- Email: [email protected]
In vivo study of a fluorocarbon polymer-coated intraocular lens in a rabbit model
In vivo study of a fluorocarbon polymer-coated intraocular lens in a rabbit model Jean-Marc Legeais, MD, PhD, Liliana Pacini Werner, MD, Gilbert Legeay, PhD, Benoit Briat, MD, Gilles Renard, MD ABSTRACT Purpose: To evaluate the biocompatibility in rabbit eyes of poly(methyl methacrylate) (PMMA) intraocular lenses (IOLs) that were surface modified using TeflOn AF. Setting: HOtel-Dieu Hospital, Paris Cedex, France. Methods: The IOls were coated with Teflon AF, an amorphous, transparent, and highly hydrophobic fluorocarbon polymer, by immersing them ih Teflon AF 5% and evaporating the solvent (CsF1s). The surface quality of the Teflon-coated IOls was evaluated by scanning electron microscopy (SEM). Teflon-coated (n == 20) and control PMMA (n = 10) IOls were implanted in rabbit eyes. The presence of irisIOl synechias and the number of deposits on thelOl surfaces were clinically evaluated in both groups to assess the antiadhesive effect of Teflon AF. The Tefloncoated IOLs were removed, their surfaces were evaluated by SEM, and their elemental composition was checked by EDXA and Raman spectrometry. Results: The PMMA IOls were completely coated with Teflon AF. The Teflon group had no iris-iOl synechias and the control group, two extensive synechias. There were significantly fewer deposits on the surfacesof Teflon-coated IOls than on the controllOls 30 and 60 days postoperatively (P < .0001). Scanning electron microscopy showed lens epithelium proliferation and spindle-shaped cells on the surfaces of the PMMA IOls and cell deposits on the irregular regions of the Tetloncoated IOls. White-yellow spots were present on the surfaces of both tOl types. The elemental composition of Teflon-coated IOls was stable. Conclusion: Teflon AF had an antiadhesive effect that increased the biocompatibility of PMMA IOls in vivo. J Cataract Refract Surg 1998; 24:371-379
C
ell adhesion to artificial surfaces may be a major obstacle to biocompatibility of artificial devices such as intraocular lenses (IOLs). Tamada and Ikada1 reported that cell adhesion and proliferation depend on the water contact angle of the substrate. In their study, clear differences in cell growth and cell morphology Reprint requests to Jean-Marc Legeais, MD, H6tel-Dieu Hopital, 1, Place du Parvis Notre-Dame, F-75181 Paris Cedex 04, France.
were observed among the substrates used. Other in vitro studies on cell adhesion have also shown a correlation with the surface properties of the substrates. 2- 13 The surface of poly(methyl methacrylate) (PMMA) 10Ls can be modified to make the lens highly hydrophilic7- 13 or highly hydrophobic. 14 These modifications reduce adhesion to the 10Ls and thus increase their biocompatibility. Several coating techniques have been developed including heparin surface modification and
J CATARACT REFRACT SURG--VOL 24, MARCH
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FLUOROCARBON POLYMER COATING OF IOLs
plasma treatment. Poly(methyl methacrylate) IOLs coated with heparinl2 are thus more hydrophilic and are reported to reduce the inflammatory response. Plasma treatment allows grafting of functional groups onto the PMMA IOL surface, making it more hydrophilic or more hydrophobic. An in vitro study showed less granulocyte activation and adhesion to the surface of PMMA IOLs that are more hydrophobic after tetrafluorocarbon (CF4) plasma treatment. 14 This study was performed to assess the biostability, biocompatibility, and antiadhesive properties of Tefloncoated PMMA IOLs implanted in rabbit eyes.
Materials and Methods Teflon AF (Dupont de Nemours) is a poly(tetrafluoroethylene co-hexafluoro-propyl-2 cyclodiethoxy difluoroethylene). Constituted entirely of high-energy bonds, it is stable at temperatures up to 260°C and chemically very resistant. The refractive index is 1.32. It transmits light from 200 to 2000 nm with a constant light absorption below 5%. The contact angle with water is 129 degrees. It can be dissolved in several liquid fluorocarbons and thus can be used in organic solution. Figure 1 shows the chemical formulas of expanded poly(tetrafluoroethylene) (PTFE) (first generation) and
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Teflon AF (third generation)Y Table 1 shows the surface energies of PMMA, PTFE, and Teflon AF. Teflon AF was chemically characterized by Raman spectrometry. Measurements were performed with a Dilor Z24 spectrometer coupled to a Zeiss optical microscope. The excitation wavelength was 488 nm. The laser beam power at the sample (Teflon AF disc) was 250 mWand the linear slit width was 1.000 /lIll. The Teflon AF Raman spectra were compared with those of opaque sheets of PTFE. The spectra obtained for Teflon AF and PTFE were significantly different, particularly in the region of 207 to 333, 714 to 828, and 1287 to 1632 cm- I (Figure 2), with complex groups of peaks in the Teflon AF spectrum and a single peak in the PTFE spectrum. 15
Surface Modification The PMMA IOLs (model 808A, Kabi Pharmacia Production B.Y.) had an overall diameter of 12.0 mm and optic diameter of 6.5 mm. The surfaces were coated by immersing the lenses in a 5% solution of Teflon AF in a fluorocarbon solvent (CsF ,s) for 3 seconds. The IOLs were then placed at a temperature of 37°C to evaporate the solvent. The surface quality of the Teflon-coated IOLs was evaluated by scanning electron microscopy (SEM). The IOLs were coated with gold, and 5EM was performed using a lEOL 15M 35C scanning microscope. The surfaces of PMMA IOLs were completely coated with Teflon AF. Scanning electron microscopy of Teflon-coated IOLs showed smooth edges overall, but there were several fold-like irregularities in the Teflon AF layer (Figure 3A, B, C). In Vivo Experiment Implantation. Lenses were implanted in 30 adult albino rabbits (New Zealand white) weighing 2.0 to Table 1. Surface energy of polymers.
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Figure 1. (Legeais) Teflon AF
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(A) and Teflon PTFE (8) chemical formulas.
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Surface Ener~
1l,
Total (mJlm-2)
Polar (mJlm-2)
..' NonpcllJr '.
