Vitreous Substitutes for Posterior-segment Surgery
A review and discussion of their mechanisms of action
William J. Foster, MD, PhD
The human vitreous humor, or vitreous, is a complex polymeric system that plays a key role in ocular health1 and may play a role in the prevention of cataract formation and the development of open-angle glaucoma.2,3 Children with a formed, gel-like vitreous rarely develop rhegmatogenous retinal detachments. Conversely, liquefaction of the vitreous, with the formation of a posterior vitreous detachment, is the most common cause of this form of detachment. A clear understanding of the structure of the native vitreous, as well as of compounds that are used to replace the vitreous, thus aids the practicing surgeon in understanding the pathogenesis of vitreoretinal disease and the selection of appropriate vitreous substitutes during surgical interventions.
THE VITREOUS ITSELF
Although the vitreous is composed of approximately 98% water, it is a natural polymeric hydrogel composed primarily of type 2 collagen and hyaluronic acid.4 The vitreous possesses both viscous and elastic properties, and its mechanical properties originate from a complex interaction between the collagen fibrils and hyaluronic acid. These two biopolymers interact to form a hydrogel that is stable, even when subjected to conditions that would normally destroy collagen networks.
Based upon these observations and biophysical measurements, others have suggested that the random-coiled hyaluronan's innate need to expand in water is counterbalanced by the collagen fibrillar mesh network, resulting in a tightly balanced network with an internal osmotic pressure.5 Any attempt to manipulate this delicate architecture leads to separation of its components (syneresis) and renders the system nonphysiological, creating the conditions for vitreoretinal disease.6
In order to understand vitreous substitutes, it is helpful to understand a few terms from the physical sciences. Viscosity (technically dynamic viscosity), often measured in stokes (or centistokes [cs]), is a number that characterizes the internal friction of a fluid.7 Surface tension is the energy per area of surface and is conventionally measured in newtons per meter (or mN/m). Molecular weight, measured in daltons (or kDa), is the molar weight in grams of a mole of the polymer. The polydispersity of a polymer solution is a measure of the breadth of the molar mass distribution (ie, the range of the molecular masses of the polymer molecules that make up the solution) in a polymer solution.8
These concepts are helpful to know because silicone oils, for example, are sold on the ophthalmic market based upon their viscosity, rather than their molecular weight. Problems previously reported9 with some 1,000-cs silicone oils, rapid dispersing10 or emulsifying (forming a “foam”), might be due to a larger polydispersity (and thus the presence of more smaller molecules in the solution) rather than viscosity alone. Thus, a silicone oil with the same viscosity but with a smaller polydispersity index may not have this problem.
Compounds in current clinical use as vitreous substitutes include gases, silicone oils and perfluoronated alkanes.
Gases in common use in vitreoretinal surgery include (in order of persistence in the eye) filtered air, sulfur hexafluoride (SF6) and perfluoronated propane (C3F8) (see Figures 1 and 2). The latter two gases can be injected into the eye in either nonexpansile mixtures with filtered air (20% SF611 and 12% C3F812) or as pure gases. Gases are, in general, limited to treating the upper retina and are limited in that they cause the formation of a cataract when in prolonged contact with the lens and can expand, leading to elevated intraocular pressure.
Figure 1. The molecular structure of sulfur hexafluoride.
Figure 2. The molecular structure of perfluoropropane.
Mechanisms of Action
Surface tension is known to play a crucial role in the ability of intraocular gases to attach the retina and to maintain that attachment.10,13,14 Buoyancy has been previously thought to play a key role in retinal detachment,10 but quantitative consideration of clinically relevant quantities of gas13,14 (when the size of the bubble is larger than the size of the area of detached retina) suggests that this consideration is of secondary importance.
Given these considerations, if (1) the bubble of intraocular gas is sufficiently large such that the retinal hole or tear is covered by the bubble, (2) the bubble is prevented from prolonged contact with the native crystalline lens (which can lead to cataract formation), and (3) the bubble does not entirely block the trabecular mesh-work (which can lead to glaucoma), then the retinal hole or tear should be able to close without additional, physically difficult positioning. This fact has been demonstrated clinically in the case of macular hole surgery.15
Perfluoro-n-octane (for example, Perfluoron, Alcon Retina; and FCI-Octa, FCI Ophthalmic Surgical Devices) and perfluoro-n-decane (FCI-Deca, FCI Ophthalmic Surgical Devices) are perfluoronated alkanes that possess low viscosity and, critically, a high specific gravity (1.94 for Perfluoron). Because they are hydrophobic compounds, their surface tension at aqueous interfaces is high, approximately 50 mN/m. Although similar compounds (Perflubron [C8F27Br, LiquiVent, Alliance Pharmaceutical Corp]) can be used for the ventilation of patients in respiratory failure16 and has been proposed for ventilation during deep-sea diving,17 current perfluoron-based compounds used in the eye have been found18-20 to be toxic to the retina when used for prolonged periods of time.
