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Laboratory science

Evaluation of long-term biocompatibility and capsular bag opacification with a new silicone–polyimide plate-type intraocular lens in the rabbit model

Li, Jack BA; Werner, Liliana MD, PhD*; Guan, Jun J. MD; Reiter, Nicholas MD; Mamalis, Nick MD

Author Information
Journal of Cataract & Refractive Surgery: July 2016 - Volume 42 - Issue 7 - p 1066-1072
doi: 10.1016/j.jcrs.2016.03.040
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Abstract

Studies of intraocular lenses (IOLs) that maintain an open or expanded capsular bag1–11,A describe the relative lack of posterior capsule opacification (PCO) and anterior capsule opacification (ACO) in association with those designs. The model SC9 IOL (Cumming Ophthalmic Research and Development LLC) is a new posterior chamber monofocal IOL that was designed to increase the depth of focus and improve near vision and intermediate vision after lens extraction. It is based on the platform of the Crystalens IOL (Bausch & Lomb), which is manufactured from a silicone material and polyimide components.12 However, the overall plate design of the new IOL was significantly changed, with the aim of ensuring a more accurate and consistent location of the IOL along the visual axis with the optic against the posterior capsule. Other changes include design features that minimize contact between the anterior capsule and the anterior optic surface and enhance aqueous flow within the capsular bag.

The aim of this current study was to evaluate the long-term uveal and capsule biocompatibility of the test IOL according to the requirements of the International Organization for Standardization (ISO).13

Materials and methods

Figure 1 shows the test IOL in this study. The IOL is comprised of 2 materials, silicone and polyimide, denoted by the clear sections and orange sections, respectively, in Figure 1. According to the manufacturer, the polyimide matrix is molded in place and has a number of holes in it that fixate the matrix and hoops in the silicone. Each plate haptic has 2 polyimide paddles that extend proximally and adjacent to the optic. The polyimide paddles are partially encased in silicone over a central portion of their surface and are then exposed peripherally.

Figure 1
Figure 1:
Schematic drawings showing the study lens (provided by Cumming Ophthalmic Research and Development LLC) (OAD = overall diameter).

On the proximal end of each plate haptic is a wide silicone protuberance or ridge that extends anteriorly across the width of the plate haptic and out over the paddles. This ridge is intended to hold the anterior capsule away from the posterior capsule. The anterior optic edge is flush with the anterior surface of the plate haptic, and the posterior optic edge is offset 0.10 mm posteriorly from the posterior surface of the plate haptic and is square. The edges of the plate haptics were also designed square; however, they were manufactured slightly rounded because of limits in the machining of the mold. The overall diameter of the IOL is 11.00 mm (hoop tip-to-hoop tip measurement). The diameter measured from the ends of the plate haptics (plate diameter) is 10.50 mm, and the plate thickness is 0.25 mm. The optic is 5.00 mm in diameter and has a fixed edge thickness of 0.35 mm, with a center thickness ranging from 0.66 mm at +10.0 diopters (D), the lowest power, to 1.33 mm at +30.0 D, the highest power, varying with each 0.5 dioptric power step. The control used in this study was a silicone plate IOL model AA4204VL (Staar Surgical Co.) with a dioptric power of +20.0 D (same power as the test IOLs used in this study) and overall diameter of 11.2 mm.

Nine New Zealand white rabbits weighing between 2.4 kg to 3.2 kg were acquired from approved vendors and treated in accordance with the requirements of the Animal Welfare Act and the Association for Research in Vision and Ophthalmology statement for the use of animals in ophthalmic and visual research.B They had bilateral phacoemulsification with IOL implantation; the right eye received the test IOL and the left eye received the control IOL. All surgeries were performed by the same surgeon (N.M.), and the IOL implantations were video recorded.

Anesthesia, surgical preparation, and bilateral phacoemulsification with IOL implantation were performed as described in previous studies.9,10 Briefly, a fornix-based conjunctival flap was fashioned. An initial 3.0 mm limbal incision was made using a 3.0 mm keratome. A capsulorhexis forceps was used to create a well-centered continuous curvilinear capsulotomy approximately 5.0 mm in diameter. After hydrodissection, the phacoemulsification handpiece (Infiniti, Alcon Surgical, Inc.) was inserted into the posterior chamber for removal of the lens nucleus and cortical material. To facilitate pupil dilation and control inflammation, 1.0 mL of epinephrine 1:1000 and 0.5 mL of heparin (10 000 USP units/mL) was added to each 500 mL of irrigation solution. After removal of the lens nucleus and cortex, sodium hyaluronate 1.6% (Amvisc Plus) was used to inflate the capsular bag. The IOLs were implanted in the capsular bag using the corresponding recommended injection system and technique (test IOL: Medicel Naviject 2.9 inserter; control IOL: MSI-TR injector with MTC-60c cartridge). The wound was closed with a 10-0 monofilament nylon suture after removal of ophthalmic viscosurgical device material using irrigation/aspiration.

