July 2006
Volume 47, Issue 7
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An In Vitro Study of Human Lens Epithelial Cell Adhesion to Intraocular Lenses with and without a Fibronectin Coating
Author Affiliations
  • Carole A. Cooke
    From the Department of Ophthalmology and the
  • Stuart McGimpsey
    From the Department of Ophthalmology and the
  • Gerald Mahon
    Queen’s University Belfast Ophthalmic Research Centre, Royal Victoria Hospital, Belfast, Northern Ireland, United Kingdom.
  • Richard M. Best
    From the Department of Ophthalmology and the
Investigative Ophthalmology & Visual Science July 2006, Vol.47, 2985-2989. doi:https://doi.org/10.1167/iovs.05-1275
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      Carole A. Cooke, Stuart McGimpsey, Gerald Mahon, Richard M. Best; An In Vitro Study of Human Lens Epithelial Cell Adhesion to Intraocular Lenses with and without a Fibronectin Coating. Invest. Ophthalmol. Vis. Sci. 2006;47(7):2985-2989. https://doi.org/10.1167/iovs.05-1275.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

purpose. To demonstrate differences in human lens epithelial cell adhesion to different intraocular lens biomaterials in vitro and to determine whether these differences can be influenced by coating the intraocular lens surface with commercially available fibronectin.

methods. A prospective laboratory-based study comparing human lens epithelial cell adhesion to silicone (n = 18), polymethylmethacrylate (PMMA; n = 18), and acrylic (n = 18) intraocular lenses in vitro. The three types of intraocular lenses were then coated with fibronectin: silicone (n = 6), PMMA (n = 6), and acrylic (n = 6). The main outcome measure was the mean number of lens epithelial cells attached to each lens type after 24 hours of incubation.

results. In the uncoated lens group, there was a significantly higher number of lens epithelial cells attached to the acrylic than to the silicone or PMMA lenses (P < 0.001). Coating the lenses with fibronectin caused a significant increase in attachment of lens epithelial cells for all three lens types.

conclusions. There was a significant difference in the degree of lens epithelial cell attachment to the various types of intraocular lenses in vitro. Cell attachment was more prominent in the acrylic lenses, but the fibronectin coating negated differences in lens type and caused a significant increase in cell attachment across all groups.

