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Biocompatibility and Light Transmission of Liposomal Lenses


doi: 10.1097/OPX.0b013e318157a6d5
Original Article

Purpose. To validate the biocompatibility and transmittance properties of contact lenses bearing intact liposomes. These liposomal lenses loaded with therapeutics can be used as ophthalmic drug delivery systems.

Methods. The biocompatibility of soft contact lenses, coated with liposomes was evaluated through in vitro direct and indirect cytocompatibility assays on human corneal epithelial cells, on reconstructed human corneas and on ex vivo rabbit corneas. The direct and indirect transmission spectra of liposome-covered lenses were also evaluated to test if they transmit all wavelengths of the ultraviolet-visible spectrum, to thereby fulfill their optical function, without gross alteration of the colors perception and with a minimum of light dispersion.

Results. Contact lenses bearing layers of stable liposomes did not induce any significant changes in cell viability and in cell growth, compared with lenses bearing no liposome. Elution assays revealed that no cytotoxic compound leaks from the lenses whether bearing liposomes or not. Histological analyses of reconstructed human corneas and ex vivo rabbit corneas directly exposed to liposomal lenses revealed neither alteration to the cell nor to the tissue structures. Contact lenses bearing layers of liposomes did not significantly affect light transmission compared with control lenses without liposome at the wavelength of maximal photopic sensitivity, i.e., 550 nm. In addition, the contact lenses afford more eye protection in the ultraviolet spectrum, compared with the control lenses.

Conclusions. Liposomal contact lenses are biocompatible and their transmittance properties are not affected in the visible light range.

Laboratoire de Bioingénierie et de Biophysique de l’Université de Sherbrooke, Department of Chemical Engineering, Université de Sherbrooke, Sherbrooke, Québec, Canada (AD, PV), Research Centre on Aging, Institut universitaire de gériatrie de Sherbrooke, Sherbrooke, Québec, Canada (AD, PV), Oncology and Molecular Endocrinology Research Center, CHUL’s Research Center, CHUQ, Québec, Québec, Canada (CJD, RP), École d’optométrie, Université de Montréal, Montréal, Québec, Canada (CJG, SD, PS), Laboratoire d’Organogenèse Expérimentale (LOEX), and CHA Pavilllon Saint-Sacrement and Département d’ORL-ophtalmologie, Faculté de Médecine, Université Laval, Québec, Québec, Canada (CJG, SD, PS)

This work was supported by the NSERC through an Idea-to-Innovation grant (PV and CJD), by the Canada Foundation for Innovation (CJG and PV), and by the Canadian Optometric Trust Fund (CJG). The contact lenses were kindly supplied by Robert Mercure from Les Laboratories Opti-Centre (Sherbrooke, Québec, Canada).

Some of these results were originally presented as a poster at the annual meeting of the American Academy of Optometry; December 8, 2006; Denver, CO.

Received December 2, 2006; accepted May 7, 2007.

Although some ocular infections may occur in everyday life, the most serious usually result from accidental or surgical trauma.1 As eye surgery is regularly performed in modern ophthalmology, the risk of perioperative infections has become a major concern. To address this concern, not only new drugs with increased potency are developed, but also new modes of their administration. This is because the fraction of a topical drug, instilled into the tear film available for a biological action, is not only limited by absorption, but also by the physical properties of the blinking system, i.e., the lid margin loss, tear dilution, and punctal drainage, which occurs during each blink.2

Topical instillations greatly limit the penetration of drugs because of poor permeability of the cornea and the efficient protective mechanisms present, such as solution drainage, lacrimation, and the diversion of exogenous substances into the systemic circulation, via conjunctival absorption.3 Systemic treatment needs the administration of large amounts of drug, increasing the risk of side effects.4,5 In addition, dose concentration and regimen through eye drops are inconsistent and difficult to regulate, because most of the drug is released in an initial concentration “burst.”6 Thus, the development of drug delivery systems is essential to achieve long-term release, and to have available a system that delivers drugs locally, lowering the overall dose needed to achieve a desired therapeutic concentration.