Occasionally, there is discussion of the concept that heavy fluids can crush or shear the retina and that these physical phenomena account for the known damage to the inferior retina. Given that the difference in specific gravity between Perfluoron and aqueous is 0.94, while the difference between gas and aqueous is 1.0, we would expect similar superior damage in gas- or air-filled eyes.
In addition, simulations and in vivo rabbit studies21 have failed to provide a justification for this theory. Using similar physical arguments, as in the case of gas vitreous substitutes,14 it can be shown that surface tension plays a dominant role in retinal reattachment with the use of perfluorocarbons.
The poly(dimethyl)siloxanes are a group of polymeric compounds that are commonly used as vitreous substitutes, particularly in the case of complex retinal detachments. They have been used since 196222 for complex retinal detachments, retinal detachments associated with proliferative vitreoretinopathy, and for patients who are unable to position themselves. The most commonly available silicone oils have viscosities of 1,000 cs and 5,000 cs, and are selected primarily by surgeon preference, given the evidence that there is no difference in long-term surgical outcome.23 Silicone oils and mixtures containing silicone oil are toxic over prolonged periods of time and have long been known to emulsify in some patients, as well as lead to cataract formation, glaucoma and corneal decompensation.22
Modified Silicone Oils
Numerous so-called heavy silicone oils (mixtures of silicone oil and partially fluorinated or perfluorinated alkanes) have been tested in both in vitro and in vivo assays in order to develop compounds with improved properties for the repair of retinal detachments.24-28 Some of the clinical studies have noted both significant formation of intraocular emulsions and surgical success in particular clinical scenarios, but these compounds are not in common use.
Mechanisms of Action
Although the surface tension at the silicone oil–aqueous interface is only 30 mN/m, less than half that at the gas-aqueous interface,4 it is sufficiently high that it likely plays an important role in maintaining the retina in place.
The small difference in specific gravity between silicone oil and aqueous (1 - 0.97 = 0.03, compared with 1.0 for gas-aqueous) can be shown, using previously published reasoning,14 to be negligible in most clinically relevant situations. The primary influence of this difference is that the bubble of silicone oil will remain in the superior (away from the earth) portion of the eye.
Because the polymer backbone of silicone oil has both hydrophobic and hydrophilic components, it is both expected4 and is known31 to interact with cell membranes and ocular tissues. By adhering to the tissues, silicone oils are able to remain in contact with (and thus perhaps aid in the closure of) retinal holes. Other than histological studies, in which this behavior is found to be common,29 the extent to which this behavior is critical to success in the surgical use of silicone oils is unknown.
Given the known proinflammatory properties of silicone oil in other tissues,30 it is not surprising that silicone oil is known to induce localized intraocular inflammation,31 which is mediated by macrophages. The inflammation induced by silicone oil may contribute to effectiveness in repairing inferior retinal detachments. Furthermore, given that the specific gravity of silicone oils is lower than water (so silicone oils also float in aqueous fluids) and that the surface tension at the water-oil interface is only 30 mN/m (as compared to 72 mN/m at the water-gas interface), one might expect that there would be a lower surgical success rate with the use of silicone oil to repair complex retinal detachments.
In fact, the success rate for repair of complex retinal detachments with silicone oil is greater than the rate with SF632 and is similar to rate with the use of long-acting gas (C3F8).33 For this reason, silicone oil–based vitreous substitutes might not be ideal for the delivery of steroids, for example, because steroids might suppress the inflammation needed to create an adhesion between the retina and the underlying tissue. In addition, modulation of inflammation may be useful in the repair of retinal detachment and related retinal conditions.
Viscosity is not currently thought to play a major role in surgical efficacy because of the similar efficacy of oils of different viscosities.34 Viscosity may indirectly play a role in emulsification9 of silicone oils, for example, because a less viscous polymeric solution usually contains smaller (lower molecular weight) molecules, and smaller molecules are usually more susceptible to emulsification.
Given the limitations of current vitreous substitutes, substantial effort has been made to develop new compounds. While many of these compounds4,35 depend upon surface tension for their efficacy, a few investigators have developed alternative compounds that depend upon different physical principles and are discussed further below.
In order to attempt to replicate the young eye and to prevent complications related to a liquefied vitreous,1 we have seen an ongoing effort to develop a solid-gel polymeric system that gels after injection into the eye and re-approximates the retina using osmotic swelling.36 By utilizing formed polymer molecules that cross-link in the vitreous cavity, complications, such as thermal damage from an exothermic reaction and the toxicity of small molecules, are avoided. Careful attention has been paid to controlling the degree of swelling, as well as tuning the physical properties of the polymer to avoid having it serve as a scaffold for PVR/scar tissue.37-39
A creative approach to reattaching the retina is to make use of a magnetic analog of silicone oil and to place a magnetic band around the eye (in place of a scleral buckle).40 Because of the known toxicity of the constituents, careful evaluation of the toxicity will be critical. In addition, after surgical removal of the vitreous substitute, the band (now encased in scar tissue) will likely have to be left on the eye, limiting the patient's ability to undergo MRI imaging (or pass through an airport scanner).