Postoperative topical therapy included a combination neomycin, polymyxin B sulfates, and dexamethasone ointment during the first postoperative week and prednisolone acetate drops during the second postoperative week. At 2 months, 2 rabbits were randomly selected to be humanely killed for gross examination, implant cytology, and histopathology. The remaining 6 rabbits were humanely killed at 6 months.

The eyes were evaluated by slitlamp examination and scored for ocular inflammatory response at 1 week and 4 weeks and then at 2 months, 3 months, and 6 months. Clinical color photographs of each eye at each timepoint were obtained with a digital camera attached to the slitlamp. A standard scoring method in 11 specific categories was used at each examination, including assessment of corneal edema and the presence of cell and flare in the anterior chamber. Retroillumination images with the pupil fully dilated were obtained for photographic documentation of capsular bag opacification.

After the final clinical examination at 2 months or 6 months, the animals were anesthetized and then humanely killed with a 1.0 mL intravenous injection of pentobarbital sodium–phenytoin sodium. Their globes were enucleated and placed in 10% neutral buffered formalin. The globes were then bisected coronally just posterior to the equator. Gross examination and photographs from the posterior aspect (Miyake-Apple view14) were performed to assess capsular bag opacification and IOL fixation. The extent and severity of ACO and PCO were scored according to previously described methods.9,10 Briefly, the ACO was scored from 0 to 4 at the area of the anterior capsule contacting the anterior optic surface. The central PCO (related to the central area, 3.0 mm behind the optic) was scored from 0 to 4. The peripheral PCO (related to the peripheral area behind the optic) was also scored from 0 to 4. Soemmerring ring formation (related to proliferative material within the equatorial region of the capsular bag, outside the optic) had a score of intensity from 0 to 4 and a score of area related to the number of quadrants involving the highest intensity (0 to 4). Selected eyes were placed in an appropriate support and evaluated under anterior segment optical coherence tomography (AS-OCT) (Visante, Carl Zeiss Meditec AG).

After gross examination, all test and control IOLs were carefully removed from the eyes. Selected IOLs in each group were evaluated for surface cellular reactions using a modified implant cytology technique. The anterior and posterior segments of all globes were processed for standard light microscopy (LM) and stained with hematoxylin–eosin (H&E).

Results

There was a learning curve by the surgeon for the injection of the test IOL. In some instances, manipulation was necessary to flip the IOL in the appropriate orientation and to complete in-the-bag fixation. Overall, by the third implantation of the test IOL, full injection within the capsular bag could be obtained without extra manipulation to complete in-the-bag fixation of the proximal haptic. At the end of the procedures, all test IOLs as well as the control IOLs were fully fixated in the capsular bag.

Slitlamp Examinations

At the 1-week examination, a mild inflammatory reaction was observed in both groups of eyes. Mild to moderate corneal opacity at the incision site was observed in 3 test eyes. A small oval hole (<2.0 mm in diameter) in the posterior capsule was observed in 1 test eye.

At the 4-week examination, the degree of clinical capsular bag opacification was significantly higher in the control group. The mean PCO score at 4 weeks was 0.22 ± 0.26 (SD) in the test group and 1.66 ± 1.0 in the control group (P = .001, 2-tailed t test: paired 2-sample for means). The ACO was scored as 0 in all eyes in the test group but 1; it was scored as 0.5 or 1.0 in the control group. A mild decentration was observed in some eyes in the control group, whereas all test IOLs appeared well centered.

As expected in long-term rabbit studies, increasing proliferative material started to be observed within the capsular bag at 2 months, leading to significant PCO formation. However, at the 6-month examination, the control group had significantly more progressive PCO than the test group (Figure 2). The mean PCO score was 0.80 ± 0.27 in the eyes with test IOLs and 4.00 ± 0.00 in the eyes with control IOLs (P < .0001, 2-tailed; paired t test). Posterior synechia formation at 6 months was scored as 1.28 ± 1.25 in the test group and as 2.71 ± 0.75 in the control group (P = .02, 2-tailed t test: paired 2-sample for means). The ACO was scored as 0 in 2 test eyes; the ACO was scored as 1 in all control eyes that could be assessed for this parameter.

Figure 2
Figure 2:
Slitlamp photographs of both eyes of the same rabbit taken 6 months postoperatively. The study eye (A) maintained clear anterior and posterior capsules. The control eye (B) developed dense diffuse PCO.