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44.9
20.8
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19.1
0.3
18.8
Teflon AF
16.2
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15.9
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PMMA
. (inJ/m"'"
= poly(methyl methacrylate); PTFE = poly(tetrafluoroethylene)
J CATARACf REFRACf SURG-VOL 24, MARCH 1998
FLUOROCARBON POLYMER COATING OF IOLs SPECfRE 3
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cially in the regions of 207 to 333, 714 to 828, and 1287 to 1362 cm - ' . The PTFE CF4 values were 908 cm - ' (A, symmetry); 435 cm- ' (E symmetry) ; 628 and 1281 cm- ' (F2 symmetry) .
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Figure 3. (Legeais) Scanning electron microscopic photograph of a Teflon-coated IOL shows a surface with many irregularities (original magnification x 20 [A, B) ; x 300 [C) ; x 600 [OJ).
c
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FLUOROCARBON POLYMER COATING OF IOLs
2.5 kg. One hour before surgery, the right eye of each rabbit was dilated with three doses of phenylephrine hydrochloride 10% (Neo-Synephrine®) and tropicamide 1% (Mydriaticum®) given every 15 minutes. The rabbits were anesthetized with an intramuscular injection of flunitrazepam (Narcozep®) 0.5 mg/kg and ketamine hydrochloride (Ketalar®) 100 mg/kg. Topical oxybuprocaine chlorhydrate 0.40% (Novesine®) was used for local anesthesia. A 6.5 mm scleral groove incision was made, and the anterior chamber was entered using a 3.2 mm keratome. Next, 5000 IV heparin and sodium hyaluronate (Healon®) were injected, and a continuous curvilinear capsulorhexis was performed using a technique that takes advantage of the elasticity of the rabbit capsule. 16 The crystalline lens was removed by phacoemulsification/aspiration (Conquest®, Moria) using a balanced salt solution (Aqsia®) containing heparin 5% and epinephrine 0.001% for irrigation. The anterior chamber opening was widened and Healon injected into the capsular bag. The IOL was then implanted in the posterior chamber in the capsular bag. The Healon was removed by irrigation and the scleral incision
Figure 4. (Legeais) A surface-modified PMMA IOL that was coated with Teflon AF and thus was highly hydrophobic. It had a low surface energy and high contact angle (131 degrees). 374
closed with a continuous X-suture of 10-0 nylon. Twenty rabbit eyes were implanted with a Tefloncoated IOL (Teflon group) (Figure 4) and 10, with an unmodified PMMA IOL of the same model as the Teflon-coated lenses (control group). Postoperatively, the rabbits were treated with dexamethasone and neomycin (Chibro-Cadron®) three times daily and atropine sulfate 1% (Atropine®) twice daily for 7 days. A slitlamp examination was performed weekly with a Topcon slitlamp microscope. The pupils of the rabbits were dilated, and each feature was assessed using a scale of 0 to 4. The cornea was examined for edema and vascularization; the anterior chamber for hyphema, cells, and flare; the iris for anterior and iris-capsule synechias; the IOL for position; and the posterior lens capsule for Elschnig pearls and fibrosis. The antiadhesive effect of Teflon AF was assessed by the presence of iris-IOL posterior synechias and the number of deposits on the IOL surfaces. These parameters were semiquantitatively estimated by two blind, independently trained examiners (L.P.W, B.B.) at each examination. The results from both groups on 7, 30, and 60 days postoperatively were statistically compared using an unpaired Student's t-test. A scale of 0 to 4 was used for the first parameter (1 = synechias involving one quadrant; 2 = two quadrants; 3 = three quadrants; 4 = four quadrants). The second was assessed using a scale of 0 to 10 (1 = 1 to 5 deposits on the IOL; 2 = 6 to 10; 3 = 11 to 15; 4 = 16 to 20; 5 = 21 to 25; 6 = 26 to 30; 7 = 31 to 35; 8 = 36 to 40; 9 = 41 to 45; 10 = 46 to 50). Explantation. The rabbits were killed with an intracardiac injection of ketamine hydrochloride 90 days after surgery. The IOLs were removed and prepared for SEM (fixed in glutaraldehyde 2.5% in 0.1 mollL cacodylate buffer, postfixed in osmium tetraoxide 1.0% in 0.1 mollL cacodylate buffer dehydrated in graded ethanol, critical-point-dried in liquid carbon dioxide, coated with gold, and examined under a lEOL lSM 35C scanning electron microscope). The surfaces of the explanted lenses were examined for the presence of cells, cellular debris, and signs of degradation in the Teflon AF layer. The biological stability and elemental composition of the Teflon-coated IOL surfaces were checked by EDXA spectrometry. After SEM, the scanning electron
] CATARACT REFRACT SURG-VOL 24. MARCH 1998
FLUOROCARBON POLYMER COATING OF IOLs
Figure 5. (legeais) The Teflon group, day 90, had no iris-IOl
Figure 6. (legeais) Prominent fibrous membrane adhering to the anterior surface of a regular PMMA IOl (original magnification x 40).
synechias.
microscope was coupled to the spectrometer for electronic emission. The incident electron beam used was 3.780 to 6.160 KeY.
Results The capsulorhexis technique resulted in in-the-bag IOL implantation in all cases. No iris-IOL synechias formed in the TeHon group (n = 20) (Figure 5). Two eyes in the control group (n = 10) had extensive irisIOL synechias with adherent fibrous membranes on the anterior surfaces of the IOLs (Figure 6). Table 2 shows the number of deposits on the IOL surfaces. There were no significant statistical differences between the two investigators (P > .05). Both examiners scored significantly fewer deposits in the TeRon than in the control group 30 and 60 days postoperatively and a gradual decrease in the TeHan group from 1 to 90 days (Table 2).