The availability of current vitreous substitutes has revolutionized our ability to repair numerous complex vitreoretinal conditions successfully, such as most retinal detachments, giant retinal tears, macular holes and complex detachments. Current efforts to improve vitreous substitutes may enable even higher surgical success rates and faster visual rehabilitation. Others have even argued convincingly that vitreoretinal surgeons may someday surgically intervene to prevent such anterior-segment conditions as cataract and open-angle glaucoma.1
With our improved surgical technologies and better understanding of the vitreous, the next few years promise a series of exciting advances at the interface of vitreoretinal surgery and advanced materials. RP
1. Holekamp NM. The vitreous gel: more than meets the eye. Am J Ophthalmol. 2010;149:32-36.
2. Beebe DC, Holekamp NM, Siegfried C, Shui YB. Vitreoretinal influences on lens function and cataract. Phil Trans R Soc B. 2011;366:1293-1300.
3. Chang S. LXII Edward Jackson lecture: open angle glaucoma after vitrectomy. Am J Ophthalmol. 2006;141:1033-1043.
4. Foster WJ. Vitreous substitutes. Expert Rev Ophthalmol. 2008;3:211-218.
5. Nickerson CS, Park J, Kornfield JA, Karageozian H. Rheological properties of the vitreous and the role of hyaluronic acid. J Biomech. 2008;41:1840-1846.
6. Sebag J. Anomalous posterior vitreous detachment: a unifying concept in vitreoretinal disease. Graefes Arch Clin Exp Ophthalmol. 2004;242:690-698.
7. Landau LD, Lifshitz EM. Fluid Mechanics. 2nd ed. Course of Theoretical Physics, Volume 6. Oxford, UK; Pergamon Press; 1987:44-56.
8. Young RL, Lovell PA. Introduction to Polymers. 2nd ed. London, UK; Chapman & Hall; 1992:13.
9. Crisp A, de Juan E, Tiedeman J. Effect of silicone oil viscosity on emulsification. Arch Ophthalmol. 1987;105:546-550.
10. de Juan E, McCuen B, Tiedeman J. Intraocular tamponade and surface tension. Surv Ophthalmol. 1985;30:47-51.
11. Abrams GW, Edelhauser HF, Aaberg TM, Hamilton LH. Dynamics of intravitreal sulfur hexafluoride gas. Invest Ophthalmol. 1974;13:863-868.
12. Peters MA, Abrams GW, Hamilton LH, Burke JM, Schrieber TM. The nonexpansile, equilibrated concentration of perfluoropropane gas in the eye. Am J Ophthalmol. 1985;100:831-839.
13. Berger JW, Brucker AJ. The magnitude of the bubble buoyant pressure: implications for macular hole surgery. Retina. 1998;18:84-86.
14. Foster WJ, Chou T. Physical mechanisms of gas and perfluoron retinopexy and sub-retinal fluid displacement. Phys Med Biol. 2004;49:2989-2997.
15. Tornambe PE, Poliner LS, Grote K. Macular hole surgery without face-down positioning. Retina. 1997;17:179-185.
16. Hirschl RB, Pranikoff T, Gauger P, Schreiner RJ, Dechert R, Bartlett RH. Liquid ventilation in adults, children, and full-term neonates. Lancet. 1995; 346:1201-1202.
17. Kylstra JA. Liquid breathing. Undersea Biomed Res. 1974;1:259-269.
18. Chang S, Sparrow JR, Iwamoto T, Gershbein A, Ross R, Ortiz R. Experimental Studies of Tolerance to Intravitreal Perfluoro-n-octane Liquid. Retina. 1991;11:367-474.
19. Sparrow JR, Matthews GP, Iwamoto T, Ross R, Gershbein A, Chang S. Retinal tolerance to intravitreal perfluoroethylcyclohexane liquid in the rabbit. Retina. 1993;13:56-62.
20. Velikay M, Wedrich A, Stolba U, Datlinger P, Li Y, Binder S. Experimental long-term vitreous replacement with purified and nonpurified perfluorodecalin. Am J Ophthalmol. 1993;116:565-570.
21. Osterholz J, Winter M, Winkler J, et al. Retinale Schäden durch flüssige Perfluorkarbone - eine Frage des spezifischen Gewichts? Intraokulare Druckspitzen und Scherkräfte. Klin Monatsbl Augenheilkd. 2009;226:38-47.
