June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Mechanism of ultrasound-mediated transscleral delivery: temporary alteration of scleral structure increases permeability of macromolecules
Author Affiliations & Notes
  • Ying Chau
    Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
    Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
  • Wai-Leung Suen
    Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
  • Jun Jiang
    Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
  • Yan Zeng
    Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
  • Jianan Qu
    Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
    Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
  • Footnotes
    Commercial Relationships Ying Chau, None; Wai-Leung Suen, None; Jun Jiang, None; Yan Zeng, None; Jianan Qu, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1071. doi:
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    • Get Citation

      Ying Chau, Wai-Leung Suen, Jun Jiang, Yan Zeng, Jianan Qu; Mechanism of ultrasound-mediated transscleral delivery: temporary alteration of scleral structure increases permeability of macromolecules. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1071.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

We have proposed the use of low frequency ultrasound as a non-invasive approach to modulate the ocular barriers for transscleral drug delivery to the posterior segment of the eye. Using this approach, we observed significantly enhanced delivery in vivo. We hypothesize that ultrasound increases the porosity of scleral fiber network to allow improved diffusion of macromolecules. Here, we aim to understand the effect of ultrasound on sclera, the first barrier in the transscleral route of delivery.

 
Methods
 

The penetration of FITC-dextran of 70kDa through rabbit sclera was measured ex vivo with and without ultrasound. Sonication was applied directly above sclera at pre-designated frequency and intensity. Diffusivity was calculated by fitting the penetration profile, obtained by fluorescent microscopy of cryosectioned sclera, with 1-D diffusion equation. The collagen network structure of sclera was visualized dye-free using two-photon excitation microscopy (TPEM). Pore size of sclera was estimated by Renkin’s restricted diffusion model and textual analysis of TPEM images.

 
Results
 

Dextran penetrated deeper into ultrasound-treated sclera, confirming that the barrier function of the sclera was weakened by sonication (Figure 1a). The transscleral penetration distance increases with decreasing frequency, suggesting the role of cavitation. Diffusivity of dextran increased up to 8 times in sclera after low frequency sonication. The enhancement was temporary, with the scleral permeability restored in 3 hours (Figure 1b). TPEM image revealed that ultrasound disrupted the ordered alignment of collagen and increased the scleral pore size (Figure 2), agreeing with the prediction by Renkin’s model.

 
Conclusions
 

Low frequency ultrasound alters the collagen network structure of sclera to increase the porosity, thereby enhancing the diffusion of macromolecules through the outmost barrier in the transscleral route of delivery.

 
 
Figure 1. a) Penetration distance of 70 kDa dextran in 15 minutes in sclera immediately after sonication at the indicated frequency (n=3). b) Restoration of scleral permeability post ultrasound. Penetration distance of 70 kDa in 15 minutes in sclera at varying time lag after sonication at 40 kHz is shown (n=3).
 
Figure 1. a) Penetration distance of 70 kDa dextran in 15 minutes in sclera immediately after sonication at the indicated frequency (n=3). b) Restoration of scleral permeability post ultrasound. Penetration distance of 70 kDa in 15 minutes in sclera at varying time lag after sonication at 40 kHz is shown (n=3).
 
 
Figure 2. Two-photon excitation microscopy image (100 μm x 100 μm) of sclera before and after ultrasound treatment at 40 kHz.
 
Figure 2. Two-photon excitation microscopy image (100 μm x 100 μm) of sclera before and after ultrasound treatment at 40 kHz.
 
Keywords: 708 sclera • 666 pump/barrier function  
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