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Peer-reviewed articles

2016

Phan,C. -M, Walther,H., Gao,H., Rossy,J., Subbaraman,L. N., Jones,L. Development of an in Vitro ocular platform to test contact lenses. Journal of Visualized Experiments 2016;2016,110:e53907. [ Show Abstract ]

Currently, in vitro evaluations of contact lenses (CLs) for drug delivery are typically performed in large volume vials,1-6 which fail to mimic physiological tear volumes.7 The traditional model also lacks the natural tear flow component and the blinking reflex, both of which are defining factors of the ocular environment. The development of a novel model is described in this study, which consists of a unique 2-piece design, eyeball and eyelid piece, capable of mimicking physiological tear volume. The models are created from 3-D printed molds (Polytetrafluoroethylene or Teflon molds), which can be used to generate eye models from various polymers, such as polydimethylsiloxane (PDMS) and agar. Further modifications to the eye pieces, such as the integration of an explanted human or animal cornea or human corneal construct, will permit for more complex in vitro ocular studies. A commercial microfluidic syringe pump is integrated with the platform to emulate physiological tear secretion. Air exposure and mechanical wear are achieved using two mechanical actuators, of which one moves the eyelid piece laterally, and the other moves the eyeballeyepiece circularly. The model has been used to evaluate CLs for drug delivery and deposition of tear components on CLs.

Phan,C. -M, Subbaraman,L., Jones,L. W. The use of contact lenses as biosensors. Optometry and Vision Science 2016;93,4:419-425. [ Show Abstract ]

The tear film is a complex multilayer film consisting of various proteins, enzymes, and lipids and can express a number of biomarkers in cases of disease. The development of a contact lens sensor presents a noninvasive alternative for the detection and management of various diseases. Recent work has resulted in the commercialization of a device to monitor intraocular pressure for up to 24 h, and there are extensive efforts underway to develop a contact lens sensor capable of continuous glucose tear film monitoring to manage diabetes. This clinical perspective will highlight the major developments within this field and list some of the major challenges that still need to be addressed. © 2015 American Academy of Optometry.

Phan,C. -M, Bajgrowicz,M., Gao,H., Subbaraman,L. N., Jones,L. W. Release of fluconazole from contact lenses using a novel in vitro eye model. Optometry and Vision Science 2016;93,4:387-394. [ Show Abstract ]

Purpose. Rapid drug release followed by a plateau phase is a common observation with drug delivery from contact lenses (CLs) when evaluated in a vial. The aim of this study was to compare the release of fluconazole from seven commercially available daily disposable CLs using a conventional vial-based method with a novel in vitro eye model. Methods. An eye model was created using two 3-dimensional printed molds, which were filled with polydimethylsiloxane to obtain an inexpensive model that would mimic the eyeball and eyelid. The model was integrated with a microfluidic syringe pump, and the flow-through was collected in a 12-well microliter plate. Four commercial daily disposable conventional hydrogels (nelfilcon A, omafilcon A, etafilcon A, ocufilcon B) and three silicone hydrogels (somofilcon A, narafilcon A, delefilcon A) were evaluated. These CLs were incubated with fluconazole for 24 h. The drug release was measured in a vial containing 4.8 mL of phosphate-buffered saline and in the polydimethylsiloxane eye model with a 4.8-mL tear flow across 24 h. Results. Overall, conventional hydrogel CLs had a higher uptake and release of fluconazole than silicone hydrogel CLs (p < 0.05). A higher drug release was observed in the vial condition compared with the eye model (p < 0.001). In the vial system, the drugs were rapidly released from the CL within the first 2 h, followed by a plateau phase. In contrast, drug release in the eye model under low tear volume was sustained and did not reach a plateau across 24 h (p < 0.05). Conclusions. Rapid drug release results from using a vial as the release system. Under low tear volume at physiological tear flow, commercial CLs can maintain a sustained drug release profile for up to 24 h. However, eyes with fungal keratitis may have increased tearing, which would significantly accelerate drug release. © 2015 American Academy of Optometry.

