Ultrasound-enhanced ocular delivery of dexamethasone sodium phosphate: An in vivo study

Background The eye\u27s unique anatomy and its physiological and anatomical barriers can limit effective drug delivery into the eye. Methods An in vivo study was designed to determine the effectiveness and safety of ultrasound application in enhancing drug delivery in a rabbit model. Permeability of a steroid ophthalmic drug, dexamethasone sodium phosphate, was investigated in ultrasound- and sham-treated cases. For this study, an eye cup filled with dexamethasone sodium phosphate was placed on the cornea. Ultrasound was applied at intensity of 0.8 W/cm2 and frequency of 400 or 600 kHz for 5 min. The drug concentration in aqueous humor samples, collected 90 min after the treatment, was determined using chromatography methods. Light microscopy observations were done to determine the structural changes in the cornea as a result of ultrasound application. Results An increase in drug concentration in aqueous humor samples of 2.8 times (p \u3c 0.05) with ultrasound application at 400 kHz and 2.4 times (p \u3c 0.01) with ultrasound application at 600 kHz was observed as compared to sham-treated samples. Histological analysis showed that the structural changes in the corneas exposed to ultrasound predominantly consisted of minor epithelial disorganization. Conclusions Ultrasound application enhanced the delivery of an anti-inflammatory ocular drug, dexamethasone sodium phosphate, through the cornea in vivo. Ultrasound-enhanced ocular drug delivery appears to be a promising area of research with a potential future application in a clinical setting

Microvessel rupture induced by high-intensity therapeutic ultrasound—a study of parameter sensitivity in a simple in vivo model

Safety analyses of transcranial therapeutic ultrasound procedures require knowledge of the dependence of the rupture probability and rupture time upon sonication parameters. As previous vessel-rupture studies have concentrated on a specific set of exposure conditions, there is a need for more comprehensive parametric studies. Probability of rupture and rupture times were measured by exposing the large blood vessel of a live earthworm to high-intensity focused ultrasound pulse trains of various characteristics. Pressures generated by the ultrasound transducers were estimated through numerical solutions to the KZK (Khokhlov-Zabolotskaya-Kuznetsov) equation. Three ultrasound frequencies (1.1, 2.5, and 3.3 MHz) were considered, as were three pulse repetition frequencies (1, 3, and 10 Hz), and two duty factors (0.0001, 0.001). The pressures produced ranged from 4 to 18 MPa. Exposures of up to 10 min in duration were employed. Trials were repeated an average of 11 times. No trends as a function of pulse repetition rate were identifiable, for either probability of rupture or rupture time. Rupture time was found to be a strong function of duty factor at the lower pressures; at 1.1 MHz the rupture time was an order of magnitude lower for the 0.001 duty factor than the 0.0001. At moderate pressures, the difference between the duty factors was less, and there was essentially no difference between duty factors at the highest pressure. Probability of rupture was not found to be a strong function of duty factor. Rupture thresholds were about 4 MPa for the 1.1 MHz frequency, 7 MPa at 3.3 MHz, and 11 MPa for the 2.5 MHz, though the pressure value at 2.5 MHz frequency will likely be reduced when steep-angle corrections are accounted for in the KZK model used to estimate pressures. Mechanical index provided a better collapse of the data (less separation of the curves pertaining to the different frequencies) than peak negative pressure, for both probability of rupture and rupture time. The results provide a database with which investigations in more complex animal models can be compared, potentially establishing trends by which bioeffects in human vessels can be estimated.https://doi.org/10.1186/s40349-017-0082-

Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study

PURPOSE: Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors’ previous in vitro and in vivo studies. METHODS: The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 °C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications of different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz–1 MHz, intensities of 0.3–1 W/cm(2), and exposure duration of 5 min, which were the parameters used in the authors’ previous drug delivery experiments. The baseline eye temperature was 37 °C. RESULTS: The authors’ results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 °C in the cornea, 39.5, 40, 42, and 43 °C in the center of the lens, and 37.5, 38.5, and 39 °C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. CONCLUSIONS: The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm(2) (parameters shown in the authors’ previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety of this method in the whole orbit especially regarding potential adverse optic nerve heating at the location of the bone

Ultrasound-enhanced delivery of antibiotics and anti-inflammatory drugs into the eye

Delivery of sufficient amounts of therapeutic drugs into the eye is often a challenging task. In this study, ultrasound application (frequencies of 400 KHz to 1 MHz, intensities of 0.3–1.0 W/cm(2) and exposure duration of 5 min) was investigated to overcome the barrier properties of cornea, which is a typical route for topical administration of ophthalmic drugs. Permeability of ophthalmic drugs, tobramycin and dexamethasone and sodium fluorescein, a drug-mimicking compound, was studied in ultrasound- and sham-treated rabbit corneas in vitro using a standard diffusion cell setup. Light microscopy observations were used to determine ultrasound-induced structural changes in the cornea. For tobramycin, an increase in permeability for ultrasound- and sham-treated corneas was not statistically significant. Increase of 46%–126% and 32%–109% in corneal permeability was observed for sodium fluorescein and dexamethasone, respectively, with statistical significance (p < 0.05) achieved at all treatment parameter combinations (compared with sham treatments) except for 1-MHz ultrasound applications for dexamethasone experiments. This permeability increase was highest at 400 kHz and appeared to be higher at higher intensities applied. Histologic analysis showed structural changes that were limited to epithelial layers of cornea. In summary, ultrasound application provided enhancement of drug delivery, increasing the permeability of the cornea for the anti-inflammatory ocular drug dexamethasone. Future investigations are needed to determine the effectiveness and safety of this application in in vivo long-term survival studies. (E-mail: [email protected]

