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Calcification of Hydrophilic Acrylic Intraocular Lenses
Calcification of Hydrophilic Acrylic Intraocular Lenses LILIANA WERNER
P
OSTOPERATIVE OPTIC OPACIFICATION OF MODERN
hydrophilic acrylic intraocular lens (IOL) designs has been a significant complication leading to IOL explantation since 1999.1 The 2001 survey sent to members of the American and European Societies of Cataract and Refractive Surgery showed that hydrophilic acrylic lenses were the most frequently explanted type (28%), and in most cases (98%), explantation was required because of optic opacification.2 Different studies using histopathologic, histochemical, electron microscopic, as well as elemental or molecular surface analytic techniques demonstrated that the opacification was related to calcium or phosphate precipitation on or within the lenses, or both.3–11 The four major designs manufactured in the United States involved in the problem were the Hydroview (Bausch & Lomb, Rochester, New York, USA), the MemoryLens (Ciba Vision, Duluth, Georgia, USA), the SC60B-OUV (Medical Developmental Research, Clearwater, Florida, USA), and the Aqua-Sense (Ophthalmic Innovations International, Ontario, California, USA). Sporadic cases involving hydrophilic acrylic lenses manufactured in Europe also were described.1 Although in many cases it was difficult to determine the time at which optic opacification was first observed, the lenses involved in the problem on average were explanted during the second year after implantation. The opacification was not associated with anterior segment inflammatory reaction, and neodymium:yytrium–aluminum– garnet (Nd:YAG) laser treatment was ineffective in removing the calcified deposits from the lenses. Different experimental methods have been used in an attempt to elucidate the factors involved in the calcification of hydrophilic acrylic lenses. In the case of the Hydroview, the silicone gasket sealing the SureFold cap came under suspicion early, because the lenses in the previous packaging did not calcify. Guan and associates evaluated the role of silicone compounds interacting with long-chain saturated fatty acids present in the aqueous humor (myristic, palmitic, stearic, arachidic, and behenic) on the calcification process.7 The IOLs were exposed to cyclic silicone compounds and were treated with one of the above-mentioned fatty acids, at different concentrations. Then, they were rinsed and placed in supersaturated solutions of calcium chloride and potassium dihydrogen phosphate. The authors demonstrated that hydrophobic See accompanying Article on page 395. Accepted for publication May 7, 2008. From the Intermountain Ocular Research Center, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah. Inquiries to Liliana Werner, 65 Mario Capecchi Drive, Salt Lake City, UT 84132; e-mail: [email protected] 0002-9394/08/$34.00 doi:10.1016/j.ajo.2008.05.011
©
2008 BY
cyclic silicone compounds adsorbed at the IOL surfaces interacted strongly with the hydrophobic carbon chains of the fatty acids to create a layer of fatty acids oriented with polar, functional hydrophilic groups exposed to the aqueous solution, providing nucleation sites for calcium and phosphate. Interestingly, in a retrospective study of 949 cases of Hydroview IOL implantations carried out between 1998 and 2000, a phosphate-buffered ophthalmic viscosurgical device (OVD) preparation was used during surgery in all of the cases of calcification requiring explantation (n ⫽ 20).12 Ohrstrom and associates already had demonstrated that the amount of silicone oil within the syringes of the same OVD was one of the highest among five different brands.13 Dorey and associates analyzed 17 explanted Hydroview lenses and demonstrated the presence of the element silicon mainly at the center of the calcified deposits, in surface analyses using energy dispersive x-ray spectroscopy (EDS) coupled with transmission electron microscopy.5 Later, we demonstrated the presence of the element silicon in relation to calcified deposits with the three other major hydrophilic acrylic designs that have been associated with calcification by using an EDS system attached to an environmental scanning electron microscope.8 Ophthalmic Innovations International also confirmed the presence of siloxane silicone elastomers in the packaging components used at that time. As a result of the abovementioned research, the packaging of the Hydroview and Aqua-Sense lenses was changed significantly. When comparing different studies on surface analyses of explanted calcified lenses, one should be aware of the differences between the techniques used. The analyses carried out by the manufacturers of the Hydroview and Aqua-Sense designs give information at the molecular level. According to them, the contamination with those designs was in the form of low-molecular-weight silicone compounds forming a thin fluid film (although it is referred as particles in some publications). These kinds of techniques (e.g., x-ray photoelectron spectroscopy and surface mass spectroscopy) sample the top 75 Angstroms of a surface, against 1,000 to 50,000 Angstroms sampled by EDS. The term weight percentage of an element, used to describe the presence of the silicon element in Dorey and associates’ and my group’s studies, is actually a measurement of a volume element at one spot only. EDS analyses are probably more useful to describe particulate forms of contamination, such as silica instead of a silicone monolayer. Therefore, further investigation is necessary regarding the relationship between Dorey and associates’ and my group’s results and the silicone compounds found on the
ELSEVIER INC. ALL
RIGHTS RESERVED.
