- Email: [email protected]
Long-term uveal and capsular biocompatibility of a new accommodating intraocular lens
LABORATORY SCIENCE
Long-term uveal and capsular biocompatibility of a new accommodating intraocular lens Justin C. Kohl, MD, Liliana Werner, MD, PhD, Joshua R. Ford, MD, Scott C. Cole, MD, MS, Shail A. Vasavada, DO, DNB, FICO, Gareth L. Gardiner, BS, Rozina Noristani, BA, Nick Mamalis, MD
PURPOSE: To evaluate long-term uveal and capsular biocompatibility of a new accommodating intraocular lens (IOL). SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Bilateral phacoemulsification was performed in 14 rabbits; 1 eye received the accommodating IOL (Fluidvision) and the other received a hydrophobic acrylic control IOL. Slitlamp examinations were performed at postoperative weeks 1 to 4 and months 2, 3, 4, and 6. Six rabbits were humanely killed at 2 months and 8 rabbits at 6 months. After gross examination with the MiyakeApple view, selected IOLs were removed for implant cytology. All globes were then sectioned and processed for histopathologic examination. RESULTS: Uveal biocompatibility of study and control IOLs was similar in clinical and pathologic examinations up to 6 months postoperatively. In the study group, anterior capsule opacification appeared absent and posterior capsule opacification (PCO) was significantly less than in the control group. At the gross examination at 6 months, central PCO was 0.8 G 0.5 (SD) in the study IOLs and 3.7 G 0.4 in the control IOLs (P < .0001, 2-tailed paired t test). Histopathologic examination confirmed the relative lack of capsule opacification in study eyes compared with controls and the absence of untoward inflammatory reaction or toxicity in all eyes. CONCLUSIONS: The accommodating IOL maintained an expanded capsular bag secondary to the large size of the haptic elements without significant contact with the anterior capsule. This appeared to prevent overall capsular bag opacification and to retain uveal and capsular biocompatibility. Financial Disclosure: Dr. Werner is a member of the Scientific Advisory Board of Powervision, Inc. No other author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:2113–2119 Q 2014 ASCRS and ESCRS
Reports on intraocular lenses (IOLs) that maintain an open or expanded capsular bag describe the relative lack of posterior capsule opacification (PCO) and anterior capsule opacification (ACO) with those designs.1–11,A The Fluidvision (Powervision, Inc.) is a new accommodating IOL that incorporates large hollow haptic elements, which keep the anterior and posterior capsules apart. The optic and haptics are made of a hydrophobic acrylic material, and the haptics and interior of the optic are filled with silicone oil that is index-matched to the acrylic. The IOL is designed so that when the haptics are subjected to Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
accommodative forces, silicone oil is pushed into the optic through fluid channels that connect the haptics to the optic. As silicone oil flows into the optic, the deformable front optic surface is changed, increasing the power of the IOL. A recently completed pilot study of 20 patients demonstrated the accommodative capability of this accommodating IOL.B We previously evaluated the Fluidvision accommodating IOL in a short-term rabbit study (6 weeks follow-up).12 Overall, capsular bag opacification with this IOL was remarkably low compared with that in commercially available single-piece hydrophobic
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acrylic IOLs. The aim of the current study was to evaluate the long-term uveal and capsular biocompatibility of this accommodating IOL according to the requirements of the International Organization for Standardization (ISO) for IOLs.13 MATERIALS AND METHODS The study IOL (Fluidvision) has an overall diameter of 10.0 mm and an optic diameter of 6.0 mm (Figure 1). The control IOL, Acrysof model SA60AT IOL (Alcon Laboratories, Inc.), had a dioptric power of C20.0 diopters (D) (same power as the study IOL); the overall diameter is 13.0 mm and the optic diameter, 6.0 mm. Fourteen New Zealand white rabbits weighing between 3.2 kg and 3.6 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. Bilateral phacoemulsification with IOL implantation was performed; the right eye was randomized to receive a study or a control IOL and the contralateral eye received the other 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.10–12 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 Laboratories, Inc.) was inserted into the posterior chamber to remove the lens nucleus and cortical material. One milliliter of epinephrine 1:1000 and 0.5 mL of heparin (10 000 USP units/mL) were added to each 500 mL of irrigation solution to facilitate pupil dilation and control inflammation. After the lens nucleus and cortex were removed, an ophthalmic viscosurgical device (OVD) (Amvisc Plus) was used to inflate the capsular bag. The incision was then extended to 4.0 mm with a 4.0 mm keratome for both study and control IOLs. The IOLs were implanted in the capsular bag using the corresponding recommended injection system and technique. The wound was closed with a 10-0 monofilament nylon suture after removal of
Submitted: March 26, 2014. Final revision submitted: May 5, 2014. Accepted: May 12, 2014. From the Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, to the Department of Ophthalmology and Visual Sciences, University of Utah, and by a research grant from Powervision Inc., Belmont, California, USA.
Figure 1. The study IOL fixated within the capsular bag (provided by Powervision, Inc.).
OVD material using irrigation/aspiration. Appropriate in-the-bag placement of the IOL, IOL centration, and coverage of the IOL optic by the capsulorhexis were verified at the end of the procedure. Postoperative topical therapy included combination neomycin, polymyxin B sulfates, and dexamethasone ointment during the first postoperative week and prednisolone acetate drops during the second week. The eyes were evaluated by slitlamp examination and scored for ocular inflammatory response weekly from 1 to 4 weeks and then at 2, 3, 4, and 6 months. Clinical color photographs of each eye at each time point 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 a final clinical examination at 2 months or 6 months, the animals were anesthetized and then humanely killed with a 1 mL intravenous injection of pentobarbital sodium–phenytoin sodium. The globes were enucleated and placed in 10% neutral buffered formalin. They were then bisected coronally just posterior to the equator. Gross examination and photographs from the posterior aspect (Miyake-Apple view) 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.10–12 After gross examination, selected study and control IOLs were carefully removed from the eyes and 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 and stained with hematoxylin–eosin.
