suggests that some might benefit from vitreous liquefaction or surgical removal of the vitreous. Vitreous loss that results in increased intraocular molecular oxygen may benefit ischemic retinal disease by lowering vascular endothelial growth factor (VEGF)

and thus reduce neovascularization.94 The importance of the vitreous and a better understanding of its relationship with neighboring tissues will become more evident as studies continue.

REFERENCES

1.Fine BS, Yanoff M: The vitreous body. In Fine BS, Yanoff M, editors:­ Ocular histology, ed 2, Hagerstown, Md, 1979, Harper & Row, p 131.

2.Hogan MJ, Alvarado JA, Weddell JE: Histology of the human eye, Philadelphia, 1971, Saunders.

3.Warwick R: Eugene Wolff’s anatomy of the eye and orbit, ed 7, Philadelphia,­ 1976, Saunders.

4.Kelley MJ, Rose AY, Keller KE, et al: Stem cells in the trabecular meshwork: present and future promises, Exp Eye Res 88:747–751, 2009.

5.Lütjen-Drecoll E, Rohen JW: Functional morphology of the trabecular­ meshwork. In Tasman W, Jaeger EA, editors: Duane’s foundations of clinical ophthalmology, vol 1, Philadelphia, 1994, Lippincott, p 1.

6.Alexander RA, Garner A: Elastic and precursor fibres in the normal human eye, Exp Eye Res 36:305, 1983.

7Gong H, Ruberti J, Overby D, et al: A new view of the human trabecular­ meshwork using quick-freeze, deep-etch electron microscopy, Exp Eye Res 75:347, 2002.

8.Fine BS: Structure of the trabecular meshwork and the canal of Schlemm, Trans Am Acad Ophthalmol Otolaryngol 70:777, 1966.

9.Bhatt K, Gong F, Freddo TF: Freeze-fracture studies of interendothelial junctions in the angle of the human eye, Invest Ophthalmol Vis Sci 36(7):1379, 1995.

10.Raviola G, Raviola E: Paracellular route of aqueous in the trabecular meshwork and canal of Schlemm. A freeze-fracture study of the endothelial junctions in the sclerocorneal angle of the macaque monkey eye, Invest Ophthalmol Vis Sci 21:52, 1981.

11.Kaufman PL: Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia interrogating Mother Nature: asking why, asking how, recognizing the signs, following the trail, Exp Eye Res 86:3–17, 2008.

12.Ye W, Gong H, Sit A, et al: Interendothelial junctions in normal human Schlemm’s canal respond to changes in pressure, Invest Ophthalmol Vis Sci 38(12):2460, 1997.

13.Johnson M: What controls aqueous humour outflow resistance? Exp Eye Res 82:545–557, 2006.

14.Bill A: Scanning electron microscopic studies of the canal of Schlemm,­ Exp Eye Res 10:214, 1970.

15.Epstein DL, Rohen JW: Morphology of the trabecular meshwork and inner-wall endothelium after cationized ferritin perfusion in the monkey eye, Invest Ophthalmol Vis Sci 32:160, 1991.

16.Ethier CR, Coloma FM, Sit AJ, et al: Two pore types in the innerwall endothelium of Schlemm’s canal, Invest Ophthalmol Vis Sci 39(11):2041, 1998.

17.Lütjen-Drecoll E, Futa R, Rohen JW: Ultrahistochemical studies on tangential sections of the trabecular meshwork in normal and glaucomatous eyes, Invest Ophthalmol Vis Sci 21:563, 1981.

18.Inomata H, Bill A, Smelser GK: Aqueous humor pathways through the trabecular meshwork and into Schlemm’s canal in the cynomolgus monkey (Macaca irus), Am J Ophthalmol 73:760, 1972.

19.Rohen JW, Futa R, Lütjen-Drecoll E: The fine structure of the cribriform­ network in normal and glaucomatous eyes as seen in tangential­ sections, Invest Ophthalmol Vis Sci 21:574, 1981.

20.Umihira J, Nagata S, Nohara M, et al: Localization of elastin in the normal and glaucomatous human trabecular meshwork, Invest Ophthalmol Vis Sci 35(2):486, 1994.

21.Acott TS, Kelley MJ: Extracellular matrix in the trabecular meshwork, Exp Eye Res 86:543–561, 2008.