341
the three parameters measured were found and were believed to be associated with chronic breakdown of the blood-aqueous barrier. The authors also placed Hydroview lenses in calcium and phosphate solutions with 25 mg/dl albumin. One group of lenses was subjected to large fluctuations in the concentrations of calcium and phosphate in the solutions (simulating hemodialysis conditions), whereas the other group was kept under constant calcium and phosphate concentrations. Calcified deposits were observed on the surface of the lenses in the first group within seven days, whereas no significant calcification was observed on the lenses in the second group. Calcification of hydrophilic acrylic lenses seems to be a multifactorial problem, and factors related to IOL manufacture, IOL packaging, surgical techniques, adjuvants, as well as patient metabolic conditions, among others, may be implicated. Because the exact combination of factors and sequence of events ultimately leading to calcification of the lenses is still unknown, continuous research on this complication is warranted. This requires a multidisciplinary approach, which is complicated further by the fact that detailed manufacturing procedures are considered proprietary information, and some IOL designs are distributed in different countries with different commercial names. In the meantime, surgeons must be able to recognize this condition during clinical examination. Not recognizing it can lead to potentially avoidable surgical procedures and increased risk of complications after repeated interventions.9 Explantation or exchange of the opacified or calcified IOL to date is the only possible treatment.
Hydroview and Aqua-Sense by analyses carried out at the molecular level.5,8 In this issue of THE JOURNAL, Gartaganis and associates provided further contribution to the understanding of the IOL calcification process.11 In the current issue, they describe their three-part study involving morphologic analyses of explants (24 Hydroview, two SC60B-OUV, two MemoryLens, and two Aqua-Sense), chemical analyses of aqueous humor collected from cases of explanted calcified IOLs, and in vitro experiments using polymethylmethacrylate and poly 2-hydroxyethylmethacrylate (PHEMA) polymer powder suspended in solutions supersaturated with calcium and phosphate. They concluded that a key factor in the development of crystalline phosphate salts is represented by local conditions of supersaturation either in the vicinity of the surface of the IOLs or within their substance, where salts develop by diffusion of calcium or phosphate ions. The authors,11 as well as others before them,14 recognized that calcium and phosphate may be derived from residual cataractous lens material. Perhaps differences in surgical technique, including extent of cortical clean-up, may explain at least in part why in patients bilaterally implanted with hydrophilic acrylic IOLs from the same lot, calcification in only one of the lenses sometimes develops. Similar studies also were performed by Nakanome and associates.10 These authors measured the concentration of calcium, phosphate, and albumin in the aqueous humor collected from 10 eyes with calcified IOLs (all diabetic patients; nine with diabetic retinopathy and five from patients receiving hemodialysis). High concentrations of
THIS STUDY WAS SUPPORTED IN PART BY THE RESEARCH TO PREVENT BLINDNESS OLGA KEITH WEISS SCHOLAR AWARD, NEW York, New York; and a Research Grant from the European Society of Cataract and Refractive Surgeons (ESCRS), Dublin, Ireland. The author indicates no financial conflict of interest. The author was involved in design and conduct of study; data collection; analysis and interpretation of data; and preparation and review of manuscript.