Mary Mayfield assisted with the histopathologic processing of the eyes. Corresponding author: Liliana Werner, MD, PhD, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, Utah 84132, USA. E-mail: [email protected].
RESULTS The study IOL was implanted in the right eye in 7 rabbits and the left eye in 7 rabbits. The capsulorhexis
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Figure 2. Slitlamp photographs of both eyes of the same rabbit taken at 4 weeks, 2 months, and 6 months postoperatively. The eye with the study IOL (A, C, and E) has overall clear anterior and posterior capsules. The eye with the control IOL (B, D, and F) developed fibrosis of the capsulorhexis edge and increasingly diffuse PCO.
was oval and/or large in 2 eyes with study IOLs and in 1 eye with a control IOL. Slitlamp Examinations At the 1-week examination, eyes in both IOL groups exhibited mild degrees of corneal edema (generally limited to the incision site) and aqueous cells. They also had mild fibrin formation and blood in the anterior chamber. Corneal edema and aqueous cells were absent by the 2-week examination in all eyes. One study eye and 6 control eyes had mild fibrin in front of the IOL at the 3-week examination that resolved by the 4-week examination. At the 2-week examination, mild degrees of PCO were observed in eyes with control IOLs; the PCO increased throughout the study. At the 3-week examination, minor signs of capsular opacification were seen in some eyes with study IOLs but the opacification generally remained stable with little progression. At 2 months, 6 animals were randomly selected and humanely killed and the eyes and the IOLs were
evaluated. The PCO was 1.1 G 0.6 in eyes with study IOLs and 3.0 G 1.2 in eyes with control IOLs (P Z .0002, 2-tailed paired t test). Soemmerring ring formation was significantly greater in eyes with control IOLs than in those with study IOLs, where it was generally limited to the gap spaces between the haptics. The PCO generally started at the level of the optic–haptic junctions in eyes with control IOLs. Mild to moderate degrees of ACO were observed in eyes with control IOLs, but ACO was practically absent in those with study IOLs. Mild degrees of giant cell formation were observed in some eyes with both types of IOLs at the same time point. Posterior synechiae were also observed with both types of IOLs and were generally associated with Soemmerring ring protruding anteriorly. Up to 6 months, the examinations showed a progressive increase in PCO in both groups, more significant in the control group. At 6 months, the remaining 8 animals were humanely killed and the eyes and IOLs evaluated. The PCO was 1.3 G 0.4 in eyes with study IOLs and 4.0 G 0.0 in eyes with control IOLs
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Figure 3. Gross photographs of both eyes of 2 rabbits taken from the Miyake-Apple view. Postmortem examinations were done at 2 months (A and B) and 6 months (C and D; same eyes as in Figure 2). Postmortem examination of the eyes with the study accommodating IOL at both time points (A and C) showed overall clear anterior and posterior capsules. Postmortem examination of the eyes with the control IOL (B and D) showed PCO starting at the optic–haptic junctions in B, and diffuse PCO in D.
(P ! .0001, 2-tailed paired t test). There was also increased Soemmerring ring formation in both groups; the formation was generally limited to the gap spaces between the haptics of the study IOLs but progressively increased in the eyes with control IOLs. The increasing cell proliferation within the capsular bag was associated with increasing IOL decentration in the control group. At the end of the study, ACO appeared to be absent in the study group. Mild to moderate ACO was generally observed in the control group; 2 control eyes had capsulorhexis phimosis. Synechiae with anterior pearls as well as giant cells continued to be observed in some IOLs in both groups up to 6 months with no significant between-group differences (Figure 2).
Gross Examination Evaluation of the animals selected for the 2-month and the 6-month follow-up confirmed that less PCO was observed in eyes with the study IOLs than in those with the control IOLs (Figure 3). The results of this evaluation are shown in Table 1.
Implant Cytology Analysis of the IOLs explanted at 2 months for implant cytology (2 study and 2 control IOLs) was relatively difficult due to the presence of proliferative
Table 1. Capsular bag opacification scoring during postmortem evaluation of rabbit eyes from the Miyake-Apple view. Examination Time 2 months Central PCO Peripheral PCO Soemmering ring (intensity area) 6 months Central PCO Peripheral PCO Soemmering ring (intensity area)
Study IOL
Control IOL
P Value*
0.5 G 0.2 1.1 0.4 2.8 G 0.7
2.3 G 1.4 3.0 G 1.5 8.5 G 1.9
.03 .02 .0005
0.8 G 0.5 1.6 G 0.6 4.0 G 1.4
3.7 G 0.4 4.0 G 0 11.3 G 3.2
!.0001 !.0001 .001
ACO Z anterior capsule opacification; PCO Z posterior capsule opacification *Two-tailed paired t test
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Figure 4. Light photomicrographs from histopathologic sections cut from both eyes of a rabbit humanely killed at 2 months (same eyes as in Figure 3, A and B). A: Anterior segment of an enucleated left rabbit globe with the study accommodating IOL showing a small amount of proliferative cortical material in the periphery between the haptics (arrow) with no significant PCO. B: Anterior segment of an enucleated right rabbit globe with a control IOL showing a large Soemmerring ring formation as well as a large amount of PCO (arrow) and small amount of ACO (A and B: Composites of light photomicrographs: hematoxylin–eosin staining, original magnification 20).
