Model for Porosity Changes Occurring during Ultrasound-Enhanced Transcorneal Drug Delivery

Hariharan, Prasanna; Nabili, Marjan; Guan, Allan; Zderic, Vesna; Myers, Matthew R.

doi:10.1016/j.ultrasmedbio.2017.01.013

Cited by 11 publications

(5 citation statements)

References 32 publications

(40 reference statements)

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“…In a previous modeling study, 5.5 minutes of ultrasound treatment time was observed to be the length of time for the human eye model to reach the desired cumulative drug concentration. 38 Further, a previously published in vitro study which utilized ultrasound parameters similar to our current parameters showed that 5 minutes of ultrasound application enhanced the delivery of small molecules through the cornea without any significant corneal damage. 23 Therefore, we have selected 5 minutes of treatment time in the current study.…”

Section: Methodssupporting

confidence: 63%

“… 50 , 51 The most critical mechanism in corneal transport is the diffusion of compounds in the epithelium, namely, the porosity. 38 In addition to cavitation, ultrasound-induced thermal changes may play a role in enhancing corneal permeability, although they raise a safety concern. 34 Our previous ocular thermal safety modeling studies that utilized similar ultrasound parameters demonstrated maximal temperature increases in the cornea of 1.0°C at 400 kHz and 1.5°C at 600 kHz with intensities of 1.0 and 0.8 W/cm 2 , respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Further, our approach is the first to utilize smURFP molecules in ocular applications. Although we have published on application of ultrasound in enhancing corneal drug delivery, 23 , 24 , 35 , 38 our previous work was only focused on small molecules, and this is our first study with macromolecules.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic Ultrasound for Topical Corneal Delivery of Macromolecules

Almogbil

Montecinos-Franjola

Daszynski

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose The objective of this study was to utilize therapeutic ultrasound in enhancing delivery of topical macromolecules into the cornea. Methods Rabbit corneas were dissected and placed in a diffusion cell with a small ultra-red fluorescent protein (smURFP; molecular weight of 32,000 Da) as a macromolecule solution. The corneas were treated with continuous ultrasound application at frequencies of 400 or 600 kHz and intensities of 0.8 to 1.0 W/cm 2 for 5 minutes, or sham-treated. Fluorescence imaging of the cornea sections was used to observe the delivery of macromolecules into individual epithelial cells. Spectrophotometric analysis at smURFP maximal absorbance of 640 nm was done to determine the presence of macromolecules in the receiver compartment. Safety of ultrasound application was studied through histology analysis. Results Ultrasound-treated corneas showed smURFP delivery into epithelial cells by fluorescence in the cytoplasm, whereas sham-treated corneas lacked any appreciable fluorescence in the individual cells. The sham group showed 0% of subcellular penetration, whereas the 400 kHz ultrasound-treated group and 600 kHz ultrasound-treated group showed 31% and 57% of subcellular penetration, respectively. Spectrophotometry measurements indicated negligible presence of smURFP macromolecules in the receiver compartment solution in both the sham and ultrasound treatment groups, and these macromolecules did not cross the entire depth of the cornea. Histological studies showed no significant corneal damage due to ultrasound application. Conclusions Therapeutic ultrasound application was shown to increase the delivery of smURFP macromolecules into the cornea. Translational Relevance Our study offers a clinical potential for a minimally invasive macromolecular treatment of corneal diseases.

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Section: Methodssupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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Therapeutic Ultrasound for Topical Corneal Delivery of Macromolecules

Almogbil

Montecinos-Franjola

Daszynski

et al. 2022

Trans. Vis. Sci. Tech.

Self Cite

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“…In a previous modeling study, 5.5 minutes of ultrasound treatment time was observed to be the length of time for the human eye model to reach the desired cumulative drug concentration. 58 The ultrasound transducer was then removed, and the rabbit sclera was incubated for 55 minutes in the water bath at 34.6°C. A total of 60 minutes of drug exposure was applied for both ultrasound- and sham-treated cases; however, ultrasound-treated samples were first exposed to ultrasound for 5 minutes at the beginning of drug exposure.…”

Section: Methodsmentioning

confidence: 99%

Feasibility of Therapeutic Ultrasound Application in Topical Scleral Delivery of Avastin

Almogbil

Nasrallah

Zderic

2021

Trans. Vis. Sci. Tech.