Several types of ophthalmic drug delivery systems have been proposed to provide a sustained release over time.7–12 However, most systems offer only moderate to marginal improvement of the ocular drug bioavailability and can cause blurred vision. Soft contact lenses have become a valuable tool in the management of many ophthalmic disorders.9,13,14 Contact lenses are used to act as protective barriers between the eyelids and the ocular surface, allowing for proper healing of the corneal surface and limiting the contact between eyelids and the corneal surface, thereby reducing pain. Finally, the tear film is stabilized over the irregular corneal surface and the vision is improved.15 These so-called bandage contact lenses, extensively used to treat epithelial defects after corneal laceration, could well be combined with a prophylactic topical antibiotic after a trauma.

Contact lenses can be “loaded” with medications by presoaking them in a medication solution for therapeutic applications. For example, hydrogel lenses have been soaked in an antibiotic solution with the aim to increase the release of gentamicin.16 However, disposable lenses have been shown to release a drug for up to 3 hours after their insertion, a time period that depends on the properties of the drug itself.17 Contact lenses, presoaked in medications, provide a marginal means of delivery because the therapeutics are freely dispersed within the contact lens structure and are capable of rapid release (i.e., via a “burst-release”), often leading to increased, topical drug side effects and toxicity reactions.17 To lengthen this release period, attempts to incorporate liposomes into the contact lens structure can be used to increase the efficiency of contact lenses as drug delivery systems. The patient would simply have to wear her/his therapeutic contact lens to receive the correct amount of drug delivered to her/his diseased eye, in a sustained manner.

Recently, a research group have proposed to directly disperse liposomes, made of dimyristoylphosphatidylcholine, into the contact lens material.18,19 However, this procedure requires the use of radicals to induce the polymerization of the contact lens matrix. This procedure cannot be used with drug sensitive to radicals.

Previously, we reported the development of soft contact lenses coated with drug-loaded liposomes, to act as effective drug delivery systems for the treatment of ocular infections.20,21 Details of the fabrication and surface characterization of these soft contact lenses, bearing layers of stable liposomes, were then also reported.20 The antibacterial activity of contact lenses, bearing levofloxacin-loaded liposomes, and developed for the prevention and treatment of bacterial ocular infections such as keratitis, were successfully demonstrated.21

Before the potential of binding intact drug-loaded liposomes onto the surfaces of contact lenses becomes fully developed and validated as a generic, ophthalmic drug delivery system, of high specificity in terms of the localized and sustained application of the drug, these new liposomal contact lenses must be designed to be both biocompatible with the corneal epithelium environment and to also maintain the transparency of the contact lens.

In the present work, the biocompatibility of soft contact lenses, coated with liposomes, has been evaluated through both in vitro direct and indirect cytocompatibility assays. The investigations were performed with epithelial cells from human corneas, cultured in monolayers, on reconstructed human corneas, and on ex vivo rabbit corneas, because liposomes attached to the lens will be in direct contact with the cornea external surface. Cell-materials interaction is of great importance in the evaluation of the biomaterial compatibility and its cytotoxicity. The transmittance spectra of these liposome-covered contact lenses were also measured to test whether or not they fulfilled their intended optical function, with a minimum of either light dispersion or color alteration.

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Contact lenses (Hioxifilcon B, Opti-Gel 45G, Opti-Centre, Sherbrooke, QC, Canada) were kindly provided by Robert Mercure from Opti-Centre and used as substrates for surface immobilization of intact liposomes. All similar lenses had the following parameters: power: −3.00 D; total diameter: 14.50 mm; base curve: 8.60 mm; brand: 51% hioxifilcon B + 49% water. The elemental composition of the contact lens surface, determined by X-ray photoelectron spectroscopy,20 has been reported elsewhere and is typical of the two polymers composing the hioxifilcon material: (i) poly(2-hydroxyethylmetacrylate) and (ii) polyglycidylmetacrylate. These commercial contact lenses were made readily available to us without imposition of commercial restrictions.

