Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010

3.4 Gross photograph of a plate hydrophilic acrylic lens (Acqua) explanted because of blue discoloration related to intraoperative use of capsular dyes (trypan blue).

2 months after surgery and submitted for gross and microscopic analyses performed in a dry state and after hydration. Analyses of the lens revealed that the dark blue staining was denser within the optic component, especially in the optical periphery. The blue discoloration could not be removed after 24 hours of immersion of the lens in balanced salt solution at 37 °C. The same analyses were performed on two unused lenses of the same design, which had been immersed in diluted trypan blue solutions (0.01% and 0.001%). Permanent staining of the unused lenses was also obtained after immersion in the experimental solutions.

Most of the currently available hydrophilic acrylic lenses have water contents ranging from 18% to 28%. They are packaged in a vial containing distilled water or balanced salt solutions, thus they are implanted in the hydrated state and in their final dimensions. Hydration renders these lenses flexible, enabling the surgeons to fold and insert them through small incisions. To our knowledge, the Acqua lens is manufactured from the hydrophilic acrylic material with the highest water content (73.5%) currently used for the manufacture of IOLs. This lens is implanted in the dry state, its expansion depending on its hydration by the fluids within the capsular bag. It appears that minimal amounts of dye still present in the capsular bag during IOL implantation may be absorbed by this lens. Therefore, capsular dyes should not be used in association with the Acqua lens.

After this report, trypan blue, ICG, and fluorescein sodium have been tested in laboratory settings to evaluate their interaction with various IOL

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materials. These tests showed that only the hydrophilic acrylic lenses could significantly absorb commonly used capsular dyes.

3.4.2Calcification

Postoperative optic opacification of modern hydrophilic acrylic IOL designs has been a significant complication leading to IOL explantation since 1999.1,37 Different studies using histopathological, histochemical, electron microscopic, as well as elemental or molecular surface analytical techniques demonstrated

that the opacification was related to calcium/phosphate precipitation on (Fig. 3.5) and/or within (Fig. 3.6) the lenses.38–47 The four major designs

manufactured in the United States that were involved in the problem were the Hydroview (Bausch & Lomb), the MemoryLens (Ciba Vision), the SC60BOUV (Medical Developmental Research), and the Aqua-Sense (Ophthalmic Innovations International).Sporadic cases involving hydrophilic acrylic lenses manufactured in Europe were also described.37 Although in many cases it was difficult to determine the time that optic opacification was first observed, the lenses involved in the problem were on average explanted during the second year after implantation. The opacification was not associated with anterior segment inflammatory reaction and Nd:YAG laser 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, as the lenses in the previous packaging did not calcify. Guan et al. evaluated the role of silicone compounds interacting with longchain saturated fatty acids present in the aqueous humor (myristic, palmitic, stearic, arachidic, and behenic) on the calcification process.40 The IOLs were exposed to cyclic silicone compounds, and 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 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/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 had been used intraoperatively in all of the cases of calcification requiring explantation (N = 20).44 Ohrstrom et al. had already demonstrated that the amount of silicone oil within the syringes of the same OVD was one of the highest among five different brands.48

Dorey et al. analyzed 17 explanted Hydroview lenses and demonstrated

3.5 Calcification of hydrophilic acrylic lenses. (a) and (b)

Hydroview lens. (c) and

(d) MemoryLens. The gross (a) and (c) and light photomicrographs (b) and (d) show the calcified deposits mostly on the surfaces of the lenses.

51 lenses intraocular implanted of degradation and Opacification

3.6 Calcification of hydrophilic acrylic lenses.

(a) and (b) SC60B-OUV lens.

(c) and (d) Aqua-Sense lens. The gross (a) and (c) and light photomicrographs (b) and (d) show the calcified deposits mostly within the substance of the lenses.

ophthalmology in medicine regenerative and Biomaterials 52

the presence of the element silicon mainly at the center of the calcified deposits, in surface analyses using EDS coupled with transmission electron microscopy.38 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.47 Ophthalmic Innovations International also confirmed the presence of siloxane silicone elastomers in the packaging components used at that time. As a result of the above-mentioned research the packaging of the Hydroview and Aqua-Sense lenses was significantly changed. 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 to as ‘particles’ in some publications). Therefore, further investigation is necessary regarding the relationship between our results and those of Dorey and the silicone compounds found on the Hydroview and Aqua-Sense by analyses performed at the molecular level.

Gartaganis et al. provided further contribution to the understanding of the IOL calcification process.39 They described their three-part study involving morphological 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 PMMA and poly(2-hydroxyethyl methacrylate) (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/phosphate ions. The authors, as well as others before them,49 recognized that calcium/phosphate may be derived from residual cataractous lens material. Perhaps differences in surgical technique, including the extent of cortical clean up may explain, at least in part, why patients bilaterally implanted with hydrophilic acrylic IOLs from the same lot sometimes develop calcification in only one of the lenses.