22.Overby DR, Stamer WD, Johnson M: The changing paradigm of outflow resistance generation: towards synergistic models of the JCT and inner wall endothelium, Exp Eye Res 88:656–670, 2009.

23.Kanski JJ: Clinical ophthalmology, ed 3, Oxford, UK, 1994, Butterworth-Heinemann.

24.Krohn J, Bertelsen T: Corrosion casts of the suprachoroidal space and uveoscleral drainage routes in the human eye, Acta Ophthalmol Scand 75:32, 1997.

25.Nilsson SF: The uveoscleral outflow routes, Eye 11:149, 1997.

26.Alm A, Nilsson SF: Uveoscleral outflow—a review, Exp Eye Res 88:760–768, 2009.

27.Bill A: Some aspects of aqueous humour drainage, Eye 7:14, 1993.

28.Krohn J, Bertelsen T: Light microscopy of uveoscleral drainage routes after gelatine injections into the suprachoroidal space, Acta Ophthalmol Scand 76(5):521, 1998:(abstract).

29.Gupta N, Patel M, Ly T, et al: Evidence of a new uveolymphatic outflow pathway in human and sheep; implications for aqueous drainage and glaucoma, Invest Ophthalmol Vis Sci 49, 2008.

30.Holmberg AS: The fine structure of the inner wall of Schlemm’s canal, Arch Ophthalmol 62:956, 1959.

31.Speakman JS: Drainage channels in the trabecular wall of Schlemm’s­ canal, Br J Ophthalmol 44:513, 1960.

32.Parc CE, Johnson DH, Brilakis HS: Giant vacuoles are found preferentially near collector channels, Invest Ophthalmol Vis Sci 41:2984, 2000.

33.Feeney L: Outflow studies using an electron dense tracer, Trans Am Acad Ophthalmol Otolaryngol 70:791, 1966.

34.Anderson DR: Scanning electron microscopy of primate trabecular meshwork, Am J Ophthalmol 71:90, 1971.

35.Tripathi ERC: Mechanism of the aqueous outflow across the trabecular­ wall of Schlemm’s canal, Exp Eye Res 11:116, 1971.

36.Sit AJ, Coloma FM, Ethier CR, et al: Factors affecting the pores of the inner wall endothelium of Schlemm’s canal, Invest Ophthalmol Vis Sci 38(8):1517, 1997.

37.Alvarado JA, Alvarado RG, Yeh RF, et al: A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability­ of Schlemm’s canal endothelial cells, Br J Ophthalmol 89:1500–1505, 2005.

38.Sondermann R: The formation, morphology and function of Schlemm’s­ canal, Acta Ophthalmol 11:280, 1933.

39.Dvorak-Theobold G: Schlemm’s canal: its anastomosis and anatomic relations, Trans Am Ophthalmol Soc 32:574, 1934.

40.Ashton N: Anatomical study of Schlemm’s canal and aqueous veins by means of neoprene casts. Part I. Aqueous veins, Br J Ophthalmol­ 35:291, 1951.

41.Ascher KW: Aqueous veins: preliminary notes, Am J Ophthalmol 25:31, 1942.

42.Gabfelt BT, Kaufman PL: Aqueous humor hydrodynamics. In Kaufman PL, Alm A, editors: Adler’s physiology of the eye, ed 10, St Louis, 2003, Mosby, p 293.

43.Tamm ER: The trabecular meshwork outflow pathways: structural and functional aspects, Exp Eye Res 88:648–655, 2009.

44.Selbach JM, Gottanka J, Wittmann M, et al: Efferent and afferent­ innervation of primate trabecular meshwork and scleral spur,

Invest Ophthalmol Vis Sci 41(8):2184, 2000.

45.Faralli JA, Schwinn MK, Gonzalez JM Jr, et al: Functional properties­ of fibronectin in the trabecular meshwork, Exp Eye Res 88:689–693, 2009.

46.Lund-Andersen H, Sander B: The vitreous. In Kaufman PL, Alm A, editors: Adler’s physiology of the eye, ed 10, St Louis, 2003, Mosby, p 293.