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Purpose Macromolecules have been shown to be effective in vision-saving treatments for various ocular diseases, such as age-related macular degeneration and diabetic retinopathy. The current delivery of macromolecules requires frequent intraocular injections and carries a risk of serious adverse effects. Methods We tested the application of therapeutic ultrasound as a minimally invasive approach for the delivery of Avastin into the diseased regions of the eye. Avastin (bevacizumab) is an anti-vascular endothelial growth factor (VEGF) antibody with a molecular weight of 149 kDa. We tested the effectiveness and safety of Avastin delivery through rabbit sclera in vitro using a standard diffusion cell model. Ultrasound at frequencies of 400 kHz or 3 MHz with an intensity of 1 W/cm 2 was applied for the first 5 minutes of 1-hour drug exposure. Sham treatments mimicked the ultrasound treatments, but ultrasound was not turned on. Absorbance measurements of the receiver compartment solution were performed at 280 nm using a spectrophotometer. Results Absorbance measurements indicated no statistical difference between the sham ( n = 13) and 400 kHz ultrasound group ( n = 15) in the delivery of Avastin through the sclera. However, the absorbance values were statistically different ( P < 0.01) between the 3 MHz ultrasound group (0.004, n = 8) and the matched sham group (0.002, n = 7). There was 2.3 times increase in drug delivery in the 3 MHz ultrasound when compared to the corresponding sham group. Histological studies indicated no significant damage in the ultrasound-treated sclera due to ultrasound application. Conclusions Our preliminary results provided support that therapeutic ultrasound may be effective in the delivery of Avastin through the sclera. Translational Relevance Our study offers clinical potential for a minimally invasive retinopathy treatment.

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“…A part of OSEL's mission is to improve CDRH's ability to evaluate medical devices and support the regulatory approval of innovative medical devices more efficiently without sacrificing safety. Therefore, some of the research efforts involve demonstrating through examples that the output from computational modeling is a viable source of regulatory-grade evidence , i.e., sufficiently-credible digital evidence that can support regulatory applications ( 43 – 45 ); developing frameworks ( 46 , 47 ) and metrics ( 48 ) for assessing the trustworthiness of models, and studying workflows for creating reproducible models 11 ( 48 ), and identifying considerations for computational patient models for autonomous medical devices ( 49 ).…”

Section: Computational Modeling Researchmentioning

confidence: 99%

Advancing Regulatory Science With Computational Modeling for Medical Devices at the FDA's Office of Science and Engineering Laboratories

et al. 2018

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Protecting and promoting public health is the mission of the U.S. Food and Drug Administration (FDA). FDA's Center for Devices and Radiological Health (CDRH), which regulates medical devices marketed in the U.S., envisions itself as the world's leader in medical device innovation and regulatory science–the development of new methods, standards, and approaches to assess the safety, efficacy, quality, and performance of medical devices. Traditionally, bench testing, animal studies, and clinical trials have been the main sources of evidence for getting medical devices on the market in the U.S. In recent years, however, computational modeling has become an increasingly powerful tool for evaluating medical devices, complementing bench, animal and clinical methods. Moreover, computational modeling methods are increasingly being used within software platforms, serving as clinical decision support tools, and are being embedded in medical devices. Because of its reach and huge potential, computational modeling has been identified as a priority by CDRH, and indeed by FDA's leadership. Therefore, the Office of Science and Engineering Laboratories (OSEL)—the research arm of CDRH—has committed significant resources to transforming computational modeling from a valuable scientific tool to a valuable regulatory tool, and developing mechanisms to rely more on digital evidence in place of other evidence. This article introduces the role of computational modeling for medical devices, describes OSEL's ongoing research, and overviews how evidence from computational modeling (i.e., digital evidence) has been used in regulatory submissions by industry to CDRH in recent years. It concludes by discussing the potential future role for computational modeling and digital evidence in medical devices.

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Model for Porosity Changes Occurring during Ultrasound-Enhanced Transcorneal Drug Delivery

Cited by 11 publications

References 32 publications

Therapeutic Ultrasound for Topical Corneal Delivery of Macromolecules

Therapeutic Ultrasound for Topical Corneal Delivery of Macromolecules

Feasibility of Therapeutic Ultrasound Application in Topical Scleral Delivery of Avastin

Advancing Regulatory Science With Computational Modeling for Medical Devices at the FDA's Office of Science and Engineering Laboratories

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