Ultrasound-enhanced ocular delivery of dexamethasone sodium phosphate: An in vivo study

Background The eye\u27s unique anatomy and its physiological and anatomical barriers can limit effective drug delivery into the eye. Methods An in vivo study was designed to determine the effectiveness and safety of ultrasound application in enhancing drug delivery in a rabbit model. Permeability of a steroid ophthalmic drug, dexamethasone sodium phosphate, was investigated in ultrasound- and sham-treated cases. For this study, an eye cup filled with dexamethasone sodium phosphate was placed on the cornea. Ultrasound was applied at intensity of 0.8 W/cm2 and frequency of 400 or 600 kHz for 5 min. The drug concentration in aqueous humor samples, collected 90 min after the treatment, was determined using chromatography methods. Light microscopy observations were done to determine the structural changes in the cornea as a result of ultrasound application. Results An increase in drug concentration in aqueous humor samples of 2.8 times (p \u3c 0.05) with ultrasound application at 400 kHz and 2.4 times (p \u3c 0.01) with ultrasound application at 600 kHz was observed as compared to sham-treated samples. Histological analysis showed that the structural changes in the corneas exposed to ultrasound predominantly consisted of minor epithelial disorganization. Conclusions Ultrasound application enhanced the delivery of an anti-inflammatory ocular drug, dexamethasone sodium phosphate, through the cornea in vivo. Ultrasound-enhanced ocular drug delivery appears to be a promising area of research with a potential future application in a clinical setting

Surface Acoustic Wave devices for ocular drug delivery

In this work we are reporting on the development of a novel SurfaceAcoustic Wave (SAW) device based on MEMS technology for drug delivery in thetreatment of ocular diseases. The miniaturized SAW drug delivery device will beplaced on the eye surface to allow non-invasive long-term drug application basedon the programmed timeline and electronic control of a drug regiment. Thisnovel drug delivery method is expected to lead to better clinical outcomes inthe treatment of various eye diseases, and improved patient compliance withtherapy. The device can be programmed for delivery of precise amounts of drugsat predetermined times over several months, and will use acoustic streaming topush the drug outside of the reservoir. Our modeling results were obtained usingCOMSOL multiphysics program and Coventor microfluidic simulator. Differentforce values were applied to investigate the force necessary to push the drugthrough the outlet. © 2010 IEEE

Longitudinal Functional Assessment of Brain Injury Induced by High-Intensity Ultrasound Pulse Sequences

Exposure of the brain to high-intensity stress waves creates the potential for long-term functional deficits not related to thermal or cavitational damage. Possible sources of such exposure include overpressure from blast explosions or high-intensity focused ultrasound (HIFU). While current ultrasound clinical protocols do not normally produce long-term neurological deficits, the rapid expansion of potential therapeutic applications and ultrasound pulse-train protocols highlights the importance of establishing a safety envelope beyond which therapeutic ultrasound can cause neurological deficits not detectable by standard histological assessment for thermal and cavitational damage. In this study, we assessed the neuroinflammatory response, behavioral effects, and brain micro-electrocorticographic (microECoG) signals in mice following exposure to a train of transcranial pulses above normal clinical parameters. We found that the HIFU exposure induced a mild regional neuroinflammation not localized to the primary focal site, and impaired locomotor and exploratory behavior for up to 1 month post-exposure. In addition, low frequency (delta) and high frequency (beta, gamma) oscillations recorded by ECoG were altered at acute and chronic time points following HIFU application. ECoG signal changes on the hemisphere ipsilateral to HIFU exposure are of greater magnitude than the contralateral hemisphere, and persist for up to three months. These results are useful for describing the upper limit of transcranial ultrasound protocols, and the neurological sequelae of injury induced by high-intensity stress waves

Epidermal Electrode Technology for Detecting Ultrasonic Perturbation of Sensory Brain Activity

OBJECTIVE: We aim to demonstrate the in vivo capability of a wearable sensor technology to detect localized perturbations of sensory-evoked brain activity. METHODS: Cortical somatosensory evoked potentials (SSEPs) were recorded in mice via wearable, flexible epidermal electrode arrays. We then utilized the sensors to explore the effects of transcranial focused ultrasound, which noninvasively induced neural perturbation. SSEPs recorded with flexible epidermal sensors were quantified and benchmarked against those recorded with invasive epidural electrodes. RESULTS: We found that cortical SSEPs recorded by flexible epidermal sensors were stimulus frequency dependent. Immediately following controlled, focal ultrasound perturbation, the sensors detected significant SSEP modulation, which consisted of dynamic amplitude decreases and altered stimulus-frequency dependence. These modifications were also dependent on the ultrasound perturbation dosage. The effects were consistent with those recorded with invasive electrodes, albeit with roughly one order of magnitude lower signal-to-noise ratio. CONCLUSION: We found that flexible epidermal sensors reported multiple SSEP parameters that were sensitive to focused ultrasound. This work therefore 1) establishes that epidermal electrodes are appropriate for monitoring the integrity of major CNS functionalities through SSEP; and 2) leveraged this technology to explore ultrasound-induced neuromodulation. The sensor technology is well suited for this application because the sensor electrical properties are uninfluenced by direct exposure to ultrasound irradiation. SIGNIFICANCE: The sensors and experimental paradigm we present involve standard, safe clinical neurological assessment methods and are thus applicable to a wide range of future translational studies in humans with any manner of health condition