Figure 5. Representative light photomicrographs from histopathologic sections cut from both eyes of a rabbit humanely killed at 6 months (same eyes as in Figure 3, C and D). A: Anterior segment of an enucleated right rabbit globe with the study accommodating IOL showing a trace PCO with only minimum cortex in the periphery and a clear anterior capsule. B: Anterior segment of an enucleated left rabbit globe with a control IOL showing a large Soemmerring ring as well as a large amount of PCO and anterior cortical proliferation (A and B: Composites of light photomicrographs: hematoxylin–eosin staining, original magnification 20).
material attached to the IOL optics. All IOLs had a mixture of macrophages, epithelioid cells, giant cells, and spindle-shaped cells attached to the optic surface. Analysis of the IOLs explanted at 6 months was more difficult due to the presence of significant proliferative material attached to the IOL optics. Analysis of 1 control IOL was not possible. Both types of IOLs (2 study and 1 control) appeared to have a mixture of macrophages, epithelioid cells, giant cells, and spindle-shaped cells attached to the optic surface.
cortical material seen in the periphery as well as in the gaps between the haptics. The central area of the posterior capsule was remarkably clear in all animals evaluated. Eyes with the control IOLs showed extensive Soemmerring ring formation and PCO. There was no sign of inflammation or toxicity in the study or control eyes. The posterior segments in both (study and control eyes) were unremarkable (Figures 4 and 5).
Histopathology At 2 and 6 months, the anterior segments of the eyes with the study IOL showed a widely dilated lens capsule with only small amounts of proliferative
DISCUSSION Wallentin et al.14 have shown that components important for PCO formation in humans are also components of after-cataract formation in rabbits. A series of studies by Gwon et al.15–18 showed the potential for lens epithelial cells (LECs) in rabbits to proliferate
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in the absence of IOL implantation. This was so evident in some cases that actual lens regeneration was observed in the late postoperative period (8 months). The regeneration/proliferation of the material is also accelerated; 6 to 8 weeks in the rabbit eye correspond to approximately 2 years in the human eye.15–18 The proliferative capacity of the New Zealand rabbit LECs makes them an appropriate model for studying capsular bag proliferation within a relatively short time period. However, ISO requirements specify a 6-month in vivo study for the biocompatibility evaluation of new materials used in the manufacture of IOLs13 and we therefore performed this evaluation of the Fluidvision accommodating IOL. We previously evaluated this accommodating IOL in a short-term rabbit study.12 Bilateral phacoemulsification with IOL implantation was performed in 6 New Zealand rabbits. Each animal received a study and a control (1-piece hydrophobic acrylic) IOL. Eyes were examined at the slitlamp from 1 day to 6 weeks postoperatively. The globes were then enucleated and evaluated grossly. Capsular bag opacification was scored from the posterior aspect (Miyake-Apple view), and the eyes were then processed for complete histopathologic evaluation. At 6 weeks, the PCO clinical score was 0.5 G 0.3 in the study group and 3.0 G 0.9 in the control group (P Z .001, 2-tailed paired t test). Anterior capsule opacification was practically absent in the study group and mild in the control group. The Miyake-Apple posterior view showed central PCO of 0 G 0 in the study group and 3.0 G 1.1 in the control group (P Z .001), peripheral PCO of 0.7 G 0.4 and 3.5 G 0.8, respectively (P Z .0006), and Soemmerring ring of 2.3 G 0.8 and 7.0 G 2.8, respectively (P Z .01). It became clear that the overall capsular bag opacification was significantly reduced with this accommodating IOL.12 Although exacerbated proliferation of residual LECs in the rabbit model usually renders PCO comparisons after 4 weeks postoperatively very difficult, even impossible, up to the end of the current study (6-month follow-up) there was significantly less PCO associated with the study IOLs and ACO was practically absent. Increased PCO in the control eyes was associated with increased IOL decentration. The stability of study IOLs within the capsular bag was superior to that of control IOLs throughout the study. In terms of uveal biocompatibility, there were no significant differences between the IOL groups in the early or late postoperative period. Histopathologic examination showed no sign of untoward inflammation or toxicity in any study or control eyes evaluated. Several strategies used with this IOL may prevent capsular bag opacification.12 The IOL practically fills the entire capsular bag, with significant bag
expansion. Mechanical compression and/or stretching of the capsular bag are probably responsible for the significant prevention of capsular bag opacification in the study IOL eyes. Proliferative material is generally limited to the fornix of the capsular bag, and the presence of the haptics blocks extension of the proliferative material toward the optic, with the exception of the haptic gap sites. In those 2 areas, there appears to be a lack of mechanical compression of the inner surface of the capsular bag; the shape/contour of the bag is also not maintained. However, the optic edge generally blocks access of the material to the posterior capsule. Also, the anterior capsule remained remarkably clear with the study IOL throughout the study. The contact between the study IOL and the anterior capsule is at the periphery of the capsular bag, at the level of the haptic components, where a fine wrinkling of the anterior capsule can be observed. The anterior capsule at and around the capsulorhexis edge is generally devoid of fibrosis, as it remains at a distance from the anterior IOL surface. In summary, the Fluidvision accommodating IOL maintained an expanded capsular bag secondary to the large size of the haptic elements, without significant contact with the anterior capsule. This appeared to prevent overall capsular bag opacification while retaining uveal biocompatibility, as demonstrated in this 6-month rabbit study. Since rabbits have a more robust LEC reaction and inflammatory response than humans, 6 months would be the equivalent of several years in a human eye. Cellular proliferation within the capsular bag after implantation of an accommodating IOL could potentially impair its function; therefore, results of this long-term study are encouraging. WHAT WAS KNOWN In a 6-week in vivo study, a new silicone oil-filled accommodating IOL incorporating large haptic elements appeared to prevent capsular bag opacification by keeping the anterior capsule at a distance from the anterior optic surface and maintaining an expanded capsular bag. WHAT THIS PAPER ADDS The capsular bag opacification preventive effects exerted by the same accommodating IOL continued to be observed in this long-term 6-month study performed according to ISO requirements. The results are encouraging considering the exacerbated proliferative capacity of the rabbit model, which usually renders comparison of capsular bag opacification after 4 weeks not possible. The study IOL also exhibited appropriate long-term uveal biocompatibility.