Phan,C. -M, Bajgrowicz,M., McCanna,D. J., Subbaraman,L. N., Jones,L. Effects of Antifungal Soaked Silicone Hydrogel Contact Lenses on Candida albicans in an Agar Eye Model. Eye and Contact Lens 2016;42,5:313-317. [ Show Abstract ]

Purpose: To evaluate the effects of two commercial silicone hydrogel contact lenses (CLs) soaked with natamycin (NA) or fluconazole (FL) on the growth of Candida albicans in an in vitro eye model. Methods: Three-D printed molds were used as a cast for making eye-shaped models comprising potato dextrose agar. Senofilcon A (SA) and lotrafilcon B (LB) CLs were incubated with either 2 mL of NA or FL at a concentration of 1 mg/mL for 24 hr. To simulate a fungal infection, the eye models were coated with C. albicans. The drug-soaked lenses were placed on top of the eye models. Seven experimental conditions were examined: (1) NA-SA, (2) NA-LB, (3) FL-SA, (4) FL-LB, (5) SA, (6) LB, and (7) control - no lens. At specified time points (t1, 8, 16, 24, 48 hr), the agar eyes from each experimental condition were removed from the incubator and photographed. The yeast cells from the 24 and 48 hr time point were also analyzed using light microscopy. Results: At 24 and 48 hr, there was considerable growth observed for all conditions except for the NA-SA and NA-LB conditions. When observed under the microscope at 24 and 48 hr, the morphology of the yeast cells in the FL-SA and SA condition were similar to that of the control (oval shaped). There was limited hyphae growth observed for LB and significant visible hyphae growth for the NA-LB group. For NA-SA, NA-LB, and FL-LB groups, the cells were significantly smaller compared with the control. Conclusions: For NA-SA and NA-LB, there was limited growth of C. albicans observed on the eye models even after 48 hr. Under the microscope, the cell morphology differ noticeably between each testing condition, and is dependent on drug-lens combinations. © 2015 Contact Lens Association of Ophthalmologists.

2015

Bajgrowicz,M., Phan,C. -M, Subbaraman,L. N., Jones,L. Release of ciprofloxacin and moxifloxacin from daily disposable contact lenses from an in vitro eye model. Investigative Ophthalmology and Visual Science 2015;56,4:2234-2242. [ Show Abstract ]

Purpose. To analyze the release of two fluoroquinolones, ciprofloxacin and moxifloxacin, from conventional hydrogel (CH) and silicone hydrogel (SH) daily disposable contact lenses (CLs), comparing release from a fixed-volume vial and a novel in vitro eye model. Methods. Four CH CLs (nelfilcon A, omafilcon A, etafilcon A, ocufilcon B) and three SH CLs (somofilcon A, narafilcon A, delefilcon A) were used. The lenses were incubated in drug solutions for 24 hours. After the incubation period, the lenses were placed in two release conditions: (1) a vial containing 4.8 mL PBS for 24 hours and (2) an in vitro eye model with a flow rate at 4.8 mL over 24 hours. Results. Release in the vial for both drugs was rapid, reaching a plateau between 15 minutes and 2 hours for all lenses. In contrast, under physiological flow conditions, a constant and slow release was observed over 24 hours. The amounts of ciprofloxacin released from the lenses ranged between 49.6 ±0.7 and 62.8 ± 0.3 µg per lens in the vial, and between 35.0 ± 7.0 and 109.0 ± 5.0 µg per lens in the eye model. Moxifloxacin release ranged from 24.0 ± 4.0 to 226.0 ± 2.0 µg per lens for the vial, and between 13.0 ± 2.0 and 151.0 ± 10.0 µg per lens in the eye model. In both systems and for both drugs, HEMA-based CLs released more drugs than other materials. Conclusions. The parameters of the release system, in particular the volume and flow rate, have a significant influence on measured release profiles. Under physiological flow, release profiles are significantly slower and constant when compared with release in a vial. © 2015, The Association for Research in Vision and Ophthalmology, Inc.

2014

Hall,B., Phan,C. -M, Subbaraman,L., Jones,L. W., Forrest,J. Extraction versus in Situ techniques for measuring surface-adsorbed lysozyme. Optometry and Vision Science 2014;91,9:1062-1070. [ Show Abstract ]