Gross Examination

An evaluation of the rabbits selected for the 2-month follow-up and the 6-month follow-up confirmed that less PCO was observed with the test IOLs than with the control IOLs (Figure 3). Table 1 shows the results of this evaluation. Statistical significance was observed at 6 months only. The AS-OCT imaging of 1 eye in each group showed that the anterior capsule in the eye containing the test IOL was at a small distance from the anterior surface of the IOL. No PCO could be observed in the test eye, whereas abundant PCO material was observed in the control eye (Figure 4).

Figure 3
Figure 3:
Gross photographs of both eyes of the same rabbit (Miyake-Apple view) taken 6 months postoperatively. Postmortem examination of the eyes with the study IOL (A) showed clear anterior and posterior capsules. In contrast, the control eye (B) showed intense PCO.
Figure 4
Figure 4:
Optical coherence tomography of the anterior segment of 2 enucleated eyes from 2 rabbits taken 6 months postoperatively. In both images, the optic of the IOL can be appreciated. The study IOL (A) showed clear anterior and posterior capsules. The anterior capsule (red arrows) was not in contact with the anterior surface of the IOL, indicating that the capsular bag was open. The control IOL (B) showed diffuse and robust PCO. The opacifying material behind the central part of the optic of the control IOL had a thickness measured as 1.59 mm under AS-OCT examination.
Table 1
Table 1:
Capsular bag opacification scoring performed during postmortem evaluation of rabbit eyes from the Miyake-Apple view.

Implant Cytology

An analysis of the IOLs explanted at 2 months for implant cytology under the light microscope was difficult because of the presence of proliferative material attached to the surface of the IOLs. All 4 IOLs appeared to have a mixture of macrophages, epithelioid cells, giant cells, and spindle-shaped cells attached to their surface.

At 6 months, it was particularly difficult to explant the IOLs from the capsular bag in the control group. Two test IOLs and 2 control IOLs were selected for implant cytology. The 2 test IOLs appeared to have a mixture of macrophages, epithelioid cells, giant cells, and spindle-shaped cells attached to their surface. It was not possible to analyze the control IOLs accurately under implant cytology because of the complete wrapping by fibrotic/proliferative tissue at 6 months.

Histopathology

Histopathology at 6 months showed no sign of untoward toxicity or inflammation in the study eyes or in the control eyes when evaluated under LM. It also confirmed that the anterior and posterior capsules were remarkably clear in several of the test eyes evaluated and that there was no significant proliferative cortical material in the fornix forming Soemmerring rings (Figure 5, A).

Figure 5
Figure 5:
Light photomicrographs from histopathologic sections cut from eyes of 2 rabbits killed humanely 6 months postoperatively. A: Anterior segment of an enucleated right rabbit globe with the study IOL. The IOL was explanted before processing. The capsular bag is clear with no proliferative cortical material anteriorly, posteriorly, or in the fornix. B: Anterior segment of an enucleated rabbit globe with a control IOL. The IOL was explanted before processing. The central part of the capsular bag is missing because the proliferative tissue was completely attached to the IOL surface. There is a large amount of proliferative material in the fornix in the remnant capsule on both sides. A and B: Composites of light photomicrographs (H&E staining; original magnification ×20.)

The control IOLs showed extensive artifactual changes secondary to the disruption of the capsular bag with removal of the lens and adherent cortex, making it difficult to appreciate the degree of proliferative cortical material present. There was extensive posterior synechia formation in several of the control specimens with pupillary membrane formation and forward bowing of the iris with iris bombe. In IOLs in which the peripheral lens capsule was still intact, there was a moderately large amount of proliferative cortical material forming a Soemmerring ring (Figure 5, B).

Discussion

The model SC9 IOL, which is a plate silicone IOL with polyimide components (paddles), was based on the Crystalens IOL. However, the new design incorporates significant changes that likely effect the outcome of capsular bag opacification. Components relative to PCO formation in humans are also components of after-cataract formation in rabbits.15 A series of rabbit studies16–19 found a great potential for lens epithelial cells (LECs) to proliferate, even in the absence of IOL implantation. The regeneration and proliferation of the cell material are accelerated in the rabbit model; 6 to 8 weeks in the rabbit eye corresponds to approximately 2 years in the human eye.16–19 The LECs’ proliferative capacity makes the animals used in this study an appropriate model for assessing capsular bag proliferation within a relatively short period of time. However, ISO requirements specify a 6-month in vivo study for the biocompatibility evaluation of new IOLs,13 and therefore we performed this evaluation of the SC9 IOL. The potential effect of the new IOL design on parameters such as depth of focus cannot be assessed in this rabbit model.