Posterior capsular opacification (PCO) is a well-recognized late complication of modern phacoemulsification cataract surgery and occurs in 25% to 50% of patients by 5 years after surgery. 1 2 It results in a disabling decrease in visual acuity and is treated with neodymium:YAG laser capsulotomy. However, this requires further hospital attendances and exposes patients to the risk of complications such as retinal detachment and cystoid macular edema. 3 4 The incidence of PCO has not decreased significantly despite surgical advances. 2 Ideally, if PCO could be eliminated, there would be considerable economic benefit to healthcare systems and improvements in patients’ quality of life. 
After cataract surgery, the three of the commonest types of intraocular lens (IOL) implant biomaterials used are polymethylmethacrylate (PMMA), silicone, and acrylic. Previous studies have shown a significant difference in the PCO rate among these lens materials. It has been shown that there is a lower PCO rate with acrylic IOLs, 5 6 7 8 9 10 11 the exact reasons for which are unclear. It may be that multiple factors are involved. Some reports suggest that the design of the IOL is important, 10 12 13 others state that the adhesive properties of the lens material may be relevant, 6 7 10 as soft acrylic IOLs show greater lens epithelial cell (LEC) adhesion than do PMMA and silicone lenses. 14 Fibronectin is an important extracellular matrix protein and has been shown to be the main extracellular protein responsible for the attachment of the hydrophobic soft acrylate IOL (AcrySof IOL; Alcon Laboratories, Fort Worth, TX) to the lens capsule. 15 Linnola 16 has proposed the “sandwich theory” to explain the lower rate of development of PCO in acrylic IOLs. He suggests that further ingrowth of epithelial cells is prevented by the adhesion of the IOL to the LEC and this then to the capsule. 
The focus of the present study was to examine the adhesion of human LECs to different IOL biomaterials. To our knowledge, there have been no reports outlining the in vitro rate of LEC attachment to IOLs after coating them with a commercially available fibronectin preparation. The second part of this experiment therefore was to see whether coating different IOLs with fibronectin would alter the rates of lens epithelial adhesion. If it were possible to alter the LEC adhesive properties of different IOL biomaterials, it might eventually promote adherence of the IOL to the lens capsule and reduce PCO. 
The goals of this study were to measure LEC attachment rates in vitro to silicone, PMMA, and acrylic IOLs and then to determine the effect on these cell attachment rates after applying a fibronectin coating to all three types of lenses. 
Methods
An extensive literature review was performed, and previous reported techniques 17 18 were modified as follows. In this study, a human LEC line was used. The cell line had been immortalized with the large T-antigen of SV40 and the epithelial nature of the lens cells was confirmed in our laboratory with a pancytokeratin antibody (clone C-11; Sigma-Aldrich, Poole, UK; Fig. 1 ). 
The cells were grown to confluence in T75 flasks containing DMEM (Dulbecco’s modified Eagle’s medium; Invitrogen, Paisley, Scotland, UK) supplemented with 10% fetal calf serum and 5 mg/mL Primocin (InvivoGen, San Diego, CA). At confluence, the cells were washed in phosphate-buffered saline (PBS), trypsinized, centrifuged at 1600 rpm, and resuspended in medium to give a cell concentration of 6 × 104/mL. For each experiment, three IOLs of the three materials were used. The IOLs chosen were silicone (SI40NB Phacoflex; Advanced Medical Optics [AMO], Santa Ana, CA), PMMA (Optical Innovations International [OII], Inc., Ontario, CA), and acrylic (Sensar AR40e; AMO). The dioptric power was matched for each IOL type, and the lenses were placed in a 12-well multiplate. A cell suspension (20 μL) was placed on the surface of each IOL and left to adhere for 2 hours at 37°C. After this time, 1 mL of DMEM with fetal calf serum was gently added to the well and the cells incubated at 37°C for 24 hours. After incubation, the lenses were examined with a phase-contrast inverted microscope (Nikon, Tokyo, Japan). With the aid of an eyepiece graticule, the total number of attached LECs per IOL was recorded. This procedure was performed by one of the authors (GM) who was blinded to the lens type. The counts were then repeated to ensure reproducibility by another of the authors (CAC). The cell counts were comparable between authors. Each experiment was duplicated (18 IOLs) and then repeated with different cell concentrations. In total, cell concentrations of 4 × 104/mL, 6 × 104/mL, and 7.5 × 104/mL were used (18 IOLs at each concentration), to test reproducibility at each dilution. 
A second experiment was performed with IOLs coated with fibronectin (from bovine plasma, Sigma-Aldrich). Six lenses of each material were coated with fibronectin (total number, 18) and these coated IOLs were then seeded and incubated as before with LECs at the chosen cell concentration of 6 × 104/mL. The total number of attached LECs per IOL was again recorded and the results compared with an equal number of matched uncoated lenses (n = 18). The technique for coating the lenses was as follows; Fibronectin (from bovine plasma; Sigma-Aldrich) was diluted with sterile distilled water to give a working concentration of 2 μg/cm2. Fibronectin solution (300 μL) was added to each well of a 12-well multiplate, and an IOL was then placed in each well. The lens was allowed to incubate for 1 hour and then removed and placed in a fresh multiplate to dry at room temperature. Using the cell concentration of 6 × 104/mL the lenses were seeded and incubated as before. Statistical analysis was performed on computer (SPSS ver. 12.0.1; SPSS, Chicago, IL). Before analysis, all cell count data was log transformed. Initially, groups were analyzed with analysis of variance. Subsequent post hoc analysis was performed with the Student-Newman-Keuls test. P < 0.05 indicated statistical significance. 
Results
In the uncoated lens group, the LECs were more readily attached to the acrylic lenses than to the silicone or PMMA lenses (Fig. 2)