Hexane (American Chemical Society [ACS] grade) was purchased from ACP (Montreal, QC, Canada). Disuccimidylcarbonate (technical grade, 25827), anhydrous acetonitrile (CH3CN, 99.9% purity, 271004), N-hydroxysuccinimide (NHS, H-7377), N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid] (HEPES, H-3375, 99.5%), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide were purchased from Sigma-Aldrich (E-1769, Oakville, ON, Canada). Poly(ethylenimine) (PEI, 70 kDa MW, no. 00618) was obtained from Polysciences Inc. (Warrington, PA). Sodium chloride (NaCl, ACS grade), sodium sulfate (Na2SO4, ACS grade), and chloroform (high performance liquid chromatography-grade) were all purchased from Fisher Scientific (Ottawa, Ontario, Canada). Other chemicals such as 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, >99%, 850365), cholesterol (>99%, 700000), N-[ω-(biotinoylamino)poly(ethylene glycol) 2000]-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG(2000)-biotin, >96%, 890129) were all obtained from Avanti Polar Lipids Inc. (Alabaster, AL). Biotin-PEG-NHS (NHS-PEG-Biotin, 0H4M0F02) was purchased from Nektar Therapeutics (Huntsville, AL). NeutrAvidin (ImmunoPure NeutrAvidin biotin-binding protein, P31000) and D-biotin (ImmunoPure D-Biotin, 29,129) were obtained from Pierce (Rockford, IL).

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Liposome Preparation and Immobilization.

Details of the procedures used to produce liposomes and to then immobilize these intact liposomes on contact lens surfaces, have been reported elsewhere.20,21 Briefly, 100-nm unilamellar vesicles22 were made, using DSPC, cholesterol, and DSPC-PEG(2000)-biotin [2:1:(5 mol%) mol ratios], by means of extrusion through 100-nm pore polycarbonate Avestin track-etch membranes, using the Avestin Liposofast extruder (Avestin Inc., Ottawa, Ontario, Canada). The contact lenses were initially activated in a disuccimidylcarbonate solution, made in anhydrous acetonitrile, and then immersed in a solution of PEI in Milli-Q water (pH adjusted to 7.4). The PEI-coated lenses were immersed in a 1 mg/ml NHS-PEG-biotin solution, made under cloud point conditions, i.e., 170 mg/ml of Na2SO4 was added to the NHS-PEG-biotin solution to form PEG aggregates. Under these conditions, the resulting PEG layers exhibited excellent, low-fouling properties.23 The next step involved the immersion of the PEG-biotin-coated contact lenses in a 50 μg/ml NeutrAvidin solution of 10 mM HEPES buffer, at pH 7.4.24 Immobilization of liposomes was performed by incubating the NeutrAvidin-coated lenses in a 1 mg/ml (total lipid concentration) biotinylated-liposome suspension, made of DSPC:cholesterol: DSPE-PEG(2000)-biotin [2:1:(5 mol%) mol ratios], for 1 h. Multilayers of liposomes were fabricated by the addition, after the attachment of the first liposome layer, of more NeutrAvidin, which can add to biotins on the solution side of the liposomes present. Subsequently, more liposomes were added to bind onto the NeutrAvidin molecules, and so on to build up the desired coating. The lenses were thoroughly rinsed between each modification step.

Contact lenses were sterilized by a 5-min soaking in 70% ethanol (HPLC-grade) just before liposome attachment and the subsequent steps were performed in a laminar flow cabinet under sterile conditions. This method was shown to be sufficient to sterilize the lenses as no contamination was found during all procedures. The ethanol- incubated lenses were thoroughly rinsed overnight in sterile Milli-Q water, the water solution being changed several times in the period to remove any traces of ethanol.

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Cell Culture Studies.

For all procedures in cell cultures, corneal epithelial and stromal cells were isolated from postmortem human corneas, following the previously reported methodology.25 Cells were grown in Dulbecco’s modified Eagle’s medium (Sigma-Aldrich Canada Ltd.) using 10% fetal bovine serum (FBS; Qualified US/ Invitrogen Co., Burlington, ON) in the presence of l-glutamine (2 mM) and 1% insulin-transferrin-selenium-A (ITS; Invitrogen Co.). In the quantitative measurements, data were compared by the analysis of variance tests for significant differences, with a p value set at 0.05. Cell culture assays, with or without serum, were used to investigate whether or not the presence of serum proteins affected the interactions of cells with the liposome-modified lenses. For example, protein adsorption may affect the cell’s response toward biomaterials, such as the case where the lens is in direct contact with epithelial cells.