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REFERENCES 1. Hara T, Hara T, Yasuda A, Yamada Y. Accommodative intraocular lens with spring action. Part 1. Design and placement in an excised animal eye. Ophthalmic Surg 1990; 21:128–133 2. Hara T, Hara T, Yasuda A, Mizumoto Y, Yamada Y. Accommodative intraocular lens with spring action – Part 2. Fixation in the living rabbit. Ophthalmic Surg 1992; 23:632–635 3. McLeod SD, Portney V, Ting A. A dual optic accommodating foldable intraocular lens. Br J Ophthalmol 2003; 87:1083–1085. Available at: http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC1771831/pdf/bjo08701083.pdf. Accessed September 1, 2014 4. Werner L, Pandey SK, Izak AM, Vargas LG, Trivedi RH, Apple DJ, Mamalis N. Capsular bag opacification after experimental implantation of a new accommodating intraocular lens in rabbit eyes. J Cataract Refract Surg 2004; 30:1114–1123 5. Werner L, Mamalis N, Stevens S, Hunter B, Chew JJL, Vargas LG. Interlenticular opacification: dual-optic versus piggyback intraocular lenses. J Cataract Refract Surg 2006; 32:655–661 6. McLeod SD. Optical principles, biomechanics, and initial clinical performance of a dual-optic accommodating intraocular lens (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2006; 104:437–452. Available at: http://www.pubmed central.nih.gov/picrender.fcgi?artidZ1809902&blobtypeZpdf. Accessed September 1, 2014 7. McLeod SD, Vargas LG, Portney V, Ting A. Synchrony dual-optic accommodating intraocular lens. Part 1: optical and biomechanical principles and design considerations. J Cataract Refract Surg 2007; 33:37–46 8. Ossma IL, Galvis A, Vargas LG, Trager MJ, Vagefi MR, McLeod SD. Synchrony dual-optic accommodating intraocular lens. Part 2: pilot clinical evaluation. J Cataract Refract Surg 2007; 33:47–52 9. Kavoussi SC, Werner L, Fuller SR, Hill M, Burrow MK, McIntyre JS, Mamalis N. Prevention of capsular bag opacification with a new hydrophilic acrylic disk-shaped intraocular lens. J Cataract Refract Surg 2011; 37:2194–2200 10. Leishman L, Werner L, Bodnar Z, Ollerton A, Michelson J, Schmutz M, Mamalis N. Prevention of capsular bag opacification with a modified hydrophilic acrylic disk-shaped intraocular lens. J Cataract Refract Surg 2012; 38:1664–1670 11. Werner L, Hickman MS, LeBoyer RM, Mamalis N. Experimental evaluation of the Corneal Concept 360 intraocular lens with the Miyake-Apple view. J Cataract Refract Surg 2005; 31:1231–1237
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12. Floyd AM, Werner L, Liu E, Stallings S, Ollerton A, Leishman L, Bodnar Z, Morris C, Mamalis N. Capsular bag opacification with a new accommodating intraocular lens. J Cataract Refract Surg 2013; 39:1415–1420 13. International Organization for Standardization. Ophthalmic Implants – Intraocular Lenses – Part 5: Biocompatibility. Geneva, Switzerland, ISO, 2006; (ISO 11979–5) n JB, Lundberg C. Development 14. Wallentin N, Lundgren B, Holme of posterior capsule opacification in the rabbit. Ophthalmic Res 2002; 34:14–22 15. Gwon AE, Gruber LJ, Mundwiler KE. A histologic study of lens regeneration in aphakic rabbits. Invest Ophthalmol Vis Sci 1990; 31:540–547. Available at: http://www.iovs.org/content/ 31/3/540.full.pdf. Accessed September 1, 2014 16. Gwon AE, Jones RL, Gruber LJ, Mantras C. Lens regeneration in juvenile and adult rabbits measured by image analysis. Invest Ophthalmol Vis Sci 1992; 33:2279–2283. Available at: http:// www.iovs.org/cgi/reprint/33/7/2279.pdf. Accessed September 1, 2014 17. Gwon A, Gruber L, Mantras C, Cunanan C. Lens regeneration in New Zealand albino rabbits after endocapsular cataract extraction. Invest Ophthalmol Vis Sci 1993; 34:2124–2129. Available at: http://www.iovs.org/cgi/reprint/34/6/2124.pdf. Accessed September 1, 2014 18. Gwon A, Gruber LJ, Mantras C. Restoring lens capsule integrity enhances lens regeneration in New Zealand albino rabbits and cats. J Cataract Refract Surg 1993; 19:735–746
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 B. Potgieter F, “FluidVisionÒ Lens Design Principles and Early Clinical Experience,” Presented at the International Society of Presbyopia (ISOP), Amsterdam, Netherlands, October 2013
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First author: Justin C. Kohl, MD Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA
Long-term uveal and capsular biocompatibility of a new accommodating intraocular lens Justin C. Kohl, MD, Liliana Werner, MD, PhD, Joshua R. Ford, MD, Scott C. Cole, MD, MS, Shail A. Vasavada, DO, DNB, FICO, Gareth L. Gardiner, BS, Rozina Noristani, BA, Nick Mamalis, MD
PURPOSE: To evaluate long-term uveal and capsular biocompatibility of a new accommodating intraocular lens (IOL). SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Bilateral phacoemulsification was performed in 14 rabbits; 1 eye received the accommodating IOL (Fluidvision) and the other received a hydrophobic acrylic control IOL. Slitlamp examinations were performed at postoperative weeks 1 to 4 and months 2, 3, 4, and 6. Six rabbits were humanely killed at 2 months and 8 rabbits at 6 months. After gross examination with the MiyakeApple view, selected IOLs were removed for implant cytology. All globes were then sectioned and processed for histopathologic examination. RESULTS: Uveal biocompatibility of study and control IOLs was similar in clinical and pathologic examinations up to 6 months postoperatively. In the study group, anterior capsule opacification appeared absent and posterior capsule opacification (PCO) was significantly less than in the control