Analyses showed that this result was statistically significant (P < 0.001; Table 1 ). These differences were present at all three cell concentrations used (Table 2) . For IOLs coated with fibronectin, there was no significant difference in human LEC adhesion among the three IOL types (P = 0.605; Table 1 ). Coating the lenses with fibronectin had a considerable effect on cell attachment (P < 0.001; Fig. 3 ). 
The results of post hoc analysis using the Student-Newman-Keuls test show that there is a difference in LEC attachment between acrylic and silicone IOLs, and between acrylic and PMMA IOLs, but not between PMMA and silicone IOLs. 
A power calculation was not performed at the commencement of this study because of limited data availability. In retrospect, we can assess the power of the analysis of the fibronectin-coated lenses. Given the variability evident in our data, our study had 90% power to detect as statistically significant (P < 0.05) a difference between two geometric means of LEC adherence of 0.118. This corresponds to a ratio of geometric means of 1.3 (i.e., a difference of LEC adherence between two lenses of 31%). 
The basic assumptions for ANOVA (normality and variances) statistical calculations were met. For normality, the data were log transformed, and a plot of the residuals showed adherence of log-transformed data to normality (Fig. 4)
Discussion
Previous studies have shown a significantly lower PCO rate for acrylic IOLs, 5 6 7 8 9 10 11 the reasons for which are controversial. Theories postulate that it may have to do with the structural design of the IOL. The square truncated optic edge is reported to act as a mechanical barrier and impede migration and growth of the LECs behind the optic. 10 12 13 Some reports suggest that the lens surface properties themselves are more relevant, rather than edge design. 5 It may be that the adhesive properties of the lens material are also important in causing the capsular bag to stick to the capsule, leaving no space for the cells to migrate. 7 10 Soft acrylic IOLs show greater LEC adhesion than do PMMA and silicone lenses. 14 In this study, the initial experiment confirmed these findings, showing that LECs attached more readily to the acrylic lenses than to the silicone or PMMA lenses. 
IOLs coated with heparin have been used in patients with inflammatory eye disease. However, the PCO rate with these lenses, at 2 years after implantation is still much higher than that with AcrySof lenses. 19 Versura et al. determined that the density of LECs cultured on heparin-surface-modified PMMA (HSM PMMA) IOLs significantly decreased after 72 hours, and spreading was incomplete with no focal contacts. They suggested that on HSM PMMA IOLs, surface LECs form only transient focal contacts earlier than 24 hours and then disaggregate. This is in contrast to the increased epithelial cell adhesion they found with non–HSM PMMA IOLs. 20 In another study in which IOL performance was analyzed in uveitic eyes, 21 hydrophobic acrylic lenses had the lowest inflammation scores 1 day after surgery, and the trend continued up to the 3-month follow-up. Both acrylic and HSM PMMA IOL groups had the lowest incidence of uveitis relapses. The researchers concluded that IOL implantation in selected uveitic eyes was safe but acrylic IOLs had a lower complication rate than did the IOLs of other materials. Therefore, the degree of LEC adhesion to IOLs cannot be the only mechanism; other factors must be involved. 
Linnola et al. 22 evaluated the adhesion of various in vivo extracellular matrix components to IOLs in pseudophakic human donor eyes obtained at autopsy. They found that fibronectin was the mediating extracellular protein between the capsule and LECs and between the LECs and the IOL surface in eyes with an acrylate IOL and that hydrophobic soft acrylate IOLs had more fibronectin adhering to their surfaces than to PMMA or silicone lenses. They proposed that fibronectin acts as a bioactive bond between IOL and the capsule, leading to the reduced PCO rates observed in eyes with a soft acrylate lens. In another study, fibronectin was found to adhere best to acrylate IOLs. 23 However, differences in fibronectin adhesion rates between IOLs may be dependent on the fibronectin concentration used and appear to be significant at higher concentrations. 24 These observations suggest that fibronectin has a major role in the adhesion of LECs to IOLs. 
The use of human LEC lines is controversial, in that they may not be representative of human LECs in vivo. However, for this study, the cell line was used because it was convenient and readily available and has provided encouraging preliminary results. The authors have further work ongoing to see whether these differences are replicated using primary human lens cell cultures. The number of attached cells per IOL was counted using an eye-piece graticule. This technique posed several problems. The method was laborious and technically difficult initially, particularly with the acrylic lenses. However, the technique did not take long to learn and results were reproducible between the authors who performed the counts. Another possible method to count the cells would have been to use a flow cytometer or a hemocytometer. The latter technique was attempted initially in this experiment but it was found to be too inaccurate, especially with those lenses that only had a few adherent cells. Hence, it was more reproducible and accurate to count the cells in situ with the graticule. The pictures show a significant difference between the IOL types, and the graticule counting method has clearly confirmed this. 
In conclusion, this study confirms that cells from a human LEC line attach more readily to acrylic IOLs than to PMMA or to silicone IOLs in vitro. Coating the lenses with a commercially available fibronectin preparation appears to negate the effect of the lens material in vitro, and markedly increased the cell adherence to all three types of lenses. We hypothesize that the fibronectin coating may act as a bond between the LECs and the IOL. The present study, however, provides no information on whether fibronectin would also promote adhesion of inflammatory cells to the IOL in vivo. Future experiments are necessary to determine whether coating IOLs with fibronectin can increase the adhesion between the IOL and the lens capsule after cataract surgery and consequently to determine whether this effect would have further implications for the prevention of PCO. 
 