47.Johnson S, Chan D, Read AT, et al: The pore density in the inner wall endothelium of Schlemm’s canal of glaucomatous eyes,

Invest Ophthalmol Vis Sci 43(9):2950, 2002.

48.Allingham RR, de Kater AW, Ethier CR: Schlemm’s canal and primary open angle glaucoma: correlation between Schlemm’s canal dimensions and outflow facility, Exp Eye Res 62(1):101, 1996:(abstract).

49.Rohen J, Unger HH: Studies on the morphology and pathology of the trabecular meshwork in the human eye, Am J Ophthalmol 46:802, 1958.

50.Grierson I, Lee WR, Abraham S: Effects of pilocarpine on the morphology­ of human outflow apparatus, Br J Ophthalmol 62:302, 1978.

51.Keil JW, Reithamer HA: Relationship between ciliary blood flow and aqueous production: does it play a role in glaucoma therapy? J Glaucoma 15:172–181, 2006.

52.Zimmerman TJ: Topical ophthalmic beta blockers: a comparative review, J Ocul Pharmacol 9:373–384, 1993.

53.Alm A: Uveoscleral outflow, Eye 14:488, 2000.

54.Lütjen-Drecoll E, Gabelt AT, Tian B, et al: Outflow of aqueous humor, J Glaucoma 10(Suppl 1):42, 2001.

55.Cracknell KPB, Grierson I: Prostaglandin analogues in the anterior eye: their pressure lowering action and side effects, Exp Eye Res 88:786–791, 2009.

56.Toris CB, Gabelt BT, Kaufman PL: Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction, Surv Ophthalmol 53(Suppl1):S107–S120, 2008.

57.Chen HB, Kashiwagi K, Yamabayashi S, et al: Anterior chamber angle biometry: quadrant variation, age change and sex difference, Curr Eye Res 17(2):120, 1998:(abstract).

58.Toris CB, Yablonski ME, Wang YL, et al: Aqueous humor dynamics in the aging human eye, Am J Ophthalmol 127:407, 1999.

59.Boldea RC, Roy S, Mermoud A: Ageing of Schlemm’s canal in nonglaucomatous subjects, Int Ophthalmol 24:67, 2001.

60.Sebag J: The vitreous. In Hart WM Jr, editor: Adler’s physiology of the eye, ed 9, St Louis, 1992, Mosby, p 268.

61.Mutlu F, Leopold IH: Structure of the human retinal vascular system, Arch Ophthalmol 71:93, 1964.

62.Lund-Andersen H, Sebag J, Sander B, et al: The vitreous. In Fischbarg­ J, editor: The biology of the eye, Amsterdam, 2006, ­Elsevier, pp 181–194.

63.Wolter JR: Pores in the internal limiting membrane of the human retina, Arch Ophthalmol 42:971, 1964.

64.Gaertner J: Vitreous electron microscopic studies on the fine structure­ of the normal and pathologically changed vitreoretinal limiting membrane, Surv Ophthalmol 9:219, 1964.

65.Matsumato B, Blanks JC, Ryan SJ: Topographic variations in rabbit­

and primate internal limiting membrane, Invest Ophthalmol Vis Sci 25:71, 1984.

66.Malecaze F, Caratero C, Caratero A, et al: Some ultrastructural aspects of the vitreoretinal juncture, Ophthalmologica 191:22, 1985.

67.Russell SR, Shepherd JD, Hageman GS: Distribution of glycoconjugates in the human retinal internal limiting membrane, Invest Ophthalmol Vis Sci 32(7):1986, 1991.

68.La Goff MM, Bishop PN: Adult vitreous structure and postnatal changes, Eye 22:1214–1222, 2008.

69.Schwarz W: Electron microscopic observations on the human vitreous­ body. In Smelser GK, editor: Structure of the eye, New York, 1961, Academic Press, p 283.

70.Balazs EA: Functional anatomy of the vitreous. In Tasman W, Jaeger­ EA, editors: Duane’s foundations of clinical ophthalmology, vol 1, Philadelphia, 1994, Lippincott.

71.Eisner G: Clinical anatomy of the vitreous. In Tasman W, Jaeger EA, editors: Duane’s foundations of clinical ophthalmology, vol 1, Philadelphia, 1994, Lippincott.