PURPOSE: To compare two techniques for measuring the activity of lysozyme deposited onto hydrogel contact lens and to image the binding of Micrococcus lysodeikticus to contact lenses. METHODS: Using a previously described protein extraction technique and a recently developed in situ technique, we measured the time-dependent activity of adsorbed lysozyme on six different contact lens materials during the first minute and up to 1 week of interaction with the material surface. Total activity of extracted lysozyme, total in situ activity, and the activity of the outer surface layer of sorbed lysozyme were determined using the two different techniques. Micrococcal cellular interaction with surface-adsorbed lysozyme was imaged using confocal microscopy. RESULTS: The differences between total extracted activities, total in situ activities, and surface activities were both measurable and material specific. In most cases, total extracted activity is greater than total in situ activity, which, in turn, is greater than surface activity. After 1 week, etafilcon A had the highest extracted activity at 137 µg/lens, followed by omafilcon A, balafilcon A, comfilcon A, senofilcon A, and lotrafilcon B at 27.4, 2.85, 2.02, 0.46, and 0.27 µg/lens, respectively. Micrococcal cell adhesion was greatest on contact lenses with high contact angles, such as balafilcon A, omafilcon A, and senofilcon A and lowest on contact lenses with low contact angles, such as etafilcon A, comfilcon A, and lotrafilcon B. Subsequent removal/prevention of adhered micrococcal cells was greatest on balafilcon A, which had the highest surface activity, and lowest on lotrafilcon B, which had the lowest surface activity. CONCLUSIONS: This study has measured and made direct comparisons between two established techniques for measuring the activity of adsorbed lysozyme. The extraction technique determines the activity of underlying layers of lysozyme or lysozyme within the matrix of the material. Conversely, the in situ technique allows conclusions to be drawn about only the biologically relevant lysozyme including the activity of just the outer surface of adsorbed lysozyme. © American Academy of Optometry.

Phan,C. -M, Subbaraman,L. N., Jones,L. In vitro drug release of natamycin from ß-cyclodextrin and 2-hydroxypropyl-ß-cyclodextrin-functionalized contact lens materials. Journal of Biomaterials Science, Polymer Edition 2014;25,17:1907-1919. [ Show Abstract ]

Purpose: The antifungal agent natamycin can effectively form inclusion complexes with beta-cyclodextrin (ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ßCD) to improve the water solubility of natamycin by 16-fold and 152-fold, respectively (Koontz, J. Agric. Food. Chem. 2003). The purpose of this study was to develop contact lens materials functionalized with methacrylated ß-CD (MßCD) and methacrylated HP-ßCD (MHP-ßCD), and to evaluate their ability to deliver natamycin in vitro. Methods: Model conventional hydrogel (CH) materials were synthesized by adding varying amounts of MßCD and MHP-ßCD (0, 0.22, 0.44, 0.65, 0.87, 1.08% of total monomer weight) to a monomer solution containing 2-hydroxyethyl methacrylate (HEMA). Model silicone hydrogel (SH) materials were synthesized by adding similar concentrations of MßCD and MHP-ßCD to N,N-dimethylacrylamide (DMAA)/10% 3-methacryloxypropyltris(trimethylsiloxy)silane (TRIS). The gels were cured with UV light, washed with ethanol and then, hydrated for 24 h (h). The model materials were then incubated with 2 mL of 100 g/mL of natamycin in phosphate buffered saline (PBS) pH 7.4 for 48 h at room temperature. The release of natamycin from these materials in 2 mL of PBS, pH 7.4 at 32 ± 2 °C was monitored using UV-vis spectrophotometry at 304 nm over 24 h. Results: For both CH and SH materials, functionalization with MßCD and MHP-ßCD improved the total amount of drugs released up to a threshold loading concentration, after which further addition of methacrylated CDs decreased the amount of drugs released (p < 0.05). The addition of CDs did not extend the drug release duration; the release of natamycin by all model materials reached a plateau after 12 h (p < 0.05). Overall, DMAA/10% TRIS materials released significantly more drug than HEMA materials (p < 0.05). The addition of MHP-ßCD had a higher improvement in drug release than MßCD for both HEMA and DMAA/10% TRIS gels (p < 0.05). Conclusions: A high loading concentration of methacrylated CDs decreases overall drug delivery efficiency, which likely results from an unfavorable arrangement of the CDs within the polymer network leading to reduced binding of natamycin to the CDs. HEMA and DMAA/10% TRIS materials functionalized with MHP-ßCD are more effective than those functionalized with MßCD to deliver natamycin.

Phan,CM, Hui,A., Subbaraman,L., Jones,L. Insights to Using Contact Lenses for Drug Delivery. Clin Exp Pharmacol 2014;3,145:2161-1459. [ Show Abstract ]

There has been considerable interest in the potential application of contact lenses for ocular drug delivery. This short communication provides an overview of the challenges faced by delivering drugs using contact lenses, highlights the solutions to limitations that have already been achieved, and describes the barriers that remain before commercial application can be realized.