There are several design strategies used in this IOL that could help prevent capsular bag opacification. The haptics of the new IOL were changed to enhance the stability of the IOL, improving its ability to maintain a consistent position inside the capsular bag after surgery, with the optic against the posterior capsule. This, together with the square optic edge, would likely improve the barrier effect of the optic against migration of proliferative material from the equatorial region of the capsular bag onto the posterior capsule, which could initiate PCO formation. The new design uses mechanical separation of the anterior capsule from the anterior surface of the IOL optic to prevent ACO formation. This is accomplished by the silicone ridge located on the proximal end of each haptic, which extends anteriorly across the width of the plate haptic and out over the paddles. This design pushes the anterior capsule away from the IOL to the extent that the capsular bag remains open. In this configuration, it is likely that a constant flow of aqueous humor within the capsular bag compartment is maintained. Several studies20–24 found that increasing the endocapsular flow and exposure to fresh aqueous humor could have a role in the prevention of LEC proliferation and subsequent capsular bag opacification formation.

Although extensive proliferation of residual LECs in the rabbit model usually renders PCO comparisons after 4 weeks postoperatively very difficult or impossible, up to the end of the current study (6-month follow-up), there was significantly less capsular bag opacification associated with the study IOLs. Figure 3, A, shows a remarkably clear capsular bag without Soemmerring ring formation 6 months postoperatively, which is likely a result of the open-bag configuration associated with this IOL design. The AS-OCT image in Figure 4, A, provides a side view of the capsular bag containing the study IOL and shows that the capsular bag is open, although not expanded. The posterior capsule is in direct contact with the IOL optic. It is noteworthy that explantation of the study IOLs at the end of the study was relatively easy, with no fibrotic attachments with the capsular bag. In contrast, the control IOLs were completely encased within proliferative material and their explantation at the end of the study was difficult. The AS-OCT image in Figure 4, B, shows remarkably thick proliferative tissue behind the IOL optic. Increased PCO in the control eyes was associated with increased IOL decentration, although decentration in this group remained mild overall. Proliferative material can also be seen anterior to the optic in Figure 4, B (right side of image). This might lead to synechia formation in the rabbit eye, and indeed, synechia formation was significantly higher in the control group.

In terms of uveal biocompatibility, there were no significant differences between the 2 groups of IOLs in the early postoperative period. However, in the late postoperative period, posterior synechia formation was significantly less in the study group, which, as previously mentioned, might be related to less proliferation within the bag and a lack of proliferative material anterior to the IOL optic. Histopathologic examination showed no sign of untoward inflammation or toxicity in the study eyes or in the control eyes evaluated.

In summary, this 6-month study found that the SC9 IOL incorporates design features that seem to prevent overall capsular bag opacification while retaining uveal biocompatibility. Because rabbits have such a robust LEC reaction and inflammatory response in comparison with humans, 6 months would be the equivalent of several years in a human eye. Proliferative fibrotic tissue formation was significantly prevented with this new IOL design, which is encouraging considering that the optic–haptic junctions are very flexible and therefore could be susceptible to deformation under excessive contraction forces. Our results confirm the biocompatibility of the study IOL, and we look forward to studies assessing clinical outcomes. In this study, we selected a control IOL with a material and design that were close to those of the test IOL. Other IOLs on the market (eg, 1-piece hydrophobic acrylic IOLs with square optic edges) would likely lead to less PCO formation, and their comparison with the test IOL would be suitable.

What Was Known

  • Intraocular lenses that maintain an open and/or expanded capsular bag are associated with a relative lack of capsular bag opacification. Increasing endocapsular flow and exposure to fresh aqueous humor might help prevent LEC proliferation and subsequent capsular bag opacification.

What This Paper Adds

  • The design changes to the new IOL maintained an open capsular bag and improved the barrier effect of the optic to prevent PCO and produce mechanical separation to prevent ACO.
  • The test IOL also showed appropriate long-term uveal biocompatibility.

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Other Cited Material

A. Werner L, “IOL Designs Maintaining an Open or Expanded Capsular Bag,” presented at the XXVIII Congress of the European Society of Cataract and Refractive Surgeons, Paris, France, September 2010. Reported in Ophthalmology Times September 5, 2010. Available at: http://ophthalmologytimes.modernmedicine.com/news/iol-designs-maintaining-open-or-expanded-capsular-bag?page=full. Accessed May 22, 2016
B. Association for Research in Vision and Ophthalmology. Statement for the use of animals in ophthalmic and visual research. Available at: http://www.arvo.org/about_arvo/policies/statement_for_the_use_of_animals_in_ophthalmic_and_visual_research/. Accessed May 22, 2016
© 2016 by Lippincott Williams & Wilkins, Inc.