THESIS
2016
xviii, 137 pages : illustrations (some color) ; 30 cm
Abstract
Ultrasound-mediated transscleral delivery of high molecular weight compounds is
an emerging yet challenging technique for treating eye disease. Our group has
successfully demonstrated in live animal study that the application of 40 kHz ultrasound
with a mechanical index (MI) = 0.20 could overcome the ocular barriers to deliver
macromolecules into the eye. In this thesis, I mainly focus on: 1) exploring the effect of
ultrasound on the scleral collagen arrangement and its correlation to the transscleral
transport enhancement; 2) understanding the mechanism of the macromolecules
diffusivity enhancement during and after ultrasound by quantitative analysis using a
mathematical model; and 3) evaluating the effect of ultrasound on the barrier properties
and transport activities in the...[
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Ultrasound-mediated transscleral delivery of high molecular weight compounds is
an emerging yet challenging technique for treating eye disease. Our group has
successfully demonstrated in live animal study that the application of 40 kHz ultrasound
with a mechanical index (MI) = 0.20 could overcome the ocular barriers to deliver
macromolecules into the eye. In this thesis, I mainly focus on: 1) exploring the effect of
ultrasound on the scleral collagen arrangement and its correlation to the transscleral
transport enhancement; 2) understanding the mechanism of the macromolecules
diffusivity enhancement during and after ultrasound by quantitative analysis using a
mathematical model; and 3) evaluating the effect of ultrasound on the barrier properties
and transport activities in the retinal pigment epithelium cells in vitro.
Transscleral transport of macromolecules could be enhanced by ultrasound
without disturbing the scleral collagen network. Both low intensity and high intensity
ultrasound at 40 kHz did not induce statistical significant changes to the collagen fibril
arrangement in the scleral matrix. Ultrasound at the low intensity regime, i.e. stable
cavitation regime, was identified as the optimal regime to maximize the transport
enhancement along the transscleral route. The transport enhancement was most
significant during ultrasound application and was mainly due to the ultrasound-induced
chaotic mixing in the stable cavitation regime. As the MI of the system reached transient
cavitation regime, the partition of the BSA molecules was significantly enhanced. The
transport of macromolecules across the retinal pigment epithelium (RPE) cell layer was
achieved by temporary tight junction disruptions post sonication. 40 kHz ultrasound has
the most prominent effect on the temporary tight junction disruption and thus
significantly enhanced the transport of macromolecules across the RPE cells along the
paracellular pathways. In addition, folic transport across the RPE cells was upregulated
post sonication. Intracellular calcium concentration was transiently upregulated after
sonication, which could be the result of the activation of mechano-sensitive ion channels
in the cells by ultrasound.
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