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In vitro direct contact biocompatibility assay.

The possibility of a cytotoxicity effect of liposome-bearing lenses was verified in direct contact with epithelial cells in cultures. Human corneal epithelial cells were seeded at 1 × 105 cells in each well of the 24-multiwell plates, to reach subconfluence. The viability of the cells was then measured through their mitochondrial activity, using an in vitro proliferation assay kit [XTT (2,3-bis{2methoxy-4-nitro-5-sulfophenyl}-2H-tetrazolium-5-carboxyanilide inner salt) or TOX2, Sigma-Aldrich Canada Ltd]. The XTT assay was performed according to the manufacturer’s procedures. Lenses bearing stable liposomes, and those without liposome (controls), were directly laid on the monolayer of epithelial cells for a 24-h period under a serum-free medium. A phosphate buffered saline solution of XTT (1 mg/ml) was mixed with a phosphate buffered saline solution of phenazinemethosulfate and incubated at 37°C for 1 h. The absorbance was spectrophometrically measured at the wavelength of 450 nm.

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Epithelial cell growth assay.

To further investigate the cell’s response toward lenses placed in direct contact with the epithelial cells, a cell growth assay was performed. A density of 1 × 104 cornea epithelial cells was seeded in each well of the 24-multiwell plates. After 1 day of culture in the serum-supplemented media, the lenses, with or without liposomes, were laid on the epithelial layer and incubated with the cells for a 48-h period, in the serum-free medium. After this culture period, cells were lyzed in a trisodium citrate solution, in the presence of 0.02% sodium dodecyl sulfate for 1 h and then reacted with Hoechst 33,258 (0.5 μg/ml, Invitrogen Co). The fluorescence was then quantified in fluorocytometric plates, using a BioTek FL-600 fluorometer (excitation 365 nm/emission 450 nm).

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Elution assay.

To investigate the effect of a potential release of leaked compounds from the lenses, the following indirect assay was performed. Lenses were incubated for specific periods in the same culture media that were then used to grow the epithelial cells. No direct contact with the lenses was considered. The different lenses were incubated at 37°C in a 5% serum-supplemented Dulbecco’s modified Eagle’s medium, for some 3- and 10-day periods. The respective media were then tested on a monolayer of epithelial cells in culture for a 24-h period, following the same procedure as described above. The XTT assay kit was used to assess the cell viability.

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Reconstruction of bilayered human corneas.

Because the stroma in the cornea and the Bowman’s membrane may influence the organization of the cornea epithelial cell lining, a reconstructed bilayered cornea was reproduced, on which the lenses could be directly laid on the epithelial cell layer. Reconstruction of the stroma layer was first performed according to a previously reported method.25 Briefly, stromal cells were mixed in collagen gel (from rat tail tendon) at density of 5.0 × 104 cells per 500 μl of gel, for each well of the 24-multiwell plates, and a gel was formed at a neutral pH in a culture incubator. A reconstituted Bowman’s membrane was laid on the gel and corneal epithelial cells were seeded on the membrane at a density of 1.0 × 105 cells/ml. The reconstituted corneas were incubated overnight. Liposomes bearing lenses, and those without liposome (controls), were set on the epithelium formed on the surface of the cornea construct. The cell cultures were then incubated for 3 days in an incubator under 5% CO2 in water saturation at 37°C. After fixation with formaldehyde and paraffin embedding, histological sections were processed transversally and then stained for hematoxylin, phloxin, and saffron.

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Ex Vivo Study on Rabbit Corneas.

