Lens epithelial inhibition by PMMA optic: Implications for lens design

Lens epithelial inhibition by PMMA optic: Implications for lens design Byron A. Santos, M. D. Monte A. DelMonte, M.D. Reinaldo Pastora, M. D. Francis E. O'Donnell, Jr., M.D. St. Louis, Missouri ABSTRACT It has been a clinical impression that posterior chamber lens implants in some way inhibit opacification of the posterior lens capsule after extracapsular cataract extraction. The mechanism of this inhibition is unclear; it may be related to mechanical contact or blockage of migration of lens epithelial cells, or possibly to the leeching of toxic factors from the lens itself. A better understanding of the exact mechanism of opacification inhibition may have important clinical implications for intraocular lens design. For example, some lens designs that facilitate Nd:YAG capsulotomy by physically separating the posterior chamber lens and the posterior capsule may result in less inhibition and in fact more opacification of posterior capsules. We performed in vitro tissue culture studies of the effect of the polymethylmethacrylate (PMMA) optic of a planoconvex intraocular lens on cultured rabbit lens epithelium. These studies demonstrated both inhibition oflens epithelial migration beneath the PMMA optic (plano side down) as well as metaplasia and necrosis of lens cells growing directly beneath the optic. The clinical implications of these studies for intraocular lens design are discussed. Key Words: extracapsular cataract extraction, intraocular lens, lens epithelium, opacification inhibition, planoconvex, polymethylmethacrylate, posterior capsule opacification Although the Nd:YAG laser appears to be an effective and relatively safe alternative to a surgical posterior capsulotomy,1 there are risks associated with Nd:YAG posterior capsulotomy.2,3,4 Therefore it seems prudent to continue to search for ways to inhibit posterior capsule opacification. The magnitude of this problem is enormous. If at least 20% of extracapsular cases eventually require posterior capsulotomy, about 100,000 posterior capsulotomy procedures will be necessary each year in the United States. It has been the clinical impression of extracapsular surgeons that a posterior chamber lens inhibits opacification of the posterior capsule. In 1977, Simcoe suggested that "the capsule often adheres to the back lens surface, and this appears to inhibit cell migration and capsular opacification."5 In Blaydes' series, for example, the rate of discission after extracapsular cataract extraction (ECCE) and posterior chamber lens implantation was lower than after ECCE without implantation. 6 Some clinical reports suggest that a posterior

chamber lens simply retards posterior capsule opacification but does not lower the long-term risk of posterior capsule opacification. 7,8 Nevertheless, such circumstantial evidence would seem to argue for physical contact between the posterior capsule and the posterior chamber lens. The trade-off for such close physical proximity is increased risk of Nd:YAG-laser-induced damage to the intraocular lens (IOL) should opacification occur. 9,10 In order to decide if the increased risk of laserinduced damage to the optic is worthwhile, it would be valuable to know if there is any objective evidence showing that the optic inhibits lens epithelium. We performed a qualitative in vitro tissue culture experiment to study this question. MATERIALS AND METHODS The eyes of white New Zealand rabbits were enucleated immediately after death and the lenses removed by sterile technique through a pars plana

From the Bethesda Eye Institute, Department of Ophthalmology, St. Louis University School of Medicine, St. Louis, Missouri. Funded in part by a developmental grant from Research to Prevent Blindness, Inc., New Yark, New Yark. Reprint requests to Francis E. O'Donnell, Jr., M.D., 3663 Lindell Boulevard, St. Louis, Missouri 63108. J CATARACT REFRACT SURG-VOL

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inCISIon. The anterior lens capsule was excised and placed epithelial cell side up beneath a cover slip in a 35 mm tissue culture dish containingTC 199 medium0.33% lactalbumin hydrolysate in Hank's solution (1: 2 v/v) supplemented with 10% fetal bovine serum, 100 units per ml penicillin, and 100 mg per ml streptomycin. The dishes were then placed in a 95% air 5% carbon dioxide incubator at 37° centigrade. The medium was changed three times a week. Definite lens epithelial cell division and migration could be documented in several days and the dishes reached confluence in two to three weeks. At that time they were trypsinized with 0.25% trypsin. Only first passage epithelial cells were used in these experiments. After washing to remove the trypsin, the cells were resuspended in the identical lens medium and plated on specially tooled plexiglass platform inserts placed in 35-mm dishes containing 2 cc of medium. Tissue culture medium and supplements were obtained from GIBCO, Grand Island, New York.

Experiment 1: Studies of Migration Inhibition A polymethylmethacrylate (PMMA) planoconvex intraocular lens (IOL) (injection molded) suitable for clinical use was affixed plano face down to the surface of a plexiglass platform insert using 9-0 nylon sutures (Figure 1). Approximately 1 x 1()4 lens epithelial cells were suspended in lens medium and placed in a cloning ring 4 mm from the IOL edge. After cell adhesion was complete (one to two hours), the cloning ring was removed and 2 ml of lens medium was added. The migration and morphology of these cells were then observed daily for three weeks or more as the colony enlarged toward the lens optic (experimental area) or

toward an identical portion of the platform with no lens optic present (control area). Documentation of differences in migration, cell numbers, and morphology was made using inverted phase photomicrography.