Similar studies have also been performed by Nakanome et al.42 These authors measured the concentration of calcium, phosphate, and albumin in the aqueous humor collected from ten eyes with calcified IOLs (all diabetic patients; nine with diabetic retinopathy and five from patients on hemodialysis). High concentrations of the three parameters measured were found, believed to be associated with chronic breakdown of the blood–aqueous barrier. The authors also placed Hydroview lenses in calcium/phosphate solutions with 25 mg/dL albumin. One group of lenses was subjected to large fluctuations

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in the concentrations of calcium and phosphate in the solutions (simulating hemodialysis conditions), while the other group was kept under constant calcium/phosphate concentrations. Calcified deposits were observed on the surface of the lenses in the first group within 7 days, while no significant calcification was observed on the lenses in the second group.

Regarding the MemoryLens design, the manufacturer (Ciba Vision) correlated the opacification problem with a change in the polishing process in 1999.43 The modified manufacturing method used a phosphate buffer in the tumbling process, which would attract more protein. The process would then continue to progress with the deposition of minerals, most likely calcium, on top of the protein film. According to the manufacturer, a worldwide recall of this lens in April 2000 (associated with cases of sterile hypopyon) also included all MemoryLens IOLs manufactured using the modified tumbling process. Ciba Vision then changed the polishing process and re-introduced the MemoryLens in October 2000 with the models U940S and CV232, the latter featuring a square optic-edge design.

More recently, we described for the first time the case of a MemoryLens IOL model CV232 that was explanted 18 months postoperatively.50 The patient had decreased visual acuity with the presence of a well-circumscribed, centrally/paracentrally located opacification of the optic. The area had the aspect of a small ‘lens within the lens’ or a regular, round bubble. The opacification observed within the CV232 lens remained well localized, without notable changes in its aspect since it was first noted 1 year after the surgery, until the lens was explanted 6 months later. It was actually difficult to determine the clinical significance of the IOL opacity precisely in that case. The postoperative decrease in visual acuity could eventually be, at least partially, related to posterior capsule opacification (PCO) formation, and eventually to retinal and glaucoma problems. The analyses of the explanted CV232 lens revealed that within the localized round area of opacification there were deposits (large crystals) distributed within an optic ‘void’, seen as a linear breach in sagittal cuts. We hypothesized that the precipitation of calcium in this case was a process secondary to the optic defect. The origin of the optic defect remains speculative at this point. We are aware of other similar cases with the new CV232 design, including asymptomatic cases where explantation was not necessary, and cases where the localized area within the optic has the aspect of a clear bubble (Fig. 3.7), without significant opacification. Whether or not secondary calcification will occur within the optic void in these cases at some point in the postoperative period is still unknown.

Calcification of hydrophilic acrylic lenses appears to be a multifactorial problem, and factors related to IOL manufacture, IOL packaging, surgical techniques and adjuvants, as well as patient metabolic conditions, among others, may be implicated. As the exact combination of factors and sequence

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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 further complicated 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, to avoid performance of unnecessary procedures, such as Nd:YAG laser posterior capsulotomy (after a misdiagnosis of PCO), or vitrectomy (after a misdiagnosis of some form of vitreous opacity). We have recently described eight cases where calcification of the implanted MemoryLens IOLs was not recognized, with unnecessary procedures and repeated interventions ultimately leading to complications such as retinal detachment and endophthalmitis.41 Explantation/exchange of the opacified/ calcified IOL is to date the only possible treatment.

3.5Opacification and degradation of hydrophobic acrylic intraocular lenses

3.5.1Interlenticular opacification

Although not representing a cause of opacification of the IOL itself, the problem of interlenticular opacification (ILO) has only been significantly related to hydrophobic acrylic IOLs. ILO is the opacification of the opposing surfaces of IOLs implanted in a piggyback manner. The purpose of implanting two or more posterior-chamber IOLs (polypseudophakia or piggyback IOLs) is to (a) provide adequate pseudophakic optical correction for patients requiring high IOL power or (b) provide secondary correction of an undesirable optical result following cataract–IOL surgery.51,52 To date, all cases analyzed in our laboratory seemed to be related to two posterior-chamber IOLs being implanted in the capsular bag through a small capsulorhexis,

with its margins overlapping the optic edge of the anterior IOL for 360° (Fig. 3.8).51–54 In addition, all of the explanted lenses we received were

three-piece AcrySof IOLs (Alcon, Inc.). The adhesive nature of the acrylic material of this lens may play a role in the outcome of this complication, rendering removal of any opacity within the interlenticular space surgically difficult. Laboratory analyses allowed us to conclude that the opacification within the interlenticular space is derived from retained/regenerative cortex and pearls, which is similar to the pathogenesis of the pearl form of PCO. The aspect of the opacifying material varies according to the space available in the interlenticular interface.53

One should be aware that careful cortical clean up is mandatory in piggyback implantation. Also, based on the common features of different cases of ILO, some surgical methods were proposed for its prevention. The

3.8 Light photomicrograph of a pair of three-piece hydrophobic acrylic lenses, which were implanted in the capsular bag, and were explanted because of interlenticular opacification. The arrow shows the central contact area between the optic components of the lenses, where no opacification is present.

first option would be to implant both IOLs in the capsular bag but with a relatively larger diameter capsulorhexis. The other possibility is to implant the anterior IOL in the sulcus and the posterior IOL in the bag with a small rhexis. In both scenarios, the lens epithelial cells within the equatorial fornix will be sequestered.

To the best of our knowledge, ILO is not a common occurrence in association with silicone lenses. We performed an animal study to evaluate and compare the incidence of capsular bag opacification, focusing on ILO in rabbit eyes implanted with a dual-optic silicone IOL or piggyback lenses.54 Ten dual-optic study IOLs (Synchrony, Visiogen), ten control pairs of piggyback silicone-plate lenses, and ten control pairs of piggyback single-piece hydrophobic acrylic lenses were implanted in the bag following phacoemulsification. After a follow-up of 6 weeks, the rabbits were killed; their eyes were enucleated and underwent gross and microscopic evaluation after histopathological processing. In this study, ILO formation was statistically different among the three groups of lenses, but the differences between the study IOL group and the pair of silicone-plate lens group were not significant. ILO comparisons between the hydrophobic acrylic lenses and the study lens, or the silicone-plate lenses were significant. Histopathological examination showed extension of the proliferating cortical material from the peripheral Soemmering’s ring into the interlenticular space, causing ILO, especially with the pairs of hydrophobic acrylic lenses.

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3.5.2Glistenings

Glistenings are fluid-filled microvacuoles (1–20 microns in diameter) that form within the IOL optic when the lens is in an aqueous environment.55 Although they are largely described in association with hydrophobic acrylic IOLs (Fig. 3.9),56 they can actually be observed with different IOL materials, including PMMA.57–59 The majority of peer-reviewed articles on glistenings available in the literature describe them in relation to the AcrySof material. Earlier in vitro studies demonstrated that glistenings were confined to IOLs packaged in AcryPak folders maintained at constant body temperature.55 Glistenings were noted in the Wagon Wheel-packaged IOLs only under fluctuating temperature conditions. Other studies demonstrated in vitro glistening formation after incubating different types of hydrophobic acrylic lenses in salt solution, and subjecting them to changes in temperature. The change in the equilibrium water content caused by temperature changes between 30 and 40 °C was found to be an important factor in glistening formation, and IOL materials featuring less temperature-dependent water absorption would be less likely to form glistenings.60–62

There is still controversy on whether or not glistenings have any impact on the visual function of the patient, and if they progress over time. Regarding clinical significance, an earlier study evaluated 17 patients implanted with a hydrophobic acrylic IOL (three-piece AcrySof in AcryPak folders), 10 of the patients having a silicone IOL in the contralateral eye.63 All 17 eyes with the acrylic IOLs had some lenticular glistenings, ranging from trace to 2+. Statistical analysis of visual acuity, contrast sensitivity, and glare testing revealed a statistically significant difference between the acrylic and the silicone IOLs only in contrast sensitivity. A later study comparing eyes implanted with a hydrophobic acrylic IOL (Wagon Wheel-packaged three-piece AcrySof) with glistenings, and eyes with the same IOL but without glistenings, only showed a statistically significant difference in contrast sensitivity at the high spatial frequency.64 Christiansen et al. graded glistenings in 42 eyes implanted with the same hydrophobic acrylic lens from trace to 4+.65 They found a slight decrease in visual function in eyes with glistenings graded as 2+ or more, in comparison to eyes with lower grades of glistenings. However, Oshika et al. experimentally created 1+ to 4+ glistenings in Wagon Wheel-packaged three-piece AcrySof lenses, among which the 4+ glistenings were found to be beyond the range of clinical settings.66 By using optical bench tests, the authors determined that only the 4+ glistenings obtained would cause mild to moderate deterioration of the optical quality of the lens.

Different studies looked at the progression of glistenings over time. In clinical and experimental settings, Miyata et al. found that glistenings reached their peak in number within a few months of formation in all cases, showing no further increase thereafter.67 Experimental glistenings first appeared on