An ex vivo model was used to verify the epithelial cell response according to the physiological curvature of the cornea (biomechanical effect) on which the lens fitted over its total surface. The cornea equivalent exposed a rather flat surface toward the lens compared with that of the ex vivo model. Corneas, with the surrounding sclera were extracted, with great care to minimize damages to the corneas, from rabbit’s eyes retrieved from a local abattoir. Corneas/sclera were sterilized by successively soaking in an antibiotic solution, made up in phenol-free Hanks’ balanced salt solution (Sigma), with penicillin-streptomycin-neomycin (1×, Invitrogen Co.), and in a solution of 50 μg/ml gentamicin (Invitrogen Co.). The contact lenses were laid on a cornea/sclera and left floating in the culture medium of the wells of 6-multiwell plates for a 48-h period. After removal of the lenses, an ophthalmic carboxyfluorescein solution was laid on the corneal surface and observed under the fluorescence microscope. Corneas were then fixed with formaldehyde and the epithelium colored by a toluidine blue solution (0.1%) for aiding morphological observations. Histological sections were processed through corneas and stained for hematoxylin, phloxin, and saffron.

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Ultraviolet (UV)-Visible Transmission Assays.

The use of an integrating sphere during the measurement of transmission spectra, as recommended by International Organization for Standardization and American National Standards Institute specifications, allows the direct measurement of the transmitted light, as well as of the forward-scattered light. This latter light portion is then actually measured, and is not erroneously calculated as the absorbed component.26–28 The use of an integrating sphere sometimes, but not always, yields a difference in the estimated absorption. These standards ensure that the light scattered by the contact lens reaches the integrating chamber detector and is not falsely considered as absorbed component in a Beer’s law calculation.29,30

The direct and indirect transmission spectra of contact lenses were measured, using a double beam Varian UV-Vis-IR (Cary 5000) spectrophotometer, controlled by the Cary WinUV 3.0 software (Mulgrave, Australia). The indirect transmission spectra used the integrating sphere (radius of 110 mm) of the internal diffuse reflectance accessory-2500. A pupil (diameter of 6 mm) was placed in front of the measuring cell for all measurements, these were all performed at 22°C. A 100 to 0% baseline was measured before proceeding with any transmission spectrum measurement performed on the contact lenses. A quartz measuring chamber,31 filled with saline solution and centered in front of (a) the measurement beam (direct transmission), or (b) the absorption port of an integrating sphere (indirect transmission), was scanned (2 nm bandwidth, 600 nm/min) from 220 to 800 nm, while the 100% baseline transmittance was measured. A similar second measurement was made except that a black cardboard was placed in the optical path of the instrument (0% baseline transmission). Then, a contact lens was positioned in the measuring chamber and its transmission spectra were measured and corrected for baseline. The spectra were measured three times for each lens.

The transmittance values at each scanning wavelength were used to calculate mean transmittance, in addition to the standard deviation for each test wavelength. The repeatability, assessed by the standard deviation of three separate measurements, varied between 0.08 and 0.28% for direct measurements and between 0.42 and 0.73% for indirect transmittance. Differences in transmittance values between the lens types were tested for significance at 280 and 550 nm, using paired t-tests between each type of lens, using the SPSS 13.0 software for Windows (Chicago, IL).

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Direct Biocompatibility Assay

Contact lenses, bearing five layers of stable liposomes, did not induce any significant changes in the cell viability of human cornea epithelial cell layers compared with those after 24-h incubation with control lenses bearing no liposome or with liposome suspensions (Fig. 1). Conversely, the control cultures, with or without serum, exhibited higher cell viability after the 24 h. This is probably due to a decrease in the medium density, resulting from the close contact made between the cells and the contact lenses. However, the epithelial cell monolayer appeared normal under any culture conditions (Fig. 1A to D). These results clearly demonstrate that the addition of liposome layers to the contact lens surfaces does not result in decreased corneal epithelial cell viability, in comparison with bare contact lenses.



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Cell Growth Assays

The density of the cell nuclei, as specifically stained with Hoechst, was measured after 3 days to investigate the effect of lenses on cell growth (Fig. 2). Cell density did not reveal any significant differences between the control contact lens, bearing no liposome and the contact lenses bearing five layers of stable liposomes, after some 3 culture days. However, cell growth was significantly slower than in the control cultures, with or without serum. Moreover, cultures in the presence of liposome suspensions decreased the growth of epithelial cells, depending on their concentrations. Thus, “free” liposomes may possibly be involved in the decrease of cell replication. However, the liposomes attached to the lenses did not appear to impair cell growth or cell viability. In addition, the morphology of the cells (Fig. 1) was not impaired, either by the control lenses or by those lenses bearing liposomes.