6. Neuhann IM, Werner L, Izak AM, et al. Late postoperative opacification of a hydrophilic acrylic (Hydrogel) intraocular lens: A clinicopathological analysis of 106 explants. Ophthalmology 2004;111:2094 –2101. 7. Guan X, Tang R, Nancollas GH. The potential calcification of octacalcium phosphate on intraocular lens surfaces. J Biomed Mater Res 2004;71A:488 – 496. 8. Werner L, Hunter B, Stevens S, Chew JJL, Mamalis N. Role of silicon contamination on calcification of hydrophilic acrylic intraocular lenses. Am J Ophthalmol 2006;141:35– 43. 9. Haymore J, Zaidman G, Werner L, et al. Misdiagnosis of hydrophilic acrylic intraocular lens optic opacification: report of 8 cases with the MemoryLens. Ophthalmology 2007;114:1689 –1695. 10. Nakanome S, Watanabe H, Tanaka K, Tochikubo T. Calcification of Hydroview H60M intraocular lenses: aqueous humor analysis and comparisons with other intraocular lens materials. J Cataract Refract Surg 2008;34:80 – 86. 11. Gartaganis SP, Kanellopoulou DG, Mela EK, et al. Opacification of hydrophilic acrylic intraocular lens attributable
REFERENCES 1. Werner L. Causes of intraocular lens opacification or discoloration. J Cataract Refract Surg 2007;33:713–726. 2. Mamalis N. Complications of foldable intraocular lenses requiring explantation or secondary intervention—2001 survey update. J Cataract Refract Surg 2002;28:2193–2201. 3. Werner L, Apple DJ, Escobar-Gomez M, et al. Postoperative deposition of calcium on the surfaces of a hydrogel intraocular lens. Ophthalmology 2000;107:2179 –2185. 4. Werner L, Apple DJ, Kaskaloglu M, Pandey SK. Dense opacification of the optical component of a hydrophilic acrylic intraocular lens: a clinicopathological analysis of 9 explanted lenses. J Cataract Refract Surg 2001;27:1485– 1492. 5. Dorey MW, Brownstein S, Hill VE, et al. Proposed pathogenesis for the delayed postoperative opacification of the Hydroview hydrogel intraocular lens. Am J Ophthalmol 2003;135:591–598.
342
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
SEPTEMBER 2008
to calcification: Investigation on mechanism. Am J Ophthalmol 2008;146:395– 403. 12. Sher JH, Gooi P, Dubinski W, et al. Comparison of the incidence of opacification of Hydroview hydrogel intraocular lenses with the ophthalmic viscosurgical device used during surgery. J Cataract Refract Surg 2008;34:459 – 464.
VOL. 146, NO. 3
13. Ohrstrom A, Svensson B, Tegenfeldt S, Celiker C, Lignell B. Silicone oil content in ophthalmic viscosurgical devices. J Cataract Refract Surg 2004;30:1278 –1280. 14. Bucher PJM, Buchi ER, Daicker BC. Dystrophic calcification of an implanted hydroxyethylmethacrylate intraocular lens. Arch Ophthalmol 1995;113:1431–1435.
EDITORIAL
343
P
OSTOPERATIVE OPTIC OPACIFICATION OF MODERN
hydrophilic acrylic intraocular lens (IOL) designs has been a significant complication leading to IOL explantation since 1999.1 The 2001 survey sent to members of the American and European Societies of Cataract and Refractive Surgery showed that hydrophilic acrylic lenses were the most frequently explanted type (28%), and in most cases (98%), explantation was required because of optic opacification.2 Different studies using histopathologic, histochemical, electron microscopic, as well as elemental or molecular surface analytic techniques demonstrated that the opacification was related to calcium or phosphate precipitation on or within the lenses, or both.3–11 The four major designs manufactured in the United States involved in the problem were the Hydroview (Bausch & Lomb, Rochester, New York, USA), the MemoryLens (Ciba Vision, Duluth, Georgia, USA), the SC60B-OUV (Medical Developmental Research, Clearwater, Florida, USA), and the Aqua-Sense (Ophthalmic Innovations International, Ontario, California, USA). Sporadic cases involving hydrophilic acrylic lenses manufactured in Europe also were described.1 Although in many cases it was difficult to determine the time at which optic opacification was first observed, the lenses involved in the problem on average were explanted during the second year after implantation. The opacification was not associated with anterior segment inflammatory reaction, and neodymium:yytrium–aluminum– garnet (Nd:YAG) laser treatment was ineffective in removing the calcified deposits from the lenses. Different experimental methods have been used in an attempt to elucidate the factors involved in the calcification of hydrophilic acrylic lenses. In the case of the Hydroview, the silicone gasket sealing the SureFold cap came under suspicion early, because the lenses in the previous packaging did not calcify. Guan and associates evaluated the role of silicone compounds interacting with long-chain saturated fatty acids present in the aqueous humor (myristic, palmitic, stearic, arachidic, and behenic) on the calcification process.7 The IOLs were exposed to cyclic silicone compounds and were treated with one of the above-mentioned fatty acids, at different concentrations. Then, they were rinsed and placed in supersaturated solutions of calcium chloride and potassium dihydrogen phosphate. The authors demonstrated that hydrophobic See accompanying Article on page 395. Accepted for publication May 7, 2008. From the Intermountain Ocular Research Center, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah. Inquiries to Liliana Werner, 65 Mario Capecchi Drive, Salt Lake City, UT 84132; e-mail: [email protected] 0002-9394/08/$34.00 doi:10.1016/j.ajo.2008.05.011