Two rabbits in the TeHon group presented with conjunctival hyperemia, chemosis, purulent discharge, severe corneal edema, and hypopyon 2 days after surgery (Figure 7). Therapy with local instillation of gentamicin (Ophtagram®) six times daily, in addition to the routine treatment, was promptly initiated. Conjunctival, anterior chamber, and vitreous specimens were not obtained. Clinical signs rapidly improved with therapy, and the only observed sequela was corneal vascularization in both cases (Figure 8). Teflon coating had no effect on the clinical parameters such as postoperative corneal edema, anterior or iris-capsule synechias, fibrosis , and posterior capsule opacification. Scanning electron microscopy of the surfaces of the unmodified PMMA IOLs showed prominent lens epithelium proliferation and spindle-shaped cells with many cytoplasmic processes (Figure 9A). There were also irregular, white-yellow spots on the surfaces of the Teflon and control IOLs (Figure 9B). They were
Table 2. Deposits on IOls in rabbit eyes with Teflon-coated and uncoated PMMA IOls.
ex.mlri.er2
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2.05 ± 1.69
10
1.50 ± 1.26
30
20
1.65 ± 1.04
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60
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1.94 ± 1.86
10
1.60
3.70 ± 1.16
< .0001
20
1.70 ± 0.92
10
3.50 ± 1.26
=.0001
3.00 ± 1.15
<.0001
19t
0.78 ± 1.03
10
2.90 ± 0.99
<.0001
~
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± 1.57
P-value =.62
*In two rabbits, the IOLs could not be examined because of the presence of endophthalmitis. t One rabbit died after the 1 month examination.
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FLUOROCARBON POLYMER COATING OF IOLs
Figure 7. (Legeais) Endophthalmitis in a rabbit eye with a Teflon-coated IOL (postoperative day 3) (original magnification x 16).
Figure 8. (Legeais) The rabbit eye in Figure 7 on day 30. After the endophthalmitis was treated, corneal vascularization was the only observed sequela (original magnification x 16).
positive for sodium and arsenic ions (data not shown). Cell deposits were found predominantly on the irregular areas of the Teflon-coated IOLs, even in areas with slight irregularities (e.g., along the edges, at optichaptic junctions, around positioning holes) (Figure 9B, C). The surfaces of the Teflon-coated IOLs showed no signs of degradation; however, the Teflon AF layer had the same irregularities (Figure 9). The X-ray spectra showed that there was fluorocarbon over the entire IOL surface in the Teflon group.
(180 days), and intramuscular (90 days) implantation in rabbits. Implantation in the subcutaneous and intramuscular environments resulted in faster degradation than intraocular implantation due to physical contact with vascularized tissues. Nevertheless, since Teflon AF contains stable carbon-fluorine bonds, it should be resistant to biologically mediated degradation. White-yellow spots were detected by SEM on the surfaces of both types of IOLs. They contained arsenic and sodium as evaluated by EDXA-SEM. The presence of arsenic is probably correlated with the use of cacodylate buffer, which is rich in this element, during IOL preparation for SEM. Crystallization of Healon on the IOL surfaces may explain the presence of sodium ions. Crystalline deposits on IOLs have been reported in patients having cataract surgery with the use of Healon GV 18 Although the deposits were not analyzed, the only consistent finding was the use of Healon. The technique used to modify the IOL surface must be improved to eliminate the Teflon AF layer irregularities observed by SEM. Cell deposits are found predominantly on the areas of the IOLs with irregularity, even when it was minor (e.g., along the edges, at optichaptic junctions, around positioning holes) .19 This study shows that Teflon AF has antiadhesive effects, perhaps because of its highly hydrophobic nature. No posterior iris-IOL synechias were observed in the Teflon group, while two rabbits in the control
Discussion Complete, stable coating of PMMA IOLs was obtained with the Teflon AF fluorocarbon polymer. Intraocular lenses cannot be 100% Teflon AF because of its low refractive index (1.32). However, if Teflon AF is dissolved in low-boiling-point liquid fluorocarbon, it can be used to coat PMMA IOLs. For 3 months, there was no sign on SEM of degradation of the Teflon-coated IOL surface. The EDXA spectrometry showed fluorocarbon over the entire Teflon-coated surface of all lenses. However, studies with longer follow-up are needed to assess the long-term stability of Teflon AF coating. Christ et al. l ? assessed the biostability of a polyetherurethane used as a foldable IOL for intraocular (1 year), subcutaneous 376
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FLUOROCARBON POLYMER COATING OF IOLs
A
B
Figure 9. (Legeais) Scanning electron microscope photographs of IOLs after explantation. A: Prominent lens epithelium proliferation on the control IOL posterior surface (original magnification x 400). B: Teflon AF layer irregularities and white-yellow spots (original magnification x 60). C: Spindle-shaped cells with cytoplasmic processes adhering to the Teflon-IOL edge (original magnification x 400).
c group had extensive synechias with adherent fibrous membranes on the anterior surfaces of the IOLs. There were significantly fewer deposits on the IOL surfaces in the Teflon group on days 30 and 60. Menapace and coauthors 19 studied precipitate formation on silicone and PMMA IOLs and found no correlation between its prevalence and the IOL material. They found many precipitates in eyes with lenses captured in the pupil or with severe postoperative inflammatory reactions, regardless of the IOL type. Our groups of rabbits were statistically comparable with regard to the number of eyes with postoperatively captured lenses. There were slightly more cellular deposits on the surfaces of Teflon-coated IOLs 7 days postoperatively, but the difference was not significant. A gradual decrease in this number was observed in the
Teflon group. Although two Teflon group rabbits were not formally diagnosed with infectious endophthalmitis, nonsterilization after IOL coating and a prompt response to the antibiotic therapy led us to consider this diagnosis rather than toxic or sterile inflammatory reactions. The IOLs seemed well tolerated in these cases, with no synechia formation or IOL encapsulation. We therefore conclude that the lower precipitate formation on the Teflon-coated IOLs in our study is correlated with the anti adhesive effects of Teflon AF. Studies on PMMA IOLs rendered more hydrophobic by other surface modification techniques also demonstrate their antiadhesive effects. Eloy et al. 14 fluorinated PMMA IOL surfaces with CF 4 plasma. Granulocyte activation, assessed by the superoxide anion generated when the lenses were in contact with granu-
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FLUOROCARBON POLYMER COATING OF IOLs
locytes for 2 hours, was lower with fluorinated 10Ls. The percentage of 10L surfaces covered by these cells was also lower with fluorinated than with regular PMMA 10Ls. In vivo studies on CF 4 plasma treatment are not available. Controversial results have been obtained with a surface modification technique, selective molecular alteration and realignment technology (SMART).20 The goal of this process is to reduce PM~s surface energy and irregularities byeliminating molecular defect sites without bonding or coating new materials to these surfaces. However, Koch and coauthors 20 found no difference in the contact angles or surface energies of SMART-treated and regular PMMA 10Ls. In another study,21 SMART-treated 10Ls were implanted in 30 patients and compared with regular PMMA 10Ls. The degree of postoperative inflammation in the two groups, assessed by the aqueous flare intensity measured by a flare-cell meter, was not significantly different. Nevertheless, acute corneal touch studies in cats by Balyeat and coauthors22 found that SMARTtreated 10Ls caused little endothelial damage, with only single cells or small debris adhering to the 10Ls. The acute inflammatory response after cataract extraction is significantly lower with heparin-surfacemodified (HSM) 10Ls than with unmodified PMMA IOLs.12,23 There are also fewer cell deposits and fewer posterior synechias after implantation. 24 Studies in humans confirm the results of experimental studies on the increased biocompatibility of HSM IOLs. 25 The antiadhesive effects correlate with the covalent endpoint attachment of heparin to PMMA 10L surfaces. The hydrophilic chains of heparin bound to the surface of the 10L extend into the aqueous media, trapping water molecules and forming a hydrated layer around the lens, and thus preventing cell attachment. The HSM 10L also has a mobile surface that has a normal effect on the immunological system, preventing foreign-body reactions against the 10L.20 There is considerably less activation of granulocytes and outgrowth of macrophages and fibroblasts on HSM than on regular PMMA IOLs.23 This first experimental in vivo evaluation demonstrates that the physical and optical properties of Teflon AF make it suitable for coating PMMA 10Ls. The coating was stable after 3 months of intraocular implantation. The highly hydrophobic nature of the Teflon AF surface combined with an anti adhesive effect 378
to increase the biocompatibility ofPMMA 10Ls. Quan-
titative comparisons with other surface-coated PMMA 10Ls must be performed to confirm these results on cell adhesion to Teflon-coated 10Ls. Coating with Teflon AF does not influence the degree of epithelial cell proliferation on posterior capsules, but factors other than the 10L surface properties do.
