The main objective of this SBIR Phase I application is to demonstrate the feasibility of a novel technology for focusing ultrasound based on time-reversal acoustics (TRA) principle to improve the effectiveness of convection-enhanced delivery (CED) of drugs to the brain. CED is a promising method of drug delivery to the brain for the treatment of several disorders. CED bypasses the blood-brain barrier by infusing compounds through a needle or microcatheter directly into brain parenchyma or brain tumor. The infusion establishes a pressure gradient in the tissue that drives a flow of infusate away from the needle. Preclinical and clinical studies suggest that the outcome of the therapy depends strongly on the diffusion rate and extent of penetration of the drug into the brain. It has been shown that dramatic increase of the penetration depth can be obtained by combining the CED with focused ultrasound. In vivo focusing of ultrasound in the brain is complicated because of the irregular shape of the skull which distorts the acoustic wave front. TRA principles allow for compensation of any kind of acoustic wave front distortion and provide efficient focusing in composite heterogeneous media, especially within closed reverberating cavities, such as in the skull. A miniature piezotransducer attached to tip of the needle used for injecting the drug, acts as a beacon necessary for accurate focusing of ultrasound to exactly the region where the drug is injected. Highly accurate focusing of ultrasound using the TRA principle minimizes the exposure of healthy tissue to high intensity ultrasound. The goal of the proposed research is to develop an acoustic device for ultrasound-enhanced therapy for several brain disorders that can ultimately be used in a clinical setting. Optimal ultrasound exposure parameters will be determined in order to achieve the maximum enhancement of the penetration of the infusate with minimum damage to healthy cells. The performance of the TRA focusing system and enhancement of infusate penetration will be tested in tissue mimicking phantoms and in animal experiments in vivo.

Public Health Relevance

The long-term goal of this project is to develop, build and bring to the market an acoustic system for highly accurate focusing ultrasound to selected sites in the brain to improve convection enhanced drug delivery, which is a promising new therapy for the treatment of brain disorders, including brain tumors. The technology developed in the project will improve the efficacy of the therapy, which eventually should lead to better outcomes in patients suffering from a variety of brain malignancies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-ETTN-D (13))
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Fertig, Stephanie
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Artann Laboratories, Inc.
United States
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Olbricht, William; Sistla, Manjari; Ghandi, Gaurav et al. (2013) Time-reversal acoustics and ultrasound-assisted convection-enhanced drug delivery to the brain. J Acoust Soc Am 134:1569-75
Lewis Jr, George K; Schulz, Zachary R; Pannullo, Susan C et al. (2012) Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly: laboratory investigation. J Neurosurg 117:1128-40
Lewis Jr, George K; Guarino, Sabrina; Gandhi, Gaurav et al. (2011) Time-reversal Techniques in Ultrasound-assisted Convection-enhanced Drug Delivery to the Brain: Technology Development and In Vivo Evaluation. Proc Meet Acoust 11:20005-20031