Phan,C. -M, Subbaraman,L., Jones,L. Contact lenses for antifungal ocular drug delivery: A review. Expert Opinion on Drug Delivery 2014;11,4:537-546. [ Show Abstract ]

Introduction: Fungal keratitis, a potentially blinding disease, has been difficult to treat due to the limited number of approved antifungal drugs and the taxing dosing regimen. Thus, the development of a contact lens (CL) as an antifungal drug delivery platform has the potential to improve the treatment of fungal keratitis. A CL can serve as a drug reservoir to continuously release drugs to the cornea, while limiting drug loss through tears, blinking, drainage and non-specific absorption. Areas covered: This review will provide a summary of currently available methods for delivering antifungal drugs from commercial and model CLs, including vitamin E coating, impregnated drug films, cyclodextrin-functionalized hydrogels, polyelectrolyte hydrogels and molecular imprinting. This review will also highlight some of the main factors that influence antifungal drug delivery with CLs. Expert opinion: Several novel CL materials have been developed, capable of extended drug release profiles with a wide range of antifungal drugs lasting from 8 h to as long as 21 days. However, there are factors, such as first-order release kinetics, effectiveness of continuous drug release, microbial resistance, ocular toxicity and potential complications from inserting a CL in an infected eye, that still need to be addressed before commercial applications can be realized. © Informa UK, Ltd.

Phan,C. -M, Subbaraman,L., Liu,S., Gu,F., Jones,L. In vitro uptake and release of natamycin Dex -b- PLA nanoparticles from model contact lens materials. Journal of Biomaterials Science, Polymer Edition 2014;25,1:18-31. [ Show Abstract ]

Purpose: To evaluate the uptake and release of the antifungal agent natamycin encapsulated within poly(D,L-lactide)-dextran nanoparticles (Dex-b-PLA NPs) from model contact lens (CL) materials. Methods: Six model CL materials (gel 1:poly(hydroxyethyl methacrylate, pHEMA); gel 2:85% pHEMA: 15% [Tris(trimethylsiloxy)silyl]-propyl methacrylate (TRIS); gel 3: 75% pHEMA: 25% TRIS; gel 4: 85% N,N dimethylacrylamide (DMAA): 15% TRIS; gel 5:75% DMAA: 25% TRIS; and gel 6: DMAA) were prepared using a photoinitiation procedure. The gels were incubated in: (1) natamycin dissolved in deionized (DI) water and (2) natamycin encapsulated within Dex-b-PLA NPs in dimethylsulfoxide/DI water. Natamycin release from these materials was monitored using UV-visible spectrophotometry at 304 nm over 7 d. Results: Natamycin uptake by all model CL materials increased between 1 and 7 d (p < 0.001). The uptake of natamycin-NPs was higher than the uptake of the drug alone in DI water (p < 0.05). Drug release was higher in materials containing DMAA than pHEMA (p < 0.05). All gels loaded with natamycin-NPs also released more drug compared to gels soaked with natamycin in DI water (p < 0.001). After 1 h, CL materials loaded with natamycin alone released 28-82% of the total drug release. With the exception of gel 6, this burst released was reduced to 21-54% for CL materials loaded with natamycin-NPs. Conclusions: Model CL materials loaded with natamycin-Dex-b-PLA NPs were able to release natamycin for up to 12 h under infinite sink conditions. DMAA-TRIS materials may be more suitable for drug delivery of natamycin due to the higher drug release observed with these materials. © 2013 Taylor & Francis.

2013

Phan,C. -M, Subbaraman,L. N., Jones,L. In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materials. Eye and Contact Lens 2013;39,2:162-168. [ Show Abstract ]

OBJECTIVES:: To investigate the uptake and release of the antifungal ocular drug, natamycin from commercially available conventional hydrogel (CH) and silicone hydrogel (SH) contact lens (CL) materials and to evaluate the effectiveness of this delivery method. METHODS:: Five commercial SH CLs (balafilcon A, comfilcon A, galyfilcon A, senofilcon A, and lotrafilcon B) and four CH CLs (etafilcon A, omafilcon A, polymacon, vifilcon A) were examined in this study. These lenses were incubated with natamycin solubilized in dimethyl sulfoxide, and the release of the drug from these lenses, in Unisol 4 pH 7.4 at 32±1 C, was determined using UV-visible spectrophotometry at 305 nm over 24 hours. RESULTS:: There was a significant uptake of natamycin between 0 hour and 24 hours (P0.05). There was a significant difference in release between all the SH materials (P0.05). There was a significant difference in release between all the SH materials (P0.05). There was a significant difference in release between all the SH materials (P0.05). Overall, the release of natamycin was higher in CH than SH lenses (P<0.001). CONCLUSIONS:: All CLs released clinically relevant concentrations of natamycin within 30 minutes, but this release reached a plateau after approximately 1 hour. Further CL material development will be necessary to produce a slow and sustained drug releasing device for the delivery of natamycin. © 2013 Lippincott Williams & Wilkins.

Abstracts

2016

Phan C, Bajgrowicz M, Subbaraman L, Jones L. Release of moxifloxacin from daily disposable contact lenses using an in vitro eye model: Impact of artificial tear fluid composition and mechanical rubbing. Invest Ophthalmol Vis Sci 2016;57: E-abstract 1474. [ PDF ]

Walther H, Phan C, Subbaraman L, Jones L. Cholesterol Penetration into Daily Disposable Contact Lenses Using a Novel In Vitro Eye-Blink Model. Invest Ophthalmol Vis Sci 2016;57: E-abstract 1476. [ PDF ]

Qiao H, Phan C-M, Walther H, Subbaraman L, Jones L. Localizing lysozyme deposition on contact lenses using a novel in vitro eye model. Optom Vis Sci 2016;93: E-abstract 160100.

Walther H, Phan C-M, Qiao H, Liu Y, Subbaraman L, Jones L. In vitro eye model to simulate the impact of blinking on contact lens deposition and drug delivery. Optom Vis Sci 2016;93: E-abstract 160101.

Phan C-M, Walther H, Riederer D, Smith R, Subbaraman L, Jones L. Determination of the release of wetting agents from nelfilcon a using a novel in vitro eye model. Optom Vis Sci 2016;93: E-abstract 165114. [ PDF ]

2015

Phan C, Jones L, Subbaraman L, Bajgrowicz M. Release of fluconazole from daily disposable contact lenses using a novel in vitro eye model. Invest Ophthalmol Vis Sci 2015;56: E-abstract 3085.

Bajgrowicz M, Phan C, Subbaraman L, Jones L. Release of ciprofloxacin and moxifloxacin from daily disposable contact lenses using an in vitro eye model. Invest Ophthalmol Vis Sci 2015;56: E-abstract 6085. [ PDF ]

2014

Phan C, Subbaraman L, Jones L. Delivery of natamycin using cyclodextrin functionalized contact lenses. Invest Ophthalmol Vis Sci 2014;55: E-abstract 4643. [ PDF ]

2013

Hall B, Phan C, Subbaraman L, Jones L. Forrest J. Direct comparison between in situ versus extraction techniques for measuring absorbed proteins: Application to lysozome deposited onto hydrogel contact lenses. Invest Ophthalmol Vis Sci 2013;54: E-Abstract 5467.

Phan C, Subbaraman L, Jones L. Delivery of natamycin using cyclodextrin functionalized contact lenses. NSERC 20/20 Meeting, 2013.

Phan C, Subbaraman L, Liu S, Gu F, Jones L. Drug delivery of natamycin from contact lens materials using Dex-b-PLA nanoparticles. ISCLR conference, Kyoto, Japan, 2013.

Phan C, Lui S, Gu F, Jones L. In vitro uptake and release of Natamycin dex-b-PLA nanoparticles from silicone hydrogel contact lens materials. 20/20 NSERC ophthalmic materials conference, Niagara Falls, Canada, 2013.

Phan C, Subbaraman L, Liu S, Gu F, Jones L. In vitro uptake and release of natamycin Dex-b-PLA nanoparticles from silicone hydrogel contact lens materials. Canadian Optometry Schools Research Conference, Waterloo, Canada, 2013.

Hall B, Phan C, Subbaraman L, Jones L, Forrest J. Extraction versus in situ techniques for measuring surface adsorbed lysozyme. Canadian Optometry Schools Research Conference, Waterloo, Canada, 2013.

Phan C, Subbaraman L, Jones L, Liu S, Gu F. In vitro uptake and release of natamycin dex-b-pla nanoparticles from silicone hydrogel contact lens materials. Invest Ophthalmol Vis Sci 2013;54: E-Abstract 501.

2012

Phan C, Jacob J, Subbaraman L, Jones L. Visualizing the uptake and release of natamycin from commercial contact lenses using confocal microscopy. 2020 NSERC ophthalmic materials conference, Burlington, Canada, 2012.

Professional Publications

2012

Phan C. Delivering cyclosporine A from contact lenses: An article review. ContactLensUpdate.com 2012.