References 1. Tamada Y, Ikada Y. Fibroblast growth on polymer surfaces and biosynthesis of collagen. J Biomed Mater Res 1994; 28:783-789 2. Apple OJ, Mamalis N, Loftfield K, et aI. Complications of intraocular lenses. A historical and histopathological review. Surv Ophthalmol 1984; 29:1-54 3, Wolter JR. Cytopathology of intraocular lens implantation. Ophthalmology 1985; 92:135-142 4. Kaufman HE, Katz J, Valenti J, et al. Corneal endothelium damage with intraocular lenses: contact adhesion between surgical materials and tissue. Science 1977; 198:525-527 5. Liesegang TJ, Bourne WM, Ilstrup OM. Short- and long-term endothelial cell loss associated with cataract extraction and intraocular lens implantation. Am J Ophthalmol 1984; 97:32-39 6. Brokke P, Dankert J, Hogt AH, Feijen J. No relationship between the cell surface hydrophobicity of coagulasenegative staphylococci and their ability to adhere onto fluorinated poly(ethylene-propylene). J Mat Sci Mat Med 1991; 3:101-105 7. Brinen JS, Greenhouse S, Pinatti 1. ESCA and SIMS studies of plasma treatments of intraocular lenses. Surf Interface Anal 1991; 17:63-70 8. Gupta A, Van Osdel RL. Surface passivated intraocular lens. U.S. Patent No. 4,655,770.1987, 1987 9. Mateo NB, Ratner BD. Relating the surface properties of intraocular lens materials to endothelial cell adhesion damage. Invest Ophthalmol Vis Sci 1989; 5:853-860 10. Ertel SI, Chilkota A, Horbert TA, Ratner BD. Endothelial cell growth on oxygen-containing films deposited by radio-frequency plasmas: the role of surface carbonyl groups. J Biometer Sci Polymer Edn 1991; 3:163-183 11. Cunanan CM, Tarbaux NM, Knight PM. Surface properties of intraocular lens materials and their influence on in vitro cell adhesion. J Cataract Refract Surg 1991; 17:767-773 12. Lundgren B, Ocklind A, Holst A, Harfstrand A. Inflammatory response in the rabbit eye after intraocular implantation with poly(methyl methacrylate) and heparin surface modified intraocular lenses. J Cataract Refract Surg 1992; 18:65-70 13. Philipson B, Fagerholm P, Calel B, Grunge A. Heparin
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14.
15. 16.
17.
18.
19.
20.
surface modified intraocular lenses: three-month followup of a randomized, double-masked clinical trial. J Cataract Refract Surg 1992; 18:71-78 Eloy R, Parrat 0, Duc TM, et al. In vitro evaluation of inflammatory cell response after CF 4 plasma surface modification of poly(methyl methacrylate) intraocular lenses. J Cataract Refract Surg 1993; 19:364-370 Korinek P. Nouvelle generation de polymeres fluores. Materiaux et Techniques 1991; 2: 1-3 Auffarth GU, Wesendahl TA, Newland TJ, Apple OJ. Capsulorhexis in the rabbit eye as a model for pediatric capsulectomy. J Cataract Refract Surg 1994; 20:188191 Christ FR, Buchen SY, Fencil DA, et al. A comparative evaluation of the biostability of a poly (ether urethane) in the intraocular, intramuscular, and subcutaneous environments. J Biomed Mater Res 1992; 26:607-629 Jensen MK, Crandall AS, Mamalis N, Olson RJ. Crystallization on the intraocular lens surfaces associated with the use of Healon Gy. Arch Ophthalmol 1994; 112:1037-1042 Menapace R, Juchem M, Skorpik C, Kulnig W Clinicopathologic findings after in-the-bag implantation of open-loop polymethylmethacrylate and silicone lenses in the rabbit eye. J Cataract Refract Surg 1987; 13:630634 Koch DO, Samuelson Sw, Dimonie Y. Surface analysis
21.
22.
23.
24.
