SBIR-STTR Award

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.

Public Health Relevance Statement:
Project Narrative 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.

NIH Spending Category:
Bioengineering; Biotechnology; Brain Cancer; Brain Disorders; Cancer; Neurosciences

Project Terms:
3-D; 3-Dimensional; Acoustic; Acoustics; Animal Experiments; Astrocytoma, Grade IV; Blood - brain barrier anatomy; Blood-Brain Barrier; Body Tissues; Bone structure of cranium; Brain; Brain Diseases; Brain Disorders; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Bypass; Caliber; Cancers; Cell Communication and Signaling; Cell Signaling; Cells; Clinical; Clinical Research; Clinical Study; Coloring Agents; Common Rat Strains; Compensation; Confidential Information; Convection; Cranium; Data; Development; Devices; Diagnosis, Ultrasound; Diameter; Diffusion; Disease; Disorder; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drugs; Dyes; Echography; Echotomography; Effectiveness; Encephalon; Encephalon Diseases; Encephalons; Evaluation; Financial compensation; Focused Ultrasound; Focused Ultrasound Therapy; Forecast of outcome; Frequencies (time pattern); Frequency; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioblastoma; Glioma; Goals; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Hemato-Encephalic Barrier; High Power Focused Ultrasound; Implant; In Vitro; Infusion; Infusion procedures; Intracellular Communication and Signaling; Intracranial CNS Disorders; Intracranial Central Nervous System Disorders; Label; Laboratories; Lead; Length; Malignant Neoplasms; Malignant Tumor; Mammals, Rats; Marketing; Medical; Medical Imaging, Ultrasound; Medication; Methods; Methods and Techniques; Methods, Other; Metric; Microbubbles; Modeling; Names; Needles; Neoplasms of Neuroglia; Nervous System Diseases; Nervous System, Brain; Neuroglial Neoplasm; Neuroglial Tumor; Neurologic Disorders; Neurological Disorders; Outcome; Patients; Pb element; Penetration; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Physiologic pulse; Position; Positioning Attribute; Pressure; Pressure- physical agent; Principal Investigator; Prognosis; Pulse; Rat; Rattus; Research; SBIR; SBIRS (R43/44); Shapes; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skull; Small Business Innovation Research; Small Business Innovation Research Grant; Spottings; System; System, LOINC Axis 4; Techniques; Technology; Testing; Therapy (Focused US); Time; Tissues; Transducers; Treatment Efficacy; Tumors of Neuroglia; Ultrasonic Imaging; Ultrasonogram; Ultrasonography; Ultrasound Test; Ultrasound, Medical; base; biological signal transduction; cranium; diagnostic ultrasound; disease/disorder; drug/agent; experiment; experimental research; experimental study; glioblastoma multiforme; heavy metal Pb; heavy metal lead; improved; in vivo; malignancy; nano particle; nanoparticle; neoplasm/cancer; nervous system disorder; neurological disease; new technology; outcome forecast; pre-clinical; preclinical; pressure; public health relevance; research study; response; sonogram; sonography; sound measurement; spongioblastoma multiforme; therapeutic efficacy; therapeutically effective; therapy outcome; time use; tissue trauma; tumors in the brain; ultrasound; ultrasound imaging; ultrasound scanning

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.

Thesaurus Terms:
3-D;3-Dimensional;Acoustic;Acoustics;Animal Experiments;Astrocytoma, Grade Iv;Blood - Brain Barrier Anatomy;Blood-Brain Barrier;Body Tissues;Bone Structure Of Cranium;Brain;Brain Diseases;Brain Disorders;Brain Neoplasia;Brain Neoplasms;Brain Tumors;Bypass;Caliber;Cancers;Cell Communication And Signaling;Cell Signaling;Cells;Clinical;Clinical Research;Clinical Study;Coloring Agents;Common Rat Strains;Compensation;Confidential Information;Convection;Cranium;Data;Development;Devices;Diagnosis, Ultrasound;Diameter;Diffusion;Disease;Disorder;Drug Delivery;Drug Delivery Systems;Drug Targeting;Drug Targetings;Drugs;Dyes;Echography;Echotomography;Effectiveness;Encephalon;Encephalon Diseases;Encephalons;Evaluation;Financial Compensation;Focused Ultrasound;Focused Ultrasound Therapy;Forecast Of Outcome;Frequencies (Time Pattern);Frequency;Glial Cell Tumors;Glial Neoplasm;Glial Tumor;Glioblastoma;Glioma;Goals;Grade Iv Astrocytic Neoplasm;Grade Iv Astrocytic Tumor;Hemato-Encephalic Barrier;High Power Focused Ultrasound;Implant;In Vitro;Infusion;Infusion Procedures;Intracellular Communication And Signaling;Intracranial Cns Disorders;Intracranial Central