©
2008 BY
cyclic silicone compounds adsorbed at the IOL surfaces interacted strongly with the hydrophobic carbon chains of the fatty acids to create a layer of fatty acids oriented with polar, functional hydrophilic groups exposed to the aqueous solution, providing nucleation sites for calcium and phosphate. Interestingly, in a retrospective study of 949 cases of Hydroview IOL implantations carried out between 1998 and 2000, a phosphate-buffered ophthalmic viscosurgical device (OVD) preparation was used during surgery in all of the cases of calcification requiring explantation (n ⫽ 20).12 Ohrstrom and associates already had demonstrated that the amount of silicone oil within the syringes of the same OVD was one of the highest among five different brands.13 Dorey and associates analyzed 17 explanted Hydroview lenses and demonstrated the presence of the element silicon mainly at the center of the calcified deposits, in surface analyses using energy dispersive x-ray spectroscopy (EDS) coupled with transmission electron microscopy.5 Later, we demonstrated the presence of the element silicon in relation to calcified deposits with the three other major hydrophilic acrylic designs that have been associated with calcification by using an EDS system attached to an environmental scanning electron microscope.8 Ophthalmic Innovations International also confirmed the presence of siloxane silicone elastomers in the packaging components used at that time. As a result of the abovementioned research, the packaging of the Hydroview and Aqua-Sense lenses was changed significantly. When comparing different studies on surface analyses of explanted calcified lenses, one should be aware of the differences between the techniques used. The analyses carried out by the manufacturers of the Hydroview and Aqua-Sense designs give information at the molecular level. According to them, the contamination with those designs was in the form of low-molecular-weight silicone compounds forming a thin fluid film (although it is referred as particles in some publications). These kinds of techniques (e.g., x-ray photoelectron spectroscopy and surface mass spectroscopy) sample the top 75 Angstroms of a surface, against 1,000 to 50,000 Angstroms sampled by EDS. The term weight percentage of an element, used to describe the presence of the silicon element in Dorey and associates’ and my group’s studies, is actually a measurement of a volume element at one spot only. EDS analyses are probably more useful to describe particulate forms of contamination, such as silica instead of a silicone monolayer. Therefore, further investigation is necessary regarding the relationship between Dorey and associates’ and my group’s results and the silicone compounds found on the
ELSEVIER INC. ALL
RIGHTS RESERVED.
341
the three parameters measured were found and were believed to be associated with chronic breakdown of the blood-aqueous barrier. The authors also placed Hydroview lenses in calcium and phosphate solutions with 25 mg/dl albumin. One group of lenses was subjected to large fluctuations in the concentrations of calcium and phosphate in the solutions (simulating hemodialysis conditions), whereas the other group was kept under constant calcium and phosphate concentrations. Calcified deposits were observed on the surface of the lenses in the first group within seven days, whereas no significant calcification was observed on the lenses in the second group. Calcification of hydrophilic acrylic lenses seems to be a multifactorial problem, and factors related to IOL manufacture, IOL packaging, surgical techniques, adjuvants, as well as patient metabolic conditions, among others, may be implicated. Because the exact combination of factors and sequence of events ultimately leading to calcification of the lenses is still unknown, continuous research on this complication is warranted. This requires a multidisciplinary approach, which is complicated further by the fact that detailed manufacturing procedures are considered proprietary information, and some IOL designs are distributed in different countries with different commercial names. In the meantime, surgeons must be able to recognize this condition during clinical examination. Not recognizing it can lead to potentially avoidable surgical procedures and increased risk of complications after repeated interventions.9 Explantation or exchange of the opacified or calcified IOL to date is the only possible treatment.