Figure 1.
 
Confocal micrograph of lens epithelial cells showing intermediate filaments labeled with Alexa Fluor conjugated to pancytokeratin (green) and nuclei labeled with propidium iodide (red).
Figure 1.
 
Confocal micrograph of lens epithelial cells showing intermediate filaments labeled with Alexa Fluor conjugated to pancytokeratin (green) and nuclei labeled with propidium iodide (red).
Figure 2.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic IOLs.
Figure 2.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic IOLs.
Table 1.
 
Geometric Mean for Uncoated and Coated Lenses
Table 1.
 
Geometric Mean for Uncoated and Coated Lenses
Uncoated Coated
PMMA 36 (19–74), 6 761 (639–906), 6
Silicone 21 (8–54), 6 738 (520–903), 6
Acrylic 163 (98–244), 6 700 (594–767), 6
Table 2.
 
Descriptive Statistics for Uncoated IOLs at Each Lens Epithelial Cell Concentration
Table 2.
 
Descriptive Statistics for Uncoated IOLs at Each Lens Epithelial Cell Concentration
n Mean SD SE 95% CI for Mean Min Max
Lower Bound Upper Bound
4 × 104
 PMMA 6 1.5969 0.12624 0.05154 1.4644 1.7294 1.38 1.72
 Silicone 6 0.9882 0.26626 0.10870 0.7088 1.2677 0.60 1.36
 AR40 6 2.1676 0.05530 0.02258 2.1096 2.2257 2.13 2.28
 Total 18 1.5843 0.52153 0.12292 1.3249 1.8436 0.60 2.28
6 × 104
 PMMA 6 1.5605 0.25381 0.10362 1.2942 1.8269 1.28 1.87
 Silicone 6 1.3314 0.29177 0.11911 1.0252 1.6376 0.90 1.73
 AR40 6 2.2130 0.13286 0.05424 2.0736 2.3525 1.99 2.39
 Total 18 1.7017 0.44372 0.10459 1.4810 1.9223 0.90 2.39
7.5 × 104
 PMMA 6 1.7032 0.20947 0.08551 1.4833 1.9230 1.49 1.97
 Silicone 6 1.4205 0.27220 0.11112 1.1348 1.7061 1.15 1.88
 AR40 6 2.4928 0.18478 0.07544 2.2989 2.6867 2.15 2.66
 Total 18 1.8721 0.51261 0.12082 1.6172 2.1271 1.15 2.66
Figure 3.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic fibronectin-coated IOLs.
Figure 3.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic fibronectin-coated IOLs.
Figure 4.
 
Normal Q–Q plot of residual for (A) uncoated and (B) coated IOLs.
Figure 4.
 