group. At the gross examination at 6 months, central PCO was 0.8 G 0.5 (SD) in the study IOLs and 3.7 G 0.4 in the control IOLs (P < .0001, 2-tailed paired t test). Histopathologic examination confirmed the relative lack of capsule opacification in study eyes compared with controls and the absence of untoward inflammatory reaction or toxicity in all eyes. CONCLUSIONS: The accommodating IOL maintained an expanded capsular bag secondary to the large size of the haptic elements without significant contact with the anterior capsule. This appeared to prevent overall capsular bag opacification and to retain uveal and capsular biocompatibility. Financial Disclosure: Dr. Werner is a member of the Scientific Advisory Board of Powervision, Inc. No other author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:2113–2119 Q 2014 ASCRS and ESCRS
Reports on intraocular lenses (IOLs) that maintain an open or expanded capsular bag describe the relative lack of posterior capsule opacification (PCO) and anterior capsule opacification (ACO) with those designs.1–11,A The Fluidvision (Powervision, Inc.) is a new accommodating IOL that incorporates large hollow haptic elements, which keep the anterior and posterior capsules apart. The optic and haptics are made of a hydrophobic acrylic material, and the haptics and interior of the optic are filled with silicone oil that is index-matched to the acrylic. The IOL is designed so that when the haptics are subjected to Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
accommodative forces, silicone oil is pushed into the optic through fluid channels that connect the haptics to the optic. As silicone oil flows into the optic, the deformable front optic surface is changed, increasing the power of the IOL. A recently completed pilot study of 20 patients demonstrated the accommodative capability of this accommodating IOL.B We previously evaluated the Fluidvision accommodating IOL in a short-term rabbit study (6 weeks follow-up).12 Overall, capsular bag opacification with this IOL was remarkably low compared with that in commercially available single-piece hydrophobic
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acrylic IOLs. The aim of the current study was to evaluate the long-term uveal and capsular biocompatibility of this accommodating IOL according to the requirements of the International Organization for Standardization (ISO) for IOLs.13 MATERIALS AND METHODS The study IOL (Fluidvision) has an overall diameter of 10.0 mm and an optic diameter of 6.0 mm (Figure 1). The control IOL, Acrysof model SA60AT IOL (Alcon Laboratories, Inc.), had a dioptric power of C20.0 diopters (D) (same power as the study IOL); the overall diameter is 13.0 mm and the optic diameter, 6.0 mm. Fourteen New Zealand white rabbits weighing between 3.2 kg and 3.6 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. Bilateral phacoemulsification with IOL implantation was performed; the right eye was randomized to receive a study or a control IOL and the contralateral eye received the other 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.10–12 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 Laboratories, Inc.) was inserted into the posterior chamber to remove the lens nucleus and cortical material. One milliliter of epinephrine 1:1000 and 0.5 mL of heparin (10 000 USP units/mL) were added to each 500 mL of irrigation solution to facilitate pupil dilation and control inflammation. After the lens nucleus and cortex were removed, an ophthalmic viscosurgical device (OVD) (Amvisc Plus) was used to inflate the capsular bag. The incision was then extended to 4.0 mm with a 4.0 mm keratome for both study and control IOLs. The IOLs were implanted in the capsular bag using the corresponding recommended injection system and technique. The wound was closed with a 10-0 monofilament nylon suture after removal of
Submitted: March 26, 2014. Final revision submitted: May 5, 2014. Accepted: May 12, 2014. From the Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, to the Department of Ophthalmology and Visual Sciences, University of Utah, and by a research grant from Powervision Inc., Belmont, California, USA.
Figure 1. The study IOL fixated within the capsular bag (provided by Powervision, Inc.).
OVD material using irrigation/aspiration. Appropriate in-the-bag placement of the IOL, IOL centration, and coverage of the IOL optic by the capsulorhexis were verified at the end of the procedure. Postoperative topical therapy included combination neomycin, polymyxin B sulfates, and dexamethasone ointment during the first postoperative week and prednisolone acetate drops during the second week. The eyes were evaluated by slitlamp examination and scored for ocular inflammatory response weekly from 1 to 4 weeks and then at 2, 3, 4, and 6 months. Clinical color photographs of each eye at each time point 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 a final clinical examination at 2 months or 6 months, the animals were anesthetized and then humanely killed with a 1 mL intravenous injection of pentobarbital sodium–phenytoin sodium. The globes were enucleated and placed in 10% neutral buffered formalin. They were then bisected coronally just posterior to the equator. Gross examination and photographs from the posterior aspect (Miyake-Apple view) 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.10–12 After gross examination, selected study and control IOLs were carefully removed from the eyes and 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 and stained with hematoxylin–eosin.