Hydroview and Aqua-Sense by analyses carried out at the molecular level.5,8 In this issue of THE JOURNAL, Gartaganis and associates provided further contribution to the understanding of the IOL calcification process.11 In the current issue, they describe their three-part study involving morphologic analyses of explants (24 Hydroview, two SC60B-OUV, two MemoryLens, and two Aqua-Sense), chemical analyses of aqueous humor collected from cases of explanted calcified IOLs, and in vitro experiments using polymethylmethacrylate and poly 2-hydroxyethylmethacrylate (PHEMA) polymer powder suspended in solutions supersaturated with calcium and phosphate. They concluded that a key factor in the development of crystalline phosphate salts is represented by local conditions of supersaturation either in the vicinity of the surface of the IOLs or within their substance, where salts develop by diffusion of calcium or phosphate ions. The authors,11 as well as others before them,14 recognized that calcium and phosphate may be derived from residual cataractous lens material. Perhaps differences in surgical technique, including extent of cortical clean-up, may explain at least in part why in patients bilaterally implanted with hydrophilic acrylic IOLs from the same lot, calcification in only one of the lenses sometimes develops. Similar studies also were performed by Nakanome and associates.10 These authors measured the concentration of calcium, phosphate, and albumin in the aqueous humor collected from 10 eyes with calcified IOLs (all diabetic patients; nine with diabetic retinopathy and five from patients receiving hemodialysis). High concentrations of
THIS STUDY WAS SUPPORTED IN PART BY THE RESEARCH TO PREVENT BLINDNESS OLGA KEITH WEISS SCHOLAR AWARD, NEW York, New York; and a Research Grant from the European Society of Cataract and Refractive Surgeons (ESCRS), Dublin, Ireland. The author indicates no financial conflict of interest. The author was involved in design and conduct of study; data collection; analysis and interpretation of data; and preparation and review of manuscript.
6. Neuhann IM, Werner L, Izak AM, et al. Late postoperative opacification of a hydrophilic acrylic (Hydrogel) intraocular lens: A clinicopathological analysis of 106 explants. Ophthalmology 2004;111:2094 –2101. 7. Guan X, Tang R, Nancollas GH. The potential calcification of octacalcium phosphate on intraocular lens surfaces. J Biomed Mater Res 2004;71A:488 – 496. 8. Werner L, Hunter B, Stevens S, Chew JJL, Mamalis N. Role of silicon contamination on calcification of hydrophilic acrylic intraocular lenses. Am J Ophthalmol 2006;141:35– 43. 9. Haymore J, Zaidman G, Werner L, et al. Misdiagnosis of hydrophilic acrylic intraocular lens optic opacification: report of 8 cases with the MemoryLens. Ophthalmology 2007;114:1689 –1695. 10. Nakanome S, Watanabe H, Tanaka K, Tochikubo T. Calcification of Hydroview H60M intraocular lenses: aqueous humor analysis and comparisons with other intraocular lens materials. J Cataract Refract Surg 2008;34:80 – 86. 11. Gartaganis SP, Kanellopoulou DG, Mela EK, et al. Opacification of hydrophilic acrylic intraocular lens attributable
REFERENCES 1. Werner L. Causes of intraocular lens opacification or discoloration. J Cataract Refract Surg 2007;33:713–726. 2. Mamalis N. Complications of foldable intraocular lenses requiring explantation or secondary intervention—2001 survey update. J Cataract Refract Surg 2002;28:2193–2201. 3. Werner L, Apple DJ, Escobar-Gomez M, et al. Postoperative deposition of calcium on the surfaces of a hydrogel intraocular lens. Ophthalmology 2000;107:2179 –2185. 4. Werner L, Apple DJ, Kaskaloglu M, Pandey SK. Dense opacification of the optical component of a hydrophilic acrylic intraocular lens: a clinicopathological analysis of 9 explanted lenses. J Cataract Refract Surg 2001;27:1485– 1492. 5. Dorey MW, Brownstein S, Hill VE, et al. Proposed pathogenesis for the delayed postoperative opacification of the Hydroview hydrogel intraocular lens. Am J Ophthalmol 2003;135:591–598.
342
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
SEPTEMBER 2008
to calcification: Investigation on mechanism. Am J Ophthalmol 2008;146:395– 403. 12. Sher JH, Gooi P, Dubinski W, et al. Comparison of the incidence of opacification of Hydroview hydrogel intraocular lenses with the ophthalmic viscosurgical device used during surgery. J Cataract Refract Surg 2008;34:459 – 464.
VOL. 146, NO. 3
13. Ohrstrom A, Svensson B, Tegenfeldt S, Celiker C, Lignell B. Silicone oil content in ophthalmic viscosurgical devices. J Cataract Refract Surg 2004;30:1278 –1280. 14. Bucher PJM, Buchi ER, Daicker BC. Dystrophic calcification of an implanted hydroxyethylmethacrylate intraocular lens. Arch Ophthalmol 1995;113:1431–1435.
EDITORIAL
343