CBET-0644713 Konofagou The project will determine the range of intensities, frequencies and other parameters of focused ultrasound (FUS) that can be used to temporarily (i.e. reversibly) open the blood brain barrier (BBB) without concomitant thermal or mechanical damage to neurons and endothelial and other tissues. The preliminary work of the PI has demonstrated that via focused ultrasound (FUS) one can open the BBB in a controlled manner. The project will explore the possibilities under which the BBB can open reversibly, noninvasively, and with regional selectivity using FUS. The specific aims are: 1) understand transcranial ultrasound propagation and induced biological effects through an in-depth theoretical analysis; 2) Investigate the mechanisms under which FUS induces reversible BBB opening in hippocampal cells in vitro; and 3) Characterize the FUS method for optimized drug delivery in wildtype and Alzheimer's-disease affected mice. The project addresses very challenging topic-reversibly opening BBB and combines mathematical models to predict the localization of FUS and in vitro and in vivo experiments.
The project utilizes ultrasound energy to temporarily open the blood brain barrier without damaging any tissue. Such modality would have a broad impact for treatments of central nervous system (CNS) diseases. The educational aims include introduction of a new course based on therapeutic use of ultrasound and ultrasound/tissue interaction and use of industrial internship at a graduate level.
Due to the impermeability of the blood-brain barrier (BBB), neurological disorders and all age-related neurodegenerative diseases remain untreatable despite the thousands of pharmacological agents available. The objective of this study was to establish the neurotherapeutic potential of trans-BBB delivery using Focused Ultrasound. A secondary objective is to develop a first prototype for transcranial FUS in humans. The goals of this CAREER proposal were to 1) help integrate my interests in medical ultrasound with the important area of drug delivery, 2) leverage my extensive prior work in therapeutic ultrasound, therefore expediting the progress and impact of my research, 3) launch a new course in biomedical engineering, that will constitute a link between two of the three tracks of the department at Columbia, 4) mentor female students that already constitute the majority in the biomedical engineering department; and 5) permit the utilization of my close ties with industrial researchers, providing students with a well-rounded perspective on biomedical ultrasound and therapeutics in industry as well as internship opportunities. The three primary research objectives of this CAREER proposal were to: 1) gain a fundamental understanding of transcranial ultrasound propagation and induced biological effects through an in-depth theoretical analysis; 2) investigate on the mechanisms under which FUS induces reversible BBB opening in hippocampal cells in vitro for r; and 3) discover the FUS method for optimized drug delivery in wildtype and Alzheimerâ€™s-disease affected mice. Despite the recent significant advances in neurotherapeutics, of the more than 7000 small-molecule drugs developed, only five percent treat the Central Nervous System (CNS). Therefore, mainly due to the impermeability of the BBB, potentially devastating CNS disorders and all age-related neurodegenerative diseases, such as Alzheimerâ€™s disease, Parkinsonâ€™s disease and amythrophic lateral scleroswas (ALS), remain untreatable. Safe and localized opening of the BBB has been proven equally challenging. Of those that have been shown effective, none can induce both non-invasive and localized BBB opening. Intellectual merit: Through this CAREER project, 1) fundamental understanding of transcranial ultrasound propagation as well as the mechanisms of BBB opening in vivo will be established; 2) both the ultrasound-induced thermal and mechanical effects will be studied through an in-depth theoretical analysis, in vitro and in vivo validation; and 3) through this thorough understanding, the feasibility of an in vivo ultrasound-based drug delivery system will be explored that will target and open the BBB in a certain brain region affected by disease in order to facilitate transport of pharmacological agents. Broad impact: Should the proposed technique be shown feasible in vivo, 1) already designed drug compounds with previously poor BBB permeability might finally be able to reach the region affected by the CNS disease they were designed to treat. The FUS technique may thus been proven pivotal for the advance of neurotherapeutics. In addition, 2) the proposed project should not only contribute to the teaching, training and learning of students within and across the fields of medical physics and biomedical engineering but also 3) significantly advance the current status of the clinical field of neurotherapeutics. More specifically, in conjunction with the research activities described, a program in therapeutic ultrasound will be developed within the Department of Biomedical Engineering at Columbia University.