Ultrasound-enhanced Delivery of Antibiotics and Anti-inflammatory Drugs into the Eye Open Access
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Delivery of sufficient amounts of therapeutic drugs into the eye in treatment of various ocular diseases is often a challenging task. This research describes applying ultrasound for increasing corneal permeability for several ocular drugs. As part of my PhD dissertation research, I have worked on developing procedures to find optimal ultrasound parameters to enhance ocular drug delivery while causing minimal changes in the corneal structure.Initial studies were carried out using flat ultrasound transducers in ultrasound- and sham-treated New Zealand rabbit corneas in vitro in a standard diffusion cell set-up. In these studies, ultrasound application (frequencies of 400 kHz-1 MHz, intensities of 0.3- 1.0 W/cm^2 , and exposure duration of 5 min) was tested to overcome the barrier properties of cornea. Permeability of ophthalmic drugs, Tobramycin and Dexamethasone Sodium Phosphate, and Sodium Fluorescein, a drug-mimicking compound, was investigated. Light microscopy observations of histology slides were used to determine ultrasound- induced structural changes in the cornea. Results showed an increase of 32-47% for Tobramycin, 46-126% (p<0.05) for Sodium Fluorescein, and 32-109% (p<0.05 except for 1-MHz ultrasound application) for Dexamethasone Sodium Phosphate in corneal permeability. Histological analysis showed some structural changes in the cornea due to ultrasound application, which were limited to epithelial layer, with no changes observed in stroma and endothelium.After in vitro studies were completed, an in vivo study on rabbit corneas was designed using the most effective parameters from in vitro experiments. In the in vivo studies, the eye cup filled with drug solution (Dexamethasone Sodium Phosphate) was placed on the cornea. Ultrasound at frequencies of 400 kHz and 600 kHz, intensity of 0.8 W/cm^2 , and exposure duration of 5 min was applied. Drug concentration in aqueous humor samples, collected after 90 min, was determined using chromatography methods. After animal was sacrificed, corneas were dissected and fixed for histology observations. Results showed that increase in drug concentration in aqueous humor samples was 2.8 times (p<0.05) at frequency of 400 kHz and 2.4 times (p<0.01) at frequency of 600 kHz, as compared to sham treated samples. Histological analysis showed that minor structural changes were present in first layers of corneal epithelium.Investigating the thermal and mechanical effects of ultrasound in enhancing ocular drug delivery showed that one of the key mechanisms was cavitation activity, especially presence of inertial cavitation.Theoretical simulations were performed using a finite element modeling software to further understand the temperature changes during ultrasound application and establish the safety of the proposed application. The maximum temperature was approximately 38.5°C and 39.5°C in the lens (increase of 1.5-2.5°C from base temperature of 37°C) at frequency of 400 kHz and 600 kHz respectively at 0.8 W/cm2 intensity. The simulation results showed that temperature was elevated at higher frequencies, and lens was the most affected eye structure.Ultrasound application provided enhancement of drug delivery, increasing the permeability of the cornea, and has a potential to provide effective and safe method for ocular drug delivery in treatment of eye infections and inflammations.
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