25.
of surface-passivated intraocular lenses. J Cataract Refract Surg 1991; 17:131-138 Umezawa S, Shimizu K. Biocompatibility of surfacemodified intraocular lenses. J Cataract Refract Surg 1993; 19:371-374 Balyeat HD, Nordquist RE, Lerner MP, Gupta A. Comparison of endothelial damage produced by control and surface modified poly(methyl methacrylate) intraocular lenses. J Cataract Refract Surg 1989; 15:491-494 Versura P, Caramazza R. Ultrastructure of cells cultured onto various intraocular lens materials. J Cataract Refract Surg 1992; 18:58-64 Spangberg M, Kihlstrom I, Bjorklund H, et al. Improved biocompatibility of intraocular lenses by heparin surface modification: a 12-month implantation study in monkeys. J Cataract Refract Surg 1990; 16: 170-177 Larsson R, Selen G, Formgren B, Holst A. Long-term stability of heparin-surface-modified intraocular lenses in vivo. J Cataract Refract Surg 1992; 18:247-251
From Hotel-Dieu Hospital, Paris Cerlex, and the Centre de Transfert de Technologie du Mans, Institut de Recherche Applique des Polymeres, Le Mans, France. Supported in part by the Direction de fa Recherche Clinique AP-HP, INSERM (French Medical Research Institute) and Fondation de l'Avenir.
J CATARACT REFRACT SURG-VOL 24, MARCH 1998
379
C
ell adhesion to artificial surfaces may be a major obstacle to biocompatibility of artificial devices such as intraocular lenses (IOLs). Tamada and Ikada1 reported that cell adhesion and proliferation depend on the water contact angle of the substrate. In their study, clear differences in cell growth and cell morphology Reprint requests to Jean-Marc Legeais, MD, H6tel-Dieu Hopital, 1, Place du Parvis Notre-Dame, F-75181 Paris Cedex 04, France.
were observed among the substrates used. Other in vitro studies on cell adhesion have also shown a correlation with the surface properties of the substrates. 2- 13 The surface of poly(methyl methacrylate) (PMMA) 10Ls can be modified to make the lens highly hydrophilic7- 13 or highly hydrophobic. 14 These modifications reduce adhesion to the 10Ls and thus increase their biocompatibility. Several coating techniques have been developed including heparin surface modification and
J CATARACT REFRACT SURG--VOL 24, MARCH
1998
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FLUOROCARBON POLYMER COATING OF IOLs
plasma treatment. Poly(methyl methacrylate) IOLs coated with heparinl2 are thus more hydrophilic and are reported to reduce the inflammatory response. Plasma treatment allows grafting of functional groups onto the PMMA IOL surface, making it more hydrophilic or more hydrophobic. An in vitro study showed less granulocyte activation and adhesion to the surface of PMMA IOLs that are more hydrophobic after tetrafluorocarbon (CF4) plasma treatment. 14 This study was performed to assess the biostability, biocompatibility, and antiadhesive properties of Tefloncoated PMMA IOLs implanted in rabbit eyes.
Materials and Methods Teflon AF (Dupont de Nemours) is a poly(tetrafluoroethylene co-hexafluoro-propyl-2 cyclodiethoxy difluoroethylene). Constituted entirely of high-energy bonds, it is stable at temperatures up to 260°C and chemically very resistant. The refractive index is 1.32. It transmits light from 200 to 2000 nm with a constant light absorption below 5%. The contact angle with water is 129 degrees. It can be dissolved in several liquid fluorocarbons and thus can be used in organic solution. Figure 1 shows the chemical formulas of expanded poly(tetrafluoroethylene) (PTFE) (first generation) and
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I F
Teflon AF (third generation)Y Table 1 shows the surface energies of PMMA, PTFE, and Teflon AF. Teflon AF was chemically characterized by Raman spectrometry. Measurements were performed with a Dilor Z24 spectrometer coupled to a Zeiss optical microscope. The excitation wavelength was 488 nm. The laser beam power at the sample (Teflon AF disc) was 250 mWand the linear slit width was 1.000 /lIll. The Teflon AF Raman spectra were compared with those of opaque sheets of PTFE. The spectra obtained for Teflon AF and PTFE were significantly different, particularly in the region of 207 to 333, 714 to 828, and 1287 to 1632 cm- I (Figure 2), with complex groups of peaks in the Teflon AF spectrum and a single peak in the PTFE spectrum. 15
Surface Modification The PMMA IOLs (model 808A, Kabi Pharmacia Production B.Y.) had an overall diameter of 12.0 mm and optic diameter of 6.5 mm. The surfaces were coated by immersing the lenses in a 5% solution of Teflon AF in a fluorocarbon solvent (CsF ,s) for 3 seconds. The IOLs were then placed at a temperature of 37°C to evaporate the solvent. The surface quality of the Teflon-coated IOLs was evaluated by scanning electron microscopy (SEM). The IOLs were coated with gold, and 5EM was performed using a lEOL 15M 35C scanning microscope. The surfaces of PMMA IOLs were completely coated with Teflon AF. Scanning electron microscopy of Teflon-coated IOLs showed smooth edges overall, but there were several fold-like irregularities in the Teflon AF layer (Figure 3A, B, C). In Vivo Experiment Implantation. Lenses were implanted in 30 adult albino rabbits (New Zealand white) weighing 2.0 to Table 1. Surface energy of polymers.
A
F
F
I
I
Figure 1. (Legeais) Teflon AF
I
(A) and Teflon PTFE (8) chemical formulas.
C-C
I
F
F
B 372
Surface Ener~
1l,
Total (mJlm-2)
Polar (mJlm-2)
..' NonpcllJr '.
PMMA
44.9
20.8
24.1
PTFE
19.1
0.3
18.8
Teflon AF
16.2
0.3
15.9
IOL TYpe
PMMA
. (inJ/m"'"
= poly(methyl methacrylate); PTFE = poly(tetrafluoroethylene)
J CATARACf REFRACf SURG-VOL 24, MARCH 1998
FLUOROCARBON POLYMER COATING OF IOLs SPECfRE 3
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700
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cially in the regions of 207 to 333, 714 to 828, and 1287 to 1362 cm - ' . The PTFE CF4 values were 908 cm - ' (A, symmetry); 435 cm- ' (E symmetry) ; 628 and 1281 cm- ' (F2 symmetry) .