Mary Mayfield assisted with the histopathologic processing of the eyes. Corresponding author: Liliana Werner, MD, PhD, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, Utah 84132, USA. E-mail: [email protected].
RESULTS The study IOL was implanted in the right eye in 7 rabbits and the left eye in 7 rabbits. The capsulorhexis
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Figure 2. Slitlamp photographs of both eyes of the same rabbit taken at 4 weeks, 2 months, and 6 months postoperatively. The eye with the study IOL (A, C, and E) has overall clear anterior and posterior capsules. The eye with the control IOL (B, D, and F) developed fibrosis of the capsulorhexis edge and increasingly diffuse PCO.
was oval and/or large in 2 eyes with study IOLs and in 1 eye with a control IOL. Slitlamp Examinations At the 1-week examination, eyes in both IOL groups exhibited mild degrees of corneal edema (generally limited to the incision site) and aqueous cells. They also had mild fibrin formation and blood in the anterior chamber. Corneal edema and aqueous cells were absent by the 2-week examination in all eyes. One study eye and 6 control eyes had mild fibrin in front of the IOL at the 3-week examination that resolved by the 4-week examination. At the 2-week examination, mild degrees of PCO were observed in eyes with control IOLs; the PCO increased throughout the study. At the 3-week examination, minor signs of capsular opacification were seen in some eyes with study IOLs but the opacification generally remained stable with little progression. At 2 months, 6 animals were randomly selected and humanely killed and the eyes and the IOLs were
evaluated. The PCO was 1.1 G 0.6 in eyes with study IOLs and 3.0 G 1.2 in eyes with control IOLs (P Z .0002, 2-tailed paired t test). Soemmerring ring formation was significantly greater in eyes with control IOLs than in those with study IOLs, where it was generally limited to the gap spaces between the haptics. The PCO generally started at the level of the optic–haptic junctions in eyes with control IOLs. Mild to moderate degrees of ACO were observed in eyes with control IOLs, but ACO was practically absent in those with study IOLs. Mild degrees of giant cell formation were observed in some eyes with both types of IOLs at the same time point. Posterior synechiae were also observed with both types of IOLs and were generally associated with Soemmerring ring protruding anteriorly. Up to 6 months, the examinations showed a progressive increase in PCO in both groups, more significant in the control group. At 6 months, the remaining 8 animals were humanely killed and the eyes and IOLs evaluated. The PCO was 1.3 G 0.4 in eyes with study IOLs and 4.0 G 0.0 in eyes with control IOLs
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Figure 3. Gross photographs of both eyes of 2 rabbits taken from the Miyake-Apple view. Postmortem examinations were done at 2 months (A and B) and 6 months (C and D; same eyes as in Figure 2). Postmortem examination of the eyes with the study accommodating IOL at both time points (A and C) showed overall clear anterior and posterior capsules. Postmortem examination of the eyes with the control IOL (B and D) showed PCO starting at the optic–haptic junctions in B, and diffuse PCO in D.
(P ! .0001, 2-tailed paired t test). There was also increased Soemmerring ring formation in both groups; the formation was generally limited to the gap spaces between the haptics of the study IOLs but progressively increased in the eyes with control IOLs. The increasing cell proliferation within the capsular bag was associated with increasing IOL decentration in the control group. At the end of the study, ACO appeared to be absent in the study group. Mild to moderate ACO was generally observed in the control group; 2 control eyes had capsulorhexis phimosis. Synechiae with anterior pearls as well as giant cells continued to be observed in some IOLs in both groups up to 6 months with no significant between-group differences (Figure 2).
Gross Examination Evaluation of the animals selected for the 2-month and the 6-month follow-up confirmed that less PCO was observed in eyes with the study IOLs than in those with the control IOLs (Figure 3). The results of this evaluation are shown in Table 1.
Implant Cytology Analysis of the IOLs explanted at 2 months for implant cytology (2 study and 2 control IOLs) was relatively difficult due to the presence of proliferative
Table 1. Capsular bag opacification scoring during postmortem evaluation of rabbit eyes from the Miyake-Apple view. Examination Time 2 months Central PCO Peripheral PCO Soemmering ring (intensity area) 6 months Central PCO Peripheral PCO Soemmering ring (intensity area)
Study IOL
Control IOL
P Value*
0.5 G 0.2 1.1 0.4 2.8 G 0.7
2.3 G 1.4 3.0 G 1.5 8.5 G 1.9
.03 .02 .0005
0.8 G 0.5 1.6 G 0.6 4.0 G 1.4
3.7 G 0.4 4.0 G 0 11.3 G 3.2
!.0001 !.0001 .001
ACO Z anterior capsule opacification; PCO Z posterior capsule opacification *Two-tailed paired t test
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Figure 4. Light photomicrographs from histopathologic sections cut from both eyes of a rabbit humanely killed at 2 months (same eyes as in Figure 3, A and B). A: Anterior segment of an enucleated left rabbit globe with the study accommodating IOL showing a small amount of proliferative cortical material in the periphery between the haptics (arrow) with no significant PCO. B: Anterior segment of an enucleated right rabbit globe with a control IOL showing a large Soemmerring ring formation as well as a large amount of PCO (arrow) and small amount of ACO (A and B: Composites of light photomicrographs: hematoxylin–eosin staining, original magnification 20).