72.Balazs EA, Toth LZ, Eckl EA, et al: Studies on the structure of the vitreous body. XII. Cytological and histochemical studies on the cortical tissue layer, Exp Eye Res 3:57, 1964.

73.Sebag J, Balazs EA: Morphology and ultrastructure of human vitreous­ fibers, Invest Ophthalmol Vis Sci 30:1867, 1989.

74.Bishop PN, Takanosu M, Le Goff M, et al: The role of the posterior ciliary body in the biosynthesis of vitreous humour, Eye 16:454, 2002.

75.Pirie A, Schmidt G, Waters JW: Ox vitreous humor. I. The residual protein, Br J Ophthalmol 32:321, 1948.

76.Matoltsy AG: A study on the structural protein of the vitreous body (vitrosin), J Gen Physiol 36:29, 1952.

77.Gross J, Matoltsy AG, Cohen C: Vitrosin: a member of the collagen class, J Biophys Biochem Cytol 1:215, 1955.

78.Bembridge BA, Crawford CN, Pirie A: Phase-contrast microscopy of the animal vitreous body, Br J Ophthalmol 36:131, 1952.

79.Osterlin SE: The synthesis of hyaluronic acid in the vitreous. IV. Regeneration in the owl monkey, Exp Eye Res 7:524, 1968.

80.Hultsch E, Balazs EA: In vitro synthesis of glycosaminoglycans and glycoproteins by cells of the vitreous, Invest Ophthalmol Vis Sci 14(Suppl):43, 1973.

81.Freeman MI, Jacobson B, Balazs EA: The chemical composition of vitreous hyalocyte granules, Exp Eye Res 29:479, 1979.

82.Ayad S, Weiss JB: A new look at vitreous-humor collagen, ­Biochem J 218:835, 1984.

83.Szirmai JA, Balazs EA: Studies on the structure of the vitreous body. Cells in the cortical layer, Arch Ophthalmol 59:34, 1958.

84.Armand G, Chakrabarti B: Conformational differences between hyaluronates of gel and liquid human vitreous: fractionation and circular dichroism studies, Curr Eye Res 6:445, 1987.

85.Ponsioen TL, Deemter M, Bank RA, et al: Mature enzymatic collagen cross-links, hydroxylysylpyridinoline and lysylpyridinoline, in the aging human vitreous, Invest Ophthalmol Vis Sci 50:1041– 1046, 2009.

86.Sebag J: Age-related differences in the human vitreoretinal interface, Arch Ophthalmol 109(7):966, 1991.

87.Kishi S, Shimizu K: Posterior precortical vitreous pocket, Arch Ophthalmol 108:979, 1990.

88.Teng CC, Che HH: Vitreous changes and the mechanism of retinal detachment, Am J Ophthalmol 44:335, 1957.

89.Wang J, McLeod D, Henson DB, et al: Age-dependent changes in the basal retinovitreous adhesion, Invest Ophthalmol Vis Sci 44(5):1793, 2003.

90.Spalton DJ, Hitchings RA, Hunter PA: Atlas of clinical ophthalmology, Philadelphia, 1984, Lippincott, p 124.

91.Lindner B: Acute posterior vitreous detachment and its retinal complications, Acta Ophthalmol Suppl 87:1, 1966.

92.Weber H, Landwehr G: A new method for the determination of the mechanical properties of the vitreous, Ophthalmic Res 14:326, 1982.

93.Weber H, Landwehr G, Kilp H, et al: The mechanical properties of the vitreous of pig and human donor eyes, Ophthalmic Res 14:335, 1982.

94.Holekamp NM: The vitreous gel: more than meets the eye, Am J Ophthalmol 149:32–36, 2010.

95.Harocopos GJ, Shui Y, McKinnon M, et al: Importance of vitreous liquefaction in age-related cataract,­ Invest Ophthalmol Vis Sci 45:77–85, 2004.

96.Melberg NS, Thomas MA: Nuclear sclerotic cataract after vitrectomy in patients younger than 50 years of age, Ophthalmology 102:1466–1471, 1995.

97.Shui B, Holekamp NM, Kramer BC, et al: The gel state of the vitreous­ and ascorbate-dependent oxygen consumption: relationship to the etiology of nuclear cataracts, Arch Ophthtalmol 127:475–482, 2009.