Normal Q–Q plot of residual for (A) uncoated and (B) coated IOLs.
The authors thank Chris Patterson (Department of Epidemiology, Queen’s University Belfast/Royal Victoria Hospital, Belfast, Northern Ireland, UK) for statistical analysis. 
AppleDJ, SolomonKD, TetzMR, et al. Posterior capsular opacification. Surv Ophthalmol. 1992;37:73–116. [CrossRef] [PubMed]
SchaumbergDA, DanaMR, ChristenWG, GlynnRJ. Systematic overview of the incidence of posterior capsular opacification. Ophthalmology,. 1998;105:1213–1221. [CrossRef]
SteinertRF, PuliafitoCA, KumarSR, DudakSD, PatelS. Cystoid macular edema, retinal detachment, and glaucoma after Nd:YAG laser posterior capsulotomy. Am J Ophthalmol. 1991;112:373–380. [CrossRef] [PubMed]
RantaP, KivelaT. Retinal detachment in pseudophakic eyes with and without Nd:YAG laser posterior capsulotomy. Ophthalmology. 1998;105:2127–2133. [CrossRef] [PubMed]
SchauersbergerJ, AmonM, KrugerA, AbelaC, SchildG, KolodjaschnaJ. Lens epithelial cell outgrowth on 3 types of intraocular lenses. J Cataract Refract Surg. 2001;27:850–854. [CrossRef] [PubMed]
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HollickEJ, SpaltonDJ, UrsellPG, et al. The effect of polymethylmethacrylate, silicone, and polyacrylic intraocular lenses on posterior capsular opacification 3 years after cataract surgery. Ophthalmology. 1999;106:49–55. [CrossRef] [PubMed]
OnerFH, GunencU, FerlielST. Posterior capsule opacification after phacoemulsification: foldable acrylic versus poly(methyl methacrylate) intraocular lenses. J Cataract Refract Surg. 2000;26:722–726. [CrossRef] [PubMed]
SundelinK, Friberg-RiadY, ÖstbergA, SjostrandJ. Posterior capsule opacification with AcrySof and poly(methyl methacrylate) intraocular lenses. Comparative study with a 3-year follow-up. J Cataract Refract Surg. 2001;27:1586–1590. [CrossRef] [PubMed]
KurosakaD, ObasawaM, KurosakaH, NakamuraK. Inhibition of lens epithelial cell migration by an acrylic intraocular lens in vitro. Ophthalmic Res. 2002;34:29–37. [CrossRef] [PubMed]
ScaramuzzaA, FernandoGT, CrayfordBB. Posterior capsule opacification and lens epithelial cell layer formation: hydroview hydrogel versus Acrysof acrylic intraocular lenses. J Cataract Refract Surg. 2001;27:1047–1054. [CrossRef] [PubMed]
PengQ, VisessookN, AppleDJ, et al. Surgical prevention of posterior capsule opacification. Part 3: Intraocular lens optic barrier effect as a second line of defense. J Cataract Refract Surg. 2000;26:198–213. [CrossRef] [PubMed]
WernerL, MamalisN, PandeySK, et al. Posterior capsule opacification in rabbit eyes implanted with hydrophilic acrylic intraocular lenses with enhanced square edge. J Cataract Refract Surg. 2004;30:2403–2409. [CrossRef] [PubMed]
MajimaK. The relationship between morphological changes of lens epithelial cells and intraocular lens optic material. Jpn J Ophthalmol. 1998;42:46–50. [CrossRef] [PubMed]
LinnolaRJ, WernerL, PandeySK, Escobar-GomezM, ZnoikoSL, AppleDJ. Adhesion of fibronectin, vitronectin, laminin, and collagen type IV to intraocular lens materials in pseudophakic human autopsy eyes. Part 1: Histological sections. J Cataract Refract Surg. 2000;26:1792–1806. [CrossRef] [PubMed]
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VersuraP, TorreggianiA, CelliniM, CaramazzaR. Adhesion mechanisms of human lens epithelial cells on 4 intraocular lens materials. J Cataract Refract Surg. 1999;25:527–533. [CrossRef] [PubMed]
AlioJL, ChipontE, BenEzraD, FakhryMA, International Ocular Inflammation Society, Study Group of Uveitic Cataract Surgery. Comparative performance of intraocular lenses in eyes with cataract and uveitis. J Cataract Refract Surg. 2002;28:2096–2108. [CrossRef] [PubMed]
LinnolaRJ, WernerL, PandeySK, Escobar-GomezM, ZnoikoSL, AppleDJ. Adhesion of fibronectin, vitronectin, laminin, and collagen type IV to intraocular lens materials in pseudophakic human autopsy eyes. Part 2: Explanted intraocular lenses. J Cataract Refract Surg. 2000;26:1807–1818. [CrossRef] [PubMed]
LinnolaRJ, SundM, YlönenR, CandM, PihlajaniemiT. Adhesion of soluble fibronectin, laminin, and collagen type IV to intraocular lens materials. J Cataract Refract Surg. 1999;25:1486–1491. [CrossRef] [PubMed]
LinnolaRJ, SundM, YlönenR, CandM, PihlajaniemiT. Adhesion of soluble fibronectin, vitronectin, and collagen type IV to intraocular lens materials. J Cataract Refract Surg. 2003;29:146–152. [CrossRef] [PubMed]
Figure 1.
 
Confocal micrograph of lens epithelial cells showing intermediate filaments labeled with Alexa Fluor conjugated to pancytokeratin (green) and nuclei labeled with propidium iodide (red).
Figure 1.
 
Confocal micrograph of lens epithelial cells showing intermediate filaments labeled with Alexa Fluor conjugated to pancytokeratin (green) and nuclei labeled with propidium iodide (red).
Figure 2.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic IOLs.
Figure 2.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic IOLs.
Figure 3.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic fibronectin-coated IOLs.
Figure 3.
 
Micrographs of LEC adhesion to (A) PMMA (B) silicone, and (C) acrylic fibronectin-coated IOLs.
Figure 4.
 
Normal Q–Q plot of residual for (A) uncoated and (B) coated IOLs.
Figure 4.
 
Normal Q–Q plot of residual for (A) uncoated and (B) coated IOLs.
Table 1.
 
Geometric Mean for Uncoated and Coated Lenses
Table 1.
 
Geometric Mean for Uncoated and Coated Lenses
Uncoated Coated
PMMA 36 (19–74), 6 761 (639–906), 6
Silicone 21 (8–54), 6 738 (520–903), 6
Acrylic 163 (98–244), 6 700 (594–767), 6
Table 2.
 
Descriptive Statistics for Uncoated IOLs at Each Lens Epithelial Cell Concentration
Table 2.
 
Descriptive Statistics for Uncoated IOLs at Each Lens Epithelial Cell Concentration
n Mean SD SE 95% CI for Mean Min Max
Lower Bound Upper Bound
4 × 104
 PMMA 6 1.5969 0.12624 0.05154 1.4644 1.7294 1.38 1.72
 Silicone 6 0.9882 0.26626 0.10870 0.7088 1.2677 0.60 1.36
 AR40 6 2.1676 0.05530 0.02258 2.1096 2.2257 2.13 2.28
 Total 18 1.5843 0.52153 0.12292 1.3249 1.8436 0.60 2.28
6 × 104
 PMMA 6 1.5605 0.25381 0.10362 1.2942 1.8269 1.28 1.87
 Silicone 6 1.3314 0.29177 0.11911 1.0252 1.6376 0.90 1.73
 AR40 6 2.2130 0.13286 0.05424 2.0736 2.3525 1.99 2.39
 Total 18 1.7017 0.44372 0.10459 1.4810 1.9223 0.90 2.39
7.5 × 104
 PMMA 6 1.7032 0.20947 0.08551 1.4833 1.9230 1.49 1.97
 Silicone 6 1.4205 0.27220 0.11112 1.1348 1.7061 1.15 1.88
 AR40 6 2.4928 0.18478 0.07544 2.2989 2.6867 2.15 2.66
 Total 18 1.8721 0.51261 0.12082 1.6172 2.1271 1.15 2.66
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