~
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Figure 3. (Legeais) Scanning electron microscopic photograph of a Teflon-coated IOL shows a surface with many irregularities (original magnification x 20 [A, B) ; x 300 [C) ; x 600 [OJ).
c
D
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FLUOROCARBON POLYMER COATING OF IOLs
2.5 kg. One hour before surgery, the right eye of each rabbit was dilated with three doses of phenylephrine hydrochloride 10% (Neo-Synephrine®) and tropicamide 1% (Mydriaticum®) given every 15 minutes. The rabbits were anesthetized with an intramuscular injection of flunitrazepam (Narcozep®) 0.5 mg/kg and ketamine hydrochloride (Ketalar®) 100 mg/kg. Topical oxybuprocaine chlorhydrate 0.40% (Novesine®) was used for local anesthesia. A 6.5 mm scleral groove incision was made, and the anterior chamber was entered using a 3.2 mm keratome. Next, 5000 IV heparin and sodium hyaluronate (Healon®) were injected, and a continuous curvilinear capsulorhexis was performed using a technique that takes advantage of the elasticity of the rabbit capsule. 16 The crystalline lens was removed by phacoemulsification/aspiration (Conquest®, Moria) using a balanced salt solution (Aqsia®) containing heparin 5% and epinephrine 0.001% for irrigation. The anterior chamber opening was widened and Healon injected into the capsular bag. The IOL was then implanted in the posterior chamber in the capsular bag. The Healon was removed by irrigation and the scleral incision
Figure 4. (Legeais) A surface-modified PMMA IOL that was coated with Teflon AF and thus was highly hydrophobic. It had a low surface energy and high contact angle (131 degrees). 374
closed with a continuous X-suture of 10-0 nylon. Twenty rabbit eyes were implanted with a Tefloncoated IOL (Teflon group) (Figure 4) and 10, with an unmodified PMMA IOL of the same model as the Teflon-coated lenses (control group). Postoperatively, the rabbits were treated with dexamethasone and neomycin (Chibro-Cadron®) three times daily and atropine sulfate 1% (Atropine®) twice daily for 7 days. A slitlamp examination was performed weekly with a Topcon slitlamp microscope. The pupils of the rabbits were dilated, and each feature was assessed using a scale of 0 to 4. The cornea was examined for edema and vascularization; the anterior chamber for hyphema, cells, and flare; the iris for anterior and iris-capsule synechias; the IOL for position; and the posterior lens capsule for Elschnig pearls and fibrosis. The antiadhesive effect of Teflon AF was assessed by the presence of iris-IOL posterior synechias and the number of deposits on the IOL surfaces. These parameters were semiquantitatively estimated by two blind, independently trained examiners (L.P.W, B.B.) at each examination. The results from both groups on 7, 30, and 60 days postoperatively were statistically compared using an unpaired Student's t-test. A scale of 0 to 4 was used for the first parameter (1 = synechias involving one quadrant; 2 = two quadrants; 3 = three quadrants; 4 = four quadrants). The second was assessed using a scale of 0 to 10 (1 = 1 to 5 deposits on the IOL; 2 = 6 to 10; 3 = 11 to 15; 4 = 16 to 20; 5 = 21 to 25; 6 = 26 to 30; 7 = 31 to 35; 8 = 36 to 40; 9 = 41 to 45; 10 = 46 to 50). Explantation. The rabbits were killed with an intracardiac injection of ketamine hydrochloride 90 days after surgery. The IOLs were removed and prepared for SEM (fixed in glutaraldehyde 2.5% in 0.1 mollL cacodylate buffer, postfixed in osmium tetraoxide 1.0% in 0.1 mollL cacodylate buffer dehydrated in graded ethanol, critical-point-dried in liquid carbon dioxide, coated with gold, and examined under a lEOL lSM 35C scanning electron microscope). The surfaces of the explanted lenses were examined for the presence of cells, cellular debris, and signs of degradation in the Teflon AF layer. The biological stability and elemental composition of the Teflon-coated IOL surfaces were checked by EDXA spectrometry. After SEM, the scanning electron
] CATARACT REFRACT SURG-VOL 24. MARCH 1998
FLUOROCARBON POLYMER COATING OF IOLs
Figure 5. (legeais) The Teflon group, day 90, had no iris-IOl
Figure 6. (legeais) Prominent fibrous membrane adhering to the anterior surface of a regular PMMA IOl (original magnification x 40).
synechias.
microscope was coupled to the spectrometer for electronic emission. The incident electron beam used was 3.780 to 6.160 KeY.
Results The capsulorhexis technique resulted in in-the-bag IOL implantation in all cases. No iris-IOL synechias formed in the TeHon group (n = 20) (Figure 5). Two eyes in the control group (n = 10) had extensive irisIOL synechias with adherent fibrous membranes on the anterior surfaces of the IOLs (Figure 6). Table 2 shows the number of deposits on the IOL surfaces. There were no significant statistical differences between the two investigators (P > .05). Both examiners scored significantly fewer deposits in the TeRon than in the control group 30 and 60 days postoperatively and a gradual decrease in the TeHan group from 1 to 90 days (Table 2).
Two rabbits in the TeHon group presented with conjunctival hyperemia, chemosis, purulent discharge, severe corneal edema, and hypopyon 2 days after surgery (Figure 7). Therapy with local instillation of gentamicin (Ophtagram®) six times daily, in addition to the routine treatment, was promptly initiated. Conjunctival, anterior chamber, and vitreous specimens were not obtained. Clinical signs rapidly improved with therapy, and the only observed sequela was corneal vascularization in both cases (Figure 8). Teflon coating had no effect on the clinical parameters such as postoperative corneal edema, anterior or iris-capsule synechias, fibrosis , and posterior capsule opacification. Scanning electron microscopy of the surfaces of the unmodified PMMA IOLs showed prominent lens epithelium proliferation and spindle-shaped cells with many cytoplasmic processes (Figure 9A). There were also irregular, white-yellow spots on the surfaces of the Teflon and control IOLs (Figure 9B). They were
Table 2. Deposits on IOls in rabbit eyes with Teflon-coated and uncoated PMMA IOls.
ex.mlri.er2
Exilmlner1 .. Postop ··· Day
Tefton:Gro~ ..
'Cori~~'~f9UP :"
··· Mean :tSD-
·n
....ean ±$Q·
18*
2.05 ± 1.69
10
1.50 ± 1.26
30
20
1.65 ± 1.04
10
60
19t
10
n
0.84 ± 1.16
Teflon Gr()UP
P;Yalue
. ¢Oritror Group
n
Mean -::!: S[)
i1
Meal)
=. 37
18*
1.94 ± 1.86
10
1.60
3.70 ± 1.16
< .0001
20
1.70 ± 0.92
10
3.50 ± 1.26
=.0001
3.00 ± 1.15
<.0001
19t
0.78 ± 1.03
10
2.90 ± 0.99
<.0001
~
S[)
± 1.57
P-value =.62
*In two rabbits, the IOLs could not be examined because of the presence of endophthalmitis. t One rabbit died after the 1 month examination.