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Indirect Biocompatibility Using an Elution Assay

To investigate the potential cytotoxicity of products, eluted from contact lenses coated with liposome layers, additional testing was conducted, using the medium in which the materials were previously soaked for 3 and 10 days. Mitochondrial activity was measured, using the XTT assay. No significant differences were found between the different dilution levels employed, and the different lenses and culture conditions tested (Fig. 3). Therefore, these findings strongly suggest that there are no cytotoxic compound leaks from the lenses bearing or not liposomes, even after some 10 days of soaking in the culture medium.



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Bilayered Cornea

As mentioned earlier, there was no alteration of the epithelial cell layer and this was confirmed by the observation of histological sections (Fig. 4). Cells appeared morphologically normal and formed one or two layers of cells, as in the control reconstructed cornea/stroma.



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Ex Vivo Testing on Rabbit Cornea

This assay confirmed that the explanted corneas that were in contact with those lenses bearing liposomes were not altered. Using toluidine blue and carboxyfluorescein, no injury of/to the surface of the cornea, as also seen by histological sections of the whole cornea, could be detected (Fig. 4).

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Transmission Spectra of Contact Lenses Bearing a Variable Number of Liposome Layers

The mean indirect spectral transmittance curves of the three tested lenses studied, are shown in Fig. 5. From wavelengths approximately 250 to 800 nm, contact lenses without liposome (controls), appear to transmit more light, in comparison with lenses bearing layers of stable liposomes. Lenses bearing five layers of stable liposomes transmit more light than those bearing 10 layers of stable liposomes. The difference between the control lenses and those coated with 5 or 10 layers of liposomes, was maximal at around 280 nm. Table 1 indicates that the difference in the indirect transmittance, between control lenses and the lenses bearing layers of stable liposomes, was statistically significant at 280 nm, but was not statistically significant at 550 nm, as revealed by the paired t-tests.





Fig. 5 also shows measurements of the direct transmittance of the same contact lenses. Direct transmittance data, also summarized in Table 1, was significantly different between the control lenses and those lenses with liposomes. The differences between the lenses with 5 liposome layers, and with 10 liposome layers, were also statistically significant at 280 nm. Again, at 550 nm, there was no significant difference between any of the transmittances measured on the contact lenses for direct measurements.

Inspection of Table 1 shows that at 280 nm, the direct average measurement was generally smaller than the indirect transmittance. This difference was only statistically significant for the lenses with five layers of liposomes. This is not unexpected as in indirect measurements diffuse light is also measured in addition to the directly transmitted light. There was no significant difference between any measurements modes for any of the contact lenses tested at 550 nm.

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Contact lenses bearing layers of stable liposomes did not induce any significant changes in cell viability and in cell growth compared with lenses bearing no liposome. Elution assays revealed that no cytotoxic compound leaked from the lenses bearing or not liposomes. Histological analyses of reconstructed human corneas and ex vivo rabbit corneas, being directly exposed to liposomal lenses, revealed no alteration to the cell and tissue structures.

Lenses bearing 5 or 10 layers of liposomes do not significantly affect light transmission compared with the control lenses without liposome, at the wavelength of the maximal photopic sensitivity, i.e., at 550 nm. However, in the UV spectrum, direct and indirect transmittance levels of the lenses with liposomes were significantly lower in comparison with the control lenses that do not contain a UV absorber.

Further studies will be warranted to study the effect of liposome immobilization on the oxygen permeability of these modified lenses. Moreover, the investigations of the inflammatory response, as well as the wear comfort, must be performed in an animal contact lens model, before the conduct of clinical applications of liposome-bearing lenses.

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We thank Peter Lanigan for his assistance in the writing of this manuscript.

Patrick Vermette

Department of Chemical Engineering

Université de Sherbrooke

2500, boulevard de l’Université

Sherbrooke, Québec, Canada, J1K 2R1


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drug delivery systems using contact lenses; immobilized layers of intact liposomes; localized drug delivery; biocompatibility; epithelial human cornea cells; light transmission

© 2007 American Academy of Optometry