Experiment 2: Studies of Direct Contact Inhibition Approximately 1 x 1()4 lens epithelial cells in lens medium were plated into each of two wells (10 mm diameter x 2 mm deep) tooled in a plexiglass platform insert (Figure 2). These cells were allowed to stabilize for 48 hours after which a planoconvex PMMA injection-molded IOL with plano side down was gently placed on top of the lens epithelial cell layer growing in one of the wells. The lens was stabilized and held in place by the gentle compression of its haptics much as it is within the lens capsular bag in vivo. The cells growing in the other well were used as controls. The behavior, growth characteristics, and morphology of the epithelial cells in both wells were observed daily for at least three weeks and any changes were documented by inverted phase microscopy as well as formalin fixation and Giesma staining.

RESULTS Experiment 1 At ten days, phase contrast photomicrographs of the PMMA optic and surrounding plate were obtained. The lens epithelium had formed a confluent layer completely surrounding the PMMA optic and extending to the limits of the plate. This confluent layer had a

cw

Fig. 2. Fig. 1.

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(Santos) In the first experiment, a cloning ring (CR) was placed 4 mm from the posterior chamber lens (PCL) on a plexiglass platform insert. By day 10, the lens epithelial cells had reached confluency, completely surrounding the PCL and covering the plexiglass platform insert to the limits of the dish.

(Santos) In the second experiment, two wells were tooled into a plexiglass platform insert and the insert was placed into a dish and bathed in tissue culture medium. Explants of lens epithelium were placed in the control well (CW) and in the test well (TW). When the lens epithelial cells reached confluency, a posterior chamber lens was gently placed in the test well. The wells were then observed for 10 days.

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uniform cell morphology of polygonal contour (Figure 3). Under the PMMA optic there were scattered epithelial cells displaying pleomorphism (Figure 4) and rare extracellular fibrils. Within the positioning holes of the optic, the epithelium appeared similar to areas surrounding the optic (Figure 5). Experiment 2 The lens epithelium subjacent to the PMMA optic underwent progressive degenerative changes. The confluency of the layer and the uniformity of the cellular morphology were lost within ten days. Cellular debris from dying cells was readily apparent under the PMMA optic (Figure 6). The surviving lens epithelial cells had a pleomorphic appearance. The control well exhibited none of these changes. DISCUSSION Our tissue culture experiments demonstrated significant inhibition oflens epithelium when in contact with

the PMMA optic of an IOL. In the first experiment, the lens epithelium migrated around the optic and under the optic, but lens epithelium failed to proliferate as exuberantly under the PMMA optic. The lens epithelium grew well immediately subjacent to positioning holes. In the second experiment, the posterior chamber lens was gently placed onto a confluent sheet of lens epithelium. Contact between the PMMA optic and the lens epithelium resulted in lens epithelial cell pleomorphism and death over ten days. Our studies did not identify the mechanism of this lens epithelium inhibition by the PMMA optic. Since lens epithelium immediately adjacent to the optic appeared as healthy as more remote epithelium, we inferred no leeching of toxic substances from the PMMA optic. Perhaps a lack of nutrients or a build-up of cellular waste resulted from the physical barrier of the optic. This seems unlikely since lens epithelium grew well under the glass coverslips. Alternatively, like corneal

Fig. 3.

(Santos) In experiment 1, the lens epithelial cells formed a compact layer of polygonal cells surrounding the PMMA optic.

Fig. 5.

(Santos) In experiment 1, note the exuberant growth of lens epithelium within the positioning hole of the optic.

Fig. 4.

(Santos) In experiment 1, under the PMMA optic the lens epithelial cells lacked confluency and they had a pleomorphic appearance.

Fig. 6.

(Santos) In experiment 2, the cellular debris from dead cells is apparent under the PMMA optic, whereas surrounding cells appear healthy.