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FLUOROCARBON POLYMER COATING OF IOLs
Figure 7. (Legeais) Endophthalmitis in a rabbit eye with a Teflon-coated IOL (postoperative day 3) (original magnification x 16).
Figure 8. (Legeais) The rabbit eye in Figure 7 on day 30. After the endophthalmitis was treated, corneal vascularization was the only observed sequela (original magnification x 16).
positive for sodium and arsenic ions (data not shown). Cell deposits were found predominantly on the irregular areas of the Teflon-coated IOLs, even in areas with slight irregularities (e.g., along the edges, at optichaptic junctions, around positioning holes) (Figure 9B, C). The surfaces of the Teflon-coated IOLs showed no signs of degradation; however, the Teflon AF layer had the same irregularities (Figure 9). The X-ray spectra showed that there was fluorocarbon over the entire IOL surface in the Teflon group.
(180 days), and intramuscular (90 days) implantation in rabbits. Implantation in the subcutaneous and intramuscular environments resulted in faster degradation than intraocular implantation due to physical contact with vascularized tissues. Nevertheless, since Teflon AF contains stable carbon-fluorine bonds, it should be resistant to biologically mediated degradation. White-yellow spots were detected by SEM on the surfaces of both types of IOLs. They contained arsenic and sodium as evaluated by EDXA-SEM. The presence of arsenic is probably correlated with the use of cacodylate buffer, which is rich in this element, during IOL preparation for SEM. Crystallization of Healon on the IOL surfaces may explain the presence of sodium ions. Crystalline deposits on IOLs have been reported in patients having cataract surgery with the use of Healon GV 18 Although the deposits were not analyzed, the only consistent finding was the use of Healon. The technique used to modify the IOL surface must be improved to eliminate the Teflon AF layer irregularities observed by SEM. Cell deposits are found predominantly on the areas of the IOLs with irregularity, even when it was minor (e.g., along the edges, at optichaptic junctions, around positioning holes) .19 This study shows that Teflon AF has antiadhesive effects, perhaps because of its highly hydrophobic nature. No posterior iris-IOL synechias were observed in the Teflon group, while two rabbits in the control
Discussion Complete, stable coating of PMMA IOLs was obtained with the Teflon AF fluorocarbon polymer. Intraocular lenses cannot be 100% Teflon AF because of its low refractive index (1.32). However, if Teflon AF is dissolved in low-boiling-point liquid fluorocarbon, it can be used to coat PMMA IOLs. For 3 months, there was no sign on SEM of degradation of the Teflon-coated IOL surface. The EDXA spectrometry showed fluorocarbon over the entire Teflon-coated surface of all lenses. However, studies with longer follow-up are needed to assess the long-term stability of Teflon AF coating. Christ et al. l ? assessed the biostability of a polyetherurethane used as a foldable IOL for intraocular (1 year), subcutaneous 376
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1998
FLUOROCARBON POLYMER COATING OF IOLs
A
B
Figure 9. (Legeais) Scanning electron microscope photographs of IOLs after explantation. A: Prominent lens epithelium proliferation on the control IOL posterior surface (original magnification x 400). B: Teflon AF layer irregularities and white-yellow spots (original magnification x 60). C: Spindle-shaped cells with cytoplasmic processes adhering to the Teflon-IOL edge (original magnification x 400).
c group had extensive synechias with adherent fibrous membranes on the anterior surfaces of the IOLs. There were significantly fewer deposits on the IOL surfaces in the Teflon group on days 30 and 60. Menapace and coauthors 19 studied precipitate formation on silicone and PMMA IOLs and found no correlation between its prevalence and the IOL material. They found many precipitates in eyes with lenses captured in the pupil or with severe postoperative inflammatory reactions, regardless of the IOL type. Our groups of rabbits were statistically comparable with regard to the number of eyes with postoperatively captured lenses. There were slightly more cellular deposits on the surfaces of Teflon-coated IOLs 7 days postoperatively, but the difference was not significant. A gradual decrease in this number was observed in the
Teflon group. Although two Teflon group rabbits were not formally diagnosed with infectious endophthalmitis, nonsterilization after IOL coating and a prompt response to the antibiotic therapy led us to consider this diagnosis rather than toxic or sterile inflammatory reactions. The IOLs seemed well tolerated in these cases, with no synechia formation or IOL encapsulation. We therefore conclude that the lower precipitate formation on the Teflon-coated IOLs in our study is correlated with the anti adhesive effects of Teflon AF. Studies on PMMA IOLs rendered more hydrophobic by other surface modification techniques also demonstrate their antiadhesive effects. Eloy et al. 14 fluorinated PMMA IOL surfaces with CF 4 plasma. Granulocyte activation, assessed by the superoxide anion generated when the lenses were in contact with granu-
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FLUOROCARBON POLYMER COATING OF IOLs
locytes for 2 hours, was lower with fluorinated 10Ls. The percentage of 10L surfaces covered by these cells was also lower with fluorinated than with regular PMMA 10Ls. In vivo studies on CF 4 plasma treatment are not available. Controversial results have been obtained with a surface modification technique, selective molecular alteration and realignment technology (SMART).20 The goal of this process is to reduce PM~s surface energy and irregularities byeliminating molecular defect sites without bonding or coating new materials to these surfaces. However, Koch and coauthors 20 found no difference in the contact angles or surface energies of SMART-treated and regular PMMA 10Ls. In another study,21 SMART-treated 10Ls were implanted in 30 patients and compared with regular PMMA 10Ls. The degree of postoperative inflammation in the two groups, assessed by the aqueous flare intensity measured by a flare-cell meter, was not significantly different. Nevertheless, acute corneal touch studies in cats by Balyeat and coauthors22 found that SMARTtreated 10Ls caused little endothelial damage, with only single cells or small debris adhering to the 10Ls. The acute inflammatory response after cataract extraction is significantly lower with heparin-surfacemodified (HSM) 10Ls than with unmodified PMMA IOLs.12,23 There are also fewer cell deposits and fewer posterior synechias after implantation. 24 Studies in humans confirm the results of experimental studies on the increased biocompatibility of HSM IOLs. 25 The antiadhesive effects correlate with the covalent endpoint attachment of heparin to PMMA 10L surfaces. The hydrophilic chains of heparin bound to the surface of the 10L extend into the aqueous media, trapping water molecules and forming a hydrated layer around the lens, and thus preventing cell attachment. The HSM 10L also has a mobile surface that has a normal effect on the immunological system, preventing foreign-body reactions against the 10L.20 There is considerably less activation of granulocytes and outgrowth of macrophages and fibroblasts on HSM than on regular PMMA IOLs.23 This first experimental in vivo evaluation demonstrates that the physical and optical properties of Teflon AF make it suitable for coating PMMA 10Ls. The coating was stable after 3 months of intraocular implantation. The highly hydrophobic nature of the Teflon AF surface combined with an anti adhesive effect 378
to increase the biocompatibility ofPMMA 10Ls. Quan-
titative comparisons with other surface-coated PMMA 10Ls must be performed to confirm these results on cell adhesion to Teflon-coated 10Ls. Coating with Teflon AF does not influence the degree of epithelial cell proliferation on posterior capsules, but factors other than the 10L surface properties do.
