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The Ohio State University

Department of Ophthalmology

Continuing Projects:

Corneal Biomechanical and Hydration Model before and after Refractive Surgery. (Grzybowski and Roberts) A combination of topography, wavefront, reflectivity, and autorefraction data will be used to create a model of corneal biomechanical response to refractive surgery that includes the critical factor of corneal hydration. Clinical measurements on 20 LASIK and 20 normal subjects were obtained. Post-LASIK corneas exhibited distinct thickness, viscoelastic, and curvature pattern changes when compared to non-surgical corneas in response to induced swelling. Other biomechanical properties are unaffected by increased hydration in both groups. These results may have an impact as subjects grow older and may require ocular interventions and/or medications that impact corneal hydration status. A book chapter was prepared and submitted based on the preliminary study, and an ARVO poster was presented this year on final results. Future directions include preparing several manuscripts for publication.

Benjamin D. Abramowitz, Ashraf M. Mahmoud, Cynthia J. Roberts, Amit Tandon, Deborah M. Grzybowski. “Swelling Analysis Of Thickness, Curvature, And Biomechanical Properties In The Post-LASIK Cornea.” ARVO 2011, E-Abstract 5186.

Grzybowski DM, Rogers NA, Mahmoud AM, Roberts CJ. Corneal Topographic Response to Swelling in Normal and post-LASIK Corneas, in Uzbek AK, Roberts CJ (eds). Corneal Topography: from Theory to Practice, Amsterdam: Kugler Publications; in press.

The Influence of Biomechanical Ocular Properties and Ocular Pulse Amplitude in Glaucoma (Roberts, Weber, Fleming, and Sawchyn) Work will continue on the hypothesis proposed previously, describing the influence of the variation in intraocular pressure caused by the heart beat (ocular pulse amplitude or OPA), in combination with ocular rigidity, on the development and progression of glaucoma. To determine the relationship between ocular pressure waves, arterial pressure waves, and venous pressure waves, a protocol has been approved and 3 subjects enrolled to record natural variation in systemic blood pressure and heart rate during general surgical cases. All three waveforms will be recorded simultaneously, and signal analysis will be performed to investigate the determinants of the ocular pulse waveform. After additional subjects are recruited, these data will be used with our previously described electrical analog model to determine a methodology to estimate ocular blood flow and ocular rigidity in various forms of glaucoma. In addition, the difference in Goldmann Applanation Tonometry (GAT) and Dynamic Contour Tonometry provide an indication of the “stiffness” or “softness” of the cornea. It was determined that this difference was greater in glaucoma subjects treated with Prostaglandins than in normal subjects matched for central corneal thickness, indicating that the glaucomatous corneas are softer than normal, and therefore GAT may be more inaccurate in patients with glaucoma. This was presented at ARVO.

Bryan R. Costin, Gloria P. Fleming, Paul A. Weber, Ashraf M. Mahmoud, Cynthia J. Roberts “Corneal Biomechanical Properties and Intraocular Pressure Measurement in Primary Open Angle Glaucoma versus Normal Control Subjects.” ARVO 2011, E-Abstract 5178.

Corneal Biomechanical Properties in Keratoconus (Roberts) Work will continue on the new hypothesis proposed for biomechanical progression in Keratoconus, in which a confined corneal region has a reduction in elastic modulus. This confined region bulges due to a specific relationship between deformation and applied force. As the bulging occurs, the cornea becomes thinner. This serves as a stress concentration and drives further deformation. We have obtained a new device for measurement of corneal biomechanical properties in vivo, called the CorVis ST, manufactured by Oculus. This device acquires a series of Scheimpflug images during a corneal deformation caused by an air puff. Data acquisition is underway, and in the coming year, we will statistically compare normal subjects to keratoconus subjects. This new theory has been reported in the following book chapter, and the theory and preliminary results have been presented at the following meetings:

“Biomechanics in Keratoconus.” In: Barbara A (ed). Textbook of Keratoconus: New Insights. Jaypee Brothers. In press

“Biomechanics in Ophthalmology,” Tel Aviv Medical Center Department of Ophthalmology, Tel Aviv, May 20, 2010.

“The Importance of Biomechanical Properties to the Clinician.” XVI International Course of Cornea and Refractive Surgery, Cancun, Mexico, October 31, 2010.

“In Vivo Measurement of Biomechanical Properties.” XVI International Course of Cornea and Refractive Surgery, Cancun, Mexico, October 31, 2010.

“Corneal Biomechanics: Implications in Cornea and Glaucoma.” Peking University, Beijing, China, January 17, 2011.

“Corneal Biomechanics.” Shanghai Jiao Tong University, Shanghai, China, Jan. 19, 2011.

“Clinical Corneal Biomechanics” Global Leaders Lecture Series, given via video link to LV Prasad Eye Institute, Hyderabad, India, Feb. 10, 2011

Cellular Response of Trabecular Meshwork Cells on Micro/Nano Scale Substrates (Zhao, Weber, Roberts) The hydraulic conductivity response of primary cultures of trabecular meshwork (TM) endothelial cells to laser irradiation has been studied for many years. In the past year, this work has transitioned to investigations of the cellular response of TM cells to micro and/or nanoscale substrates. We have found that 1) TM cells exhibit a more in vivo-like phenotype when cultured on surface with micro/nanoscale topography; 2) For TM cells cultured on microscale structures, randomly patterned structure induces higher levels of myocilin expression; and 3) Although no obvious difference of myocilin expression is

observed between random and aligned nanoscale fibrous structures, these nanoscale fibrous structure induce higher level of myocilin than aligned solid microstructure. Preliminary work resulted in external funding from the Glaucoma Research Foundation. This work was also presented at ARVO this year, and will continue next year.

“Nanoengineered In Vitro Trabecular Meshwork (TM) Model for Systematic Investigation of Aqueous Humor Outflow Resistance.” Glaucoma Research Foundation. Principal Investigator: Yi Zhao, Co-Investigators: Cynthia J. Roberts, Deborah M. Grzybowski, Paul A. Weber. $40,000.

Bongsu Kim, Cynthia J. Roberts, Ashraf M. Mahmoud, Deborah M. Grzybowski, Paul A. Weber, Zhao Yi “Topographic Effect of Micro/Nanoengineered Polymer Substrates on Cultured Trabecular Meshwork Cells.” ARVO 2011, E-abstract 4666.

The Investigation of Multifunctional Microbubbles for Sustained Release in Intravitreal Injection of anti-VEGF agents. (Xu, Letson, Roberts) The goal of this ongoing project is to investigate novel methods of encapsulation of anti-VEGF agents in the fabrication of microbubbles for sustained delivery via intravitreal injection in the treatment of age-related macular degeneration. Current double-emulsion encapsulation methods are detrimental to the bioactivity of Lucentis. It is proposed that the new methodology under study will not substantially reduce bioactivity with sustained delivery. In addition, we have shown that freeze-drying of Lucentis also does not substantially alter bioactivity, which allows reconstitution at a much higher concentration for encapsulation in microbubbles. In addition to the anti-VEGF agents, fluorescent compounds can be encapsulated simultaneously to allow visualization of the microbubbles in the vitreous chamber to monitor rate of delivery of anti-VEGF therapy. Note that the Doctoral Student in Biomedical Engineering working on this project is also our Ohio Lions Eye Research Fellow. We received a substantial amount of Lucentis from Genentech in support of our research, and this work was presented at ARVO this year. Manuscripts are in preparation.

"Targeted delivery of biodegradable multifunctional nanoparticles, conjugated with Lucentis, for integrated imaging and therapy of age-related macular degeneration." GenenTech Reagent grant, PI: Ronald Xu, Co-I’s: Cynthia Roberts, Alan Letson, $80,000 worth of Lucentis™ anti-VEGF antibody.

Leilei Zhang, Jeff Xu, Jiwei Huang, Cynthia Roberts, Ronald Xu. 2010. Bevacizumab (Avastin) conjugated microbubbles for anti-VEGF treatment of neovascular age-related macular degeneration. In: Proc. SPIE: 7550-61.

Leilei Zhang, Cynthia J Roberts, Alan D Letson, Ronald Xu. “Comparison of Avastin and Lucentis conjugated microbubbles for targeted delivery in age-related macular degeneration. ARVO E-Abstract 477.

Intravitreal anti-VEGF agents such as avastin, lucentis and macugen with wet macular degeneration. (Christoforidis) The project of radiolabeling of anti-VEGF agents was actively continued these past 12 months. The results of the work have received national and international attention as this new method provides a completely novel method to determine the pharmacokinetic properties of intravitreally placed agents. The initial phase of the study was submitted and recently published in our most esteemed eye research journal, Investigative Ophthalmology & Visual Science (early edition June 17, 2011). The topic has been presented at the following meetings:

1) ARVO, Fort Lauderdale, FL-May 1, 2011-Received Hot Topic Award, and

2) Aegean Retina Meeting-Rethymnon, Crete-July 8, 2011.