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endothelial cells, the lens epithelial cell membrane could be damaged by contact with the PMMA optic. Ongoing tissue culture studies are comparing glass, PMMA, and silicone optics. There is a potentially adverse effect of the PMMA optic on lens epithelium that might partially offset the beneficial effects of lens epithelium inhibition. Postoperative opacification of the posterior capsule is the result oflens epithelial production oflens fibers (pearls) and of lens epithelial metaplasia into myofibroblasts that induce fibrosis and contraction. l l It seems that cells of uveal origin, perhaps inflammatory cells such as macrophages, possibly can participate in the process. 12 In this respect, the lens epithelium beneath the PMMA optic underwent a pleomorphism that was occasionally associated with extracellular fibrils, suggesting myofibroblastic metaplasia. Thus, while the PMMA optic might inhibit lens epithelium, reducing pearl formation, it might also contribute to fibrosis and wrinkling of the posterior capsule. Weare performing ultrastructural studies to clarifY this point. On balance, we think that the inhibition of lens epithelium would offset the tendency for metaplasia, but this consideration underscores the complexity of the problem. What do these experiments mean for the surgeon? There are two major implications. First, the planoconvex posterior chamber lens optic did not prevent migration oflens epithelium underneath the optic, but it did inhibit growth significantly. Meniscus and ridged lenses (designed to separate the posterior capsule and the optic) may also allow migration of lens epithelium under the optic and may not as effectively retard posterior capsule opacification as a planoconvex lens. Thus, the use of these lenses could result in a selffulfilling prophecy. While enhancing the safety of Nd:YAG posterior capsulotomies, they may also contribute to opacification of the posterior capsule. On the other hand, it may be that the ridge and meniscus edge would exert more focal pressure, and thus act as a better physical barrier to lens epithelium migration. 9 - 12 Hoffer has reported preliminary clinical evidence suggesting that this is indeed the case. 13 Additional tissue culture experiments are underway to assess this aspect of optic design. Lenses with an incomplete ridge might be less efficient barriers. In contrast, a biconvex or convexplano (convex side implanted posteriorly) lens might inhibit lens epithelium more effectively if it resulted in more intimate contact between lens epithelium and the PMMA optic. 7 ,8 Similarly, angulated haptics and in-the-bag implantation would appear to be advantageous because they would promote PMMA optic and posterior capsule contact. Second, even if the capsule cannot be safely polished, residual lens epithelium may be inhibited by physical contact with the PMMA optic. Therefore, when implanting a posterior chamber lens, perhaps the 26

surgeon can be a bit less aggressive about posterior capsule polishing if using a lens design that allows contact with the posterior capsule. The limitation is that the residual lens epithelium under the influence of the PMMA optic might be more likely to undergo metaplastic differentiation into myofibroblasts that would induce capsular wrinkling and opacification. Although our study clearly demonstrated inhibition of the PMMA optic on lens epithelium, it alone cannot answer the question of which lens design features are desirable. Additional in vitro and in vivo studies are needed to compare the effects of lens design features on inhibition of lens epithelium. Our study simply underscores the need to study the lens design features comparatively, realizing that protection from laserinduced damage is not the only critical issue regarding opacification of the posterior capsule. REFERENCES 1. Keates RH, Steinert RF, Puliafito CA, Maxwell SK: Long-term follow-up of Nd:YAG laser posterior capsulotomy. Am IntraOcular Implant Soc] 10:164-168, 1984 2. Blackwell C, Hirst LW, Kinnas SJ: Neodymium-YAG capsulotomy and potential blindness. Am] Ophthalmol 98:521522, 1984 3. Channell MM, Beckman H: Intraocular pressure changes after neodymium-YAG laser posterior capsulotomy. Arch Ophthalmol 102:1024-1026, 1984 4. Fastenberg DM, Schwartz PL, Lin HZ: Retinal detachment following neodymium-YAG laser capsulotomy. Am] Ophthalmol 97:288-291, 1984 5. Simcoe CW: An ounce of prevention. In: Emery JM, Jacobson AC, eds, Current Concepts in Cataract Surgery; Selected Proceedings of the Fifth Biennial Cataract Surgical Congress. St Louis, CV Mosby Co, 1978, pp 213-231 6. Blaydes EJ: Is a primary discission necessary following the insertion of a Shearing-type lens? In: Emery JM, Jacobson AC, eds, Current Concepts in Cataract Surgery; Selected Proceedings of the Seventh Biennial Cataract Surgical Congress. New York, Appleton-Century-Crofts, 1982, pp 129-130 7. Pearce JL: New lightweight sutured posterior chamber lens implant. Trans Ophthalmol Soc UK 96:6-10, 1976 8. Lindstrom RL, Harris WS: Management of the posterior capsule following posterior chamber lens implantation. Am Intra-Ocular Implant Soc] 6:255-258, 1980 9. Datiles M, Stark WJ, Newsome DA, Terry AC, et al: Cellular toxicity of Nd:YAG laser-induced intraocular lens damage. Ophthalmology 91 (suppl 9):85, 1984 10. Myers WD, Myers TD, Marks RG, Stone RM: Intraocular lens design for the neodymium:YAG laser. Am Intra-Ocular Implant Soc] 11:35-36, 1985 11. Cobo LM, Ohsawa E, Chandler D, Arquello R, et al: Pathogenesis of capsular opacification after extracapsular cataract extraction; an animal model. Ophthalmology 91:857-863, 1984 12. Odrich MG, Hall SJ, Worgul BV, Rini FJ, etal: Cellular origins of posterior capsule opacification. ARVO Abstracts. Invest Ophthalmol Vis Sci 25 (suppl):67, 1984 13. Hoffer KJ: Five years' experience with the ridged laser lens implant. In: Emery JM, Jacobson AC, eds, Current Concepts in Cataract Surgery; Selected Proceedings of the Eighth Biennial Cataract Surgical Congress. Norwalk, Conn, AppletonCentury-Crofts, 1985, pp 296-299

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