22. Cibis PA, Becker B, Okun E, Canaan S. The use of liquid silicone in retinal detachment surgery. Arch Ophthalmol. 1962;68:590-599.
23. Scott IU, Flynn HW Jr, Murray TG, Smiddy WE, Davis JL, Feuer WJ. Outcomes of complex retinal detachment repair using 1000- vs 5000-centistoke silicone oil. Arch Ophthalmol. 2005;123:473-478.
24. Majid MA, Hussin HM, Biswas S, Haynes RJ, Mayer EJ, Dick AD. Emulsification of Densiron-68 used in inferior retinal detachment surgery. Eye (Lond). 2008;22:152-157.
25. Herbrig E, Sandner D, Engelmann K. Anatomical and functional results of endotamponade with heavy silicone oil-Densiron 68-in complicated retinal detachment. Ophthalmic Res. 2007;39:198-206.
26. Tognetto D, Minutola D, Sanguinetti G, Ravalico G. Anatomical and functional outcomes after heavy silicone oil tamponade in vitreoretinal surgery for complicated retinal detachment: a pilot study. Ophthalmology. 2005;112:1574e1-8.
27. Rizzo S, Genovesi-Ebert F, Vento A, Cresti F, Di Bartolo E, Belting C. A new heavy silicone oil (HWS 46-3000) used as a prolonged internal tamponade agent in complicated vitreoretinal surgery: a pilot study. Retina. 2007;27:613-620.
28. Theelen T, Tilanus MA, Klevering BJ. Intraocular inflammation following endotamponade with high-density silicone oil. Graefes Arch Clin Exp Ophthalmol. 2004;242:617-620.
29. Knorr HIJ, Seltsam A, Holbach LM. Intraocular silicone oil: a clinicopathological study of 36 enuculated eyes. Ophthalmologe. 1996;93:130-138.
30. Teuber SS, Yoshida SH, Gershwin ME. Immunopathologic effects of silicone breast implants. Western J Med. 1995;162:418-425.
31. Wickam L, Asaria RH, Alexander R, Luthert P, Charteris DG. Immunopathology of intraocular silicone oil: enucleated eyes. Br J Ophthalmol. 2007;91:253-257.
32. Vitrectomy with silicone oil or sulfur hexafluoride gas in eyes with severe proliferative vitreoretinopathy: results of a randomized clinical trial. Silicone Study Report 1. Arch Ophthalmol. 1992;110:770-779.
33. Vitrectomy with silicone oil or perfluoropropane gas in eyes with severe proliferative vitreoretinopathy: results of a randomized clinical trial. Silicone Study Report 2. Arch Ophthalmol. 1992;110:780-792.
34. Scott IU, Flynn HW Jr, Murray TG, Smiddy WE, Davis JL, Feuer WJ. Outcomes of complex retinal detachment repair using 1000- vs 5000-centistoke silicone oil. Arch Ophthalmol. 2005;123:473-478.
35. Colthurst MJ, Williams RL, Hiscott PS, Grierson I. Biomaterials used in the posterior segment of the eye. Biomaterials. 2000;21:649-665.
36. Foster WJ, Aliyar HA, Hamilton P, Ravi N. Internal osmotic pressure as a mechanism of retinal attachment in a vitreous substitute. J Bioact Compat Pol. 2006;21:221-235.
37. Foster WJ, Janmey PA, Flannagan LA, Ravi N. Proliferative vitreoretinopathy inhibition utilizing a nanostructured vitreous substitute. Paper presented at: Annual Meeting of the American Society of Retina Specialists; Palm Springs, CA; November 30-December 5, 2007.
38. Foster WJ, Janmey PA, Flanagan LA, Sawyer, ES. A novel, formed vitreous substitute to repair battlefield ocular trauma and complex retinal detachments: A mechanical mechanism of PVR (“scar tissue”) inhibition. Paper presented at: The Advanced Technology Applications for Combat Casualty Care Meeting; Saint Petersburg, FL; August 13-15, 2007.
39. Foster WJ, Janmey PA, Flanagan LA. A mechanical mechanism of proliferative vitreoretinopathy inhibition in vitreous substitutes. Paper presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; Fort Lauderdale, FL; April 27-May 1, 2008.
40. Phillips JP, Li C, Dailey JP, Riffle JS. Synthesis of silicone magnetic fluids for use in eye surgery. J Mag Mag Mater. 1999;194:140-148.
|William J. Foster, MD, PhD, is clinical associate professor of ophthalmology at Weill-Cornell Medical College at the Methodist Hospital in Houston, an associate member of the Methodist Hospital Research Institute, and research professor of physics at the University of Houston. Dr. Foster has no financial conflicts with the items discussed in this review, but he would like to acknowledge funding for partial salary support from the NEI and NIBIB of the NIH. He can be reached via e-mail at firstname.lastname@example.org.|