Figure 5. Representative light photomicrographs from histopathologic sections cut from both eyes of a rabbit humanely killed at 6 months (same eyes as in Figure 3, C and D). A: Anterior segment of an enucleated right rabbit globe with the study accommodating IOL showing a trace PCO with only minimum cortex in the periphery and a clear anterior capsule. B: Anterior segment of an enucleated left rabbit globe with a control IOL showing a large Soemmerring ring as well as a large amount of PCO and anterior cortical proliferation (A and B: Composites of light photomicrographs: hematoxylin–eosin staining, original magnification 20).
material attached to the IOL optics. All IOLs had a mixture of macrophages, epithelioid cells, giant cells, and spindle-shaped cells attached to the optic surface. Analysis of the IOLs explanted at 6 months was more difficult due to the presence of significant proliferative material attached to the IOL optics. Analysis of 1 control IOL was not possible. Both types of IOLs (2 study and 1 control) appeared to have a mixture of macrophages, epithelioid cells, giant cells, and spindle-shaped cells attached to the optic surface.
cortical material seen in the periphery as well as in the gaps between the haptics. The central area of the posterior capsule was remarkably clear in all animals evaluated. Eyes with the control IOLs showed extensive Soemmerring ring formation and PCO. There was no sign of inflammation or toxicity in the study or control eyes. The posterior segments in both (study and control eyes) were unremarkable (Figures 4 and 5).
Histopathology At 2 and 6 months, the anterior segments of the eyes with the study IOL showed a widely dilated lens capsule with only small amounts of proliferative
DISCUSSION Wallentin et al.14 have shown that components important for PCO formation in humans are also components of after-cataract formation in rabbits. A series of studies by Gwon et al.15–18 showed the potential for lens epithelial cells (LECs) in rabbits to proliferate
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in the absence of IOL implantation. This was so evident in some cases that actual lens regeneration was observed in the late postoperative period (8 months). The regeneration/proliferation of the material is also accelerated; 6 to 8 weeks in the rabbit eye correspond to approximately 2 years in the human eye.15–18 The proliferative capacity of the New Zealand rabbit LECs makes them an appropriate model for studying capsular bag proliferation within a relatively short time period. However, ISO requirements specify a 6-month in vivo study for the biocompatibility evaluation of new materials used in the manufacture of IOLs13 and we therefore performed this evaluation of the Fluidvision accommodating IOL. We previously evaluated this accommodating IOL in a short-term rabbit study.12 Bilateral phacoemulsification with IOL implantation was performed in 6 New Zealand rabbits. Each animal received a study and a control (1-piece hydrophobic acrylic) IOL. Eyes were examined at the slitlamp from 1 day to 6 weeks postoperatively. The globes were then enucleated and evaluated grossly. Capsular bag opacification was scored from the posterior aspect (Miyake-Apple view), and the eyes were then processed for complete histopathologic evaluation. At 6 weeks, the PCO clinical score was 0.5 G 0.3 in the study group and 3.0 G 0.9 in the control group (P Z .001, 2-tailed paired t test). Anterior capsule opacification was practically absent in the study group and mild in the control group. The Miyake-Apple posterior view showed central PCO of 0 G 0 in the study group and 3.0 G 1.1 in the control group (P Z .001), peripheral PCO of 0.7 G 0.4 and 3.5 G 0.8, respectively (P Z .0006), and Soemmerring ring of 2.3 G 0.8 and 7.0 G 2.8, respectively (P Z .01). It became clear that the overall capsular bag opacification was significantly reduced with this accommodating IOL.12 Although exacerbated proliferation of residual LECs in the rabbit model usually renders PCO comparisons after 4 weeks postoperatively very difficult, even impossible, up to the end of the current study (6-month follow-up) there was significantly less PCO associated with the study IOLs and ACO was practically absent. Increased PCO in the control eyes was associated with increased IOL decentration. The stability of study IOLs within the capsular bag was superior to that of control IOLs throughout the study. In terms of uveal biocompatibility, there were no significant differences between the IOL groups in the early or late postoperative period. Histopathologic examination showed no sign of untoward inflammation or toxicity in any study or control eyes evaluated. Several strategies used with this IOL may prevent capsular bag opacification.12 The IOL practically fills the entire capsular bag, with significant bag
expansion. Mechanical compression and/or stretching of the capsular bag are probably responsible for the significant prevention of capsular bag opacification in the study IOL eyes. Proliferative material is generally limited to the fornix of the capsular bag, and the presence of the haptics blocks extension of the proliferative material toward the optic, with the exception of the haptic gap sites. In those 2 areas, there appears to be a lack of mechanical compression of the inner surface of the capsular bag; the shape/contour of the bag is also not maintained. However, the optic edge generally blocks access of the material to the posterior capsule. Also, the anterior capsule remained remarkably clear with the study IOL throughout the study. The contact between the study IOL and the anterior capsule is at the periphery of the capsular bag, at the level of the haptic components, where a fine wrinkling of the anterior capsule can be observed. The anterior capsule at and around the capsulorhexis edge is generally devoid of fibrosis, as it remains at a distance from the anterior IOL surface. In summary, the Fluidvision accommodating IOL maintained an expanded capsular bag secondary to the large size of the haptic elements, without significant contact with the anterior capsule. This appeared to prevent overall capsular bag opacification while retaining uveal biocompatibility, as demonstrated in this 6-month rabbit study. Since rabbits have a more robust LEC reaction and inflammatory response than humans, 6 months would be the equivalent of several years in a human eye. Cellular proliferation within the capsular bag after implantation of an accommodating IOL could potentially impair its function; therefore, results of this long-term study are encouraging. WHAT WAS KNOWN In a 6-week in vivo study, a new silicone oil-filled accommodating IOL incorporating large haptic elements appeared to prevent capsular bag opacification by keeping the anterior capsule at a distance from the anterior optic surface and maintaining an expanded capsular bag. WHAT THIS PAPER ADDS The capsular bag opacification preventive effects exerted by the same accommodating IOL continued to be observed in this long-term 6-month study performed according to ISO requirements. The results are encouraging considering the exacerbated proliferative capacity of the rabbit model, which usually renders comparison of capsular bag opacification after 4 weeks not possible. The study IOL also exhibited appropriate long-term uveal biocompatibility.