References 1. Tamada Y, Ikada Y. Fibroblast growth on polymer surfaces and biosynthesis of collagen. J Biomed Mater Res 1994; 28:783-789 2. Apple OJ, Mamalis N, Loftfield K, et aI. Complications of intraocular lenses. A historical and histopathological review. Surv Ophthalmol 1984; 29:1-54 3, Wolter JR. Cytopathology of intraocular lens implantation. Ophthalmology 1985; 92:135-142 4. Kaufman HE, Katz J, Valenti J, et al. Corneal endothelium damage with intraocular lenses: contact adhesion between surgical materials and tissue. Science 1977; 198:525-527 5. Liesegang TJ, Bourne WM, Ilstrup OM. Short- and long-term endothelial cell loss associated with cataract extraction and intraocular lens implantation. Am J Ophthalmol 1984; 97:32-39 6. Brokke P, Dankert J, Hogt AH, Feijen J. No relationship between the cell surface hydrophobicity of coagulasenegative staphylococci and their ability to adhere onto fluorinated poly(ethylene-propylene). J Mat Sci Mat Med 1991; 3:101-105 7. Brinen JS, Greenhouse S, Pinatti 1. ESCA and SIMS studies of plasma treatments of intraocular lenses. Surf Interface Anal 1991; 17:63-70 8. Gupta A, Van Osdel RL. Surface passivated intraocular lens. U.S. Patent No. 4,655,770.1987, 1987 9. Mateo NB, Ratner BD. Relating the surface properties of intraocular lens materials to endothelial cell adhesion damage. Invest Ophthalmol Vis Sci 1989; 5:853-860 10. Ertel SI, Chilkota A, Horbert TA, Ratner BD. Endothelial cell growth on oxygen-containing films deposited by radio-frequency plasmas: the role of surface carbonyl groups. J Biometer Sci Polymer Edn 1991; 3:163-183 11. Cunanan CM, Tarbaux NM, Knight PM. Surface properties of intraocular lens materials and their influence on in vitro cell adhesion. J Cataract Refract Surg 1991; 17:767-773 12. Lundgren B, Ocklind A, Holst A, Harfstrand A. Inflammatory response in the rabbit eye after intraocular implantation with poly(methyl methacrylate) and heparin surface modified intraocular lenses. J Cataract Refract Surg 1992; 18:65-70 13. Philipson B, Fagerholm P, Calel B, Grunge A. Heparin
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14.
15. 16.
17.
18.
19.
20.
surface modified intraocular lenses: three-month followup of a randomized, double-masked clinical trial. J Cataract Refract Surg 1992; 18:71-78 Eloy R, Parrat 0, Duc TM, et al. In vitro evaluation of inflammatory cell response after CF 4 plasma surface modification of poly(methyl methacrylate) intraocular lenses. J Cataract Refract Surg 1993; 19:364-370 Korinek P. Nouvelle generation de polymeres fluores. Materiaux et Techniques 1991; 2: 1-3 Auffarth GU, Wesendahl TA, Newland TJ, Apple OJ. Capsulorhexis in the rabbit eye as a model for pediatric capsulectomy. J Cataract Refract Surg 1994; 20:188191 Christ FR, Buchen SY, Fencil DA, et al. A comparative evaluation of the biostability of a poly (ether urethane) in the intraocular, intramuscular, and subcutaneous environments. J Biomed Mater Res 1992; 26:607-629 Jensen MK, Crandall AS, Mamalis N, Olson RJ. Crystallization on the intraocular lens surfaces associated with the use of Healon Gy. Arch Ophthalmol 1994; 112:1037-1042 Menapace R, Juchem M, Skorpik C, Kulnig W Clinicopathologic findings after in-the-bag implantation of open-loop polymethylmethacrylate and silicone lenses in the rabbit eye. J Cataract Refract Surg 1987; 13:630634 Koch DO, Samuelson Sw, Dimonie Y. Surface analysis
21.
22.
23.
24.
25.
of surface-passivated intraocular lenses. J Cataract Refract Surg 1991; 17:131-138 Umezawa S, Shimizu K. Biocompatibility of surfacemodified intraocular lenses. J Cataract Refract Surg 1993; 19:371-374 Balyeat HD, Nordquist RE, Lerner MP, Gupta A. Comparison of endothelial damage produced by control and surface modified poly(methyl methacrylate) intraocular lenses. J Cataract Refract Surg 1989; 15:491-494 Versura P, Caramazza R. Ultrastructure of cells cultured onto various intraocular lens materials. J Cataract Refract Surg 1992; 18:58-64 Spangberg M, Kihlstrom I, Bjorklund H, et al. Improved biocompatibility of intraocular lenses by heparin surface modification: a 12-month implantation study in monkeys. J Cataract Refract Surg 1990; 16: 170-177 Larsson R, Selen G, Formgren B, Holst A. Long-term stability of heparin-surface-modified intraocular lenses in vivo. J Cataract Refract Surg 1992; 18:247-251
From Hotel-Dieu Hospital, Paris Cerlex, and the Centre de Transfert de Technologie du Mans, Institut de Recherche Applique des Polymeres, Le Mans, France. Supported in part by the Direction de fa Recherche Clinique AP-HP, INSERM (French Medical Research Institute) and Fondation de l'Avenir.
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