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Factors governing photodynamic cross-linking of ocular coat

Citation

Huynh, Joyce (2011) Factors governing photodynamic cross-linking of ocular coat. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:05202011-143758537

Abstract

This thesis addresses the challenge of minimizing toxicity of therapeutic protein-protein cross-linking of the cornea and sclera. Protein-protein cross-links include disulfide bonds, enzymatic cross-links and non-enzymatic cross-links. Disulfide bonds and enzymatic cross-links are closely regulated in the body. Non-enzymatic cross-links accumulate in an uncontrolled manner, often leading to deleterious effects. Clinically, non-enzymatic cross-links can be inserted in a controlled manner, both temporally and spatially, using photo-activation to achieve effects ranging from killing tumors to stabilizing ocular shape.

The shape of the eye is maintained by the ocular coat—the cornea and sclera. Diseases that result in progressive shape changes can lead to blindness (degenerative myopia) or necessitate a corneal transplant (keratoconus and post-LASIK ectasia). Photodynamic corneal cross-linking, pioneered by Wollensak et al. using riboflavin activated by near-ultraviolet light (riboflavin/UVA), halts the progression of keratoconus; if applied to the sclera, it might halt the progression of degenerative myopia, as well. However, this treatment suffers from severe cytotoxicity. The literature to date implicitly assumes that photodynamic cross-linking is inherently toxic. The present research demonstrates that protein-protein cross-linking can be achieved with minimal toxicity using eosin Y activated by visible light (eosin Y/visible).

At a molecular level, both eosin Y/visible and riboflavin/UVA are shown to act through a singlet oxygen mechanism; therefore, they are expected to produce similar covalent modifications of collagenous tissues. Real-time measurements of the increase in elastic modulus during irradiation show that the eosin Y/visible and riboflavin/UVA produce similar rates of cross-linking. The transport coefficients of both eosin Y and riboflavin were measured for both sclera and de-epithelialized cornea. The diffusivity and partition coefficient values, together with the cross-linking kinetics, were used in a predictive model of the cross-linking profile as a function of treatment parameters. The predictive model also serves as an optimization tool for guiding the selection of treatment parameters in pre-clinical studies. In contrast to the dramatic toxicity of the riboflavin/UVA treatment (which kills all of the keratocytes and the endothelium in the rabbit model), the eosin Y/visible treatment achieves comparable cross-linking with negligible phototoxicity.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Protein Cross-linking ; Cornea ; Sclera ; Keratoconus ; Singlet Oxygen
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemical Engineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Kornfield, Julia A.
Thesis Committee:
  • Kornfield, Julia A. (chair)
  • Tirrell, David A.
  • Davis, Mark E.
  • Schwartz, Daniel S.
Defense Date:6 May 2011
Record Number:CaltechTHESIS:05202011-143758537
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05202011-143758537
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6412
Collection:CaltechTHESIS
Deposited By: Joyce Huynh
Deposited On:01 Mar 2013 19:51
Last Modified:01 Mar 2013 19:51

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