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REFERENCES 1. Hara T, Hara T, Yasuda A, Yamada Y. Accommodative intraocular lens with spring action. Part 1. Design and placement in an excised animal eye. Ophthalmic Surg 1990; 21:128–133 2. Hara T, Hara T, Yasuda A, Mizumoto Y, Yamada Y. Accommodative intraocular lens with spring action – Part 2. Fixation in the living rabbit. Ophthalmic Surg 1992; 23:632–635 3. McLeod SD, Portney V, Ting A. A dual optic accommodating foldable intraocular lens. Br J Ophthalmol 2003; 87:1083–1085. Available at: http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC1771831/pdf/bjo08701083.pdf. Accessed September 1, 2014 4. Werner L, Pandey SK, Izak AM, Vargas LG, Trivedi RH, Apple DJ, Mamalis N. Capsular bag opacification after experimental implantation of a new accommodating intraocular lens in rabbit eyes. J Cataract Refract Surg 2004; 30:1114–1123 5. Werner L, Mamalis N, Stevens S, Hunter B, Chew JJL, Vargas LG. Interlenticular opacification: dual-optic versus piggyback intraocular lenses. J Cataract Refract Surg 2006; 32:655–661 6. McLeod SD. Optical principles, biomechanics, and initial clinical performance of a dual-optic accommodating intraocular lens (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2006; 104:437–452. Available at: http://www.pubmed central.nih.gov/picrender.fcgi?artidZ1809902&blobtypeZpdf. Accessed September 1, 2014 7. McLeod SD, Vargas LG, Portney V, Ting A. Synchrony dual-optic accommodating intraocular lens. Part 1: optical and biomechanical principles and design considerations. J Cataract Refract Surg 2007; 33:37–46 8. Ossma IL, Galvis A, Vargas LG, Trager MJ, Vagefi MR, McLeod SD. Synchrony dual-optic accommodating intraocular lens. Part 2: pilot clinical evaluation. J Cataract Refract Surg 2007; 33:47–52 9. Kavoussi SC, Werner L, Fuller SR, Hill M, Burrow MK, McIntyre JS, Mamalis N. Prevention of capsular bag opacification with a new hydrophilic acrylic disk-shaped intraocular lens. J Cataract Refract Surg 2011; 37:2194–2200 10. Leishman L, Werner L, Bodnar Z, Ollerton A, Michelson J, Schmutz M, Mamalis N. Prevention of capsular bag opacification with a modified hydrophilic acrylic disk-shaped intraocular lens. J Cataract Refract Surg 2012; 38:1664–1670 11. Werner L, Hickman MS, LeBoyer RM, Mamalis N. Experimental evaluation of the Corneal Concept 360 intraocular lens with the Miyake-Apple view. J Cataract Refract Surg 2005; 31:1231–1237
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12. Floyd AM, Werner L, Liu E, Stallings S, Ollerton A, Leishman L, Bodnar Z, Morris C, Mamalis N. Capsular bag opacification with a new accommodating intraocular lens. J Cataract Refract Surg 2013; 39:1415–1420 13. International Organization for Standardization. Ophthalmic Implants – Intraocular Lenses – Part 5: Biocompatibility. Geneva, Switzerland, ISO, 2006; (ISO 11979–5) n JB, Lundberg C. Development 14. Wallentin N, Lundgren B, Holme of posterior capsule opacification in the rabbit. Ophthalmic Res 2002; 34:14–22 15. Gwon AE, Gruber LJ, Mundwiler KE. A histologic study of lens regeneration in aphakic rabbits. Invest Ophthalmol Vis Sci 1990; 31:540–547. Available at: http://www.iovs.org/content/ 31/3/540.full.pdf. Accessed September 1, 2014 16. Gwon AE, Jones RL, Gruber LJ, Mantras C. Lens regeneration in juvenile and adult rabbits measured by image analysis. Invest Ophthalmol Vis Sci 1992; 33:2279–2283. Available at: http:// www.iovs.org/cgi/reprint/33/7/2279.pdf. Accessed September 1, 2014 17. Gwon A, Gruber L, Mantras C, Cunanan C. Lens regeneration in New Zealand albino rabbits after endocapsular cataract extraction. Invest Ophthalmol Vis Sci 1993; 34:2124–2129. Available at: http://www.iovs.org/cgi/reprint/34/6/2124.pdf. Accessed September 1, 2014 18. Gwon A, Gruber LJ, Mantras C. Restoring lens capsule integrity enhances lens regeneration in New Zealand albino rabbits and cats. J Cataract Refract Surg 1993; 19:735–746
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 B. Potgieter F, “FluidVisionÒ Lens Design Principles and Early Clinical Experience,” Presented at the International Society of Presbyopia (ISOP), Amsterdam, Netherlands, October 2013
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First author: Justin C. Kohl, MD Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA