Modeling light delivery into the rat eye for two-photon excitation photodynamic therapy treatment of age-related macular degeneration.

摘要

The research presented here was conducted in order to develop a model of light delivery to the retina for the treatment of Age-Related Macular Degeneration (ARMD) with Two-Photon Excitation Photodynamic Therapy (TPE-PDT). Here I discuss why an animal model is needed and which animal, out of three candidates, is most suited for such a project. I also investigate the effects of monochromatic aberrations and second order dispersion on the femtosecond laser pulses required for TPE as well as the effect of monochromatic aberrations on the quality of images of ocular structures. The animal model of this thesis will be supported by the experimental measurements obtained of wavefront aberration using a modified Hartmann-Shack (HS) aberroscope (Kisilak, 2005) and retinal imaging using a Confocal Scanning Laser Ophthalmoscope (CSLO).; Two schematic models of the rat eye with a gradient refractive index in the crystalline lens have been re-constructed in ZEEMAX(TM). These models predict the monochromatic aberrations as a function of pupil size and field angle and the change in the Point Spread Function (PSF) at differing focal planes. This information is used to determine the optimal pupil size for two-photon effects as well as the optimal pupil size for imaging the retina. The spread of light at the retina both laterally and in depth was also modeled. A simple water model of the nonlinear pulse broadening effect has been used to predict the minimal temporal pulse width that will propagate to the retina and the amount of pulse broadening. Experimentally, Long Evans (pigmented) and Sprague Dawley (albino) rats were both lightly restrained for ocular wavefront error measurement. The Long Evans rats were also sedated with ≤0.09 mL of somnotol (65 mg/mL). CSLO images of the eyes of awake Sprague Dawley rats were also acquired.; In a rat eye uncorrected for monochromatic aberration, a 1.65mm diameter pupil (spherical shell model (SSM)) and a 1.85 mm diameter pupil (elliptical shell model (ESM)) deliver a peak intensity acceptable for two-photon effects. A 1.75mm diameter pupil (SSM) and a 2.05 mm diameter pupil (ESM) however give an optimum full width at half height for imaging on the optical axis, in agreement with CSLO measurements on one rat. The models also agree with experimental results for one out of three rats for HS wavefront measurements. Correction of the monochromatic aberrations with adaptive optics would improve both imaging and peak intensity and potentially allow a treatment volume of 4.5 mum 3. The effect of second order dispersion is dependent on the form of the dispersion relation used. Based on theoretical approximations of second order dispersion, the minimum pulse width to reach the retina is approximately 30fs for the rat eye and approximately 60fs for the human eye.; The rat is a good choice for the development of an in vivo application of TPE-PDT for the treatment of ARMD. The optimum pupil size for TPE differs than that for optimum imaging in the uncorrected eye. Adaptive optics correction would give a significant advantage, allowing a larger pupil size to be used for light delivery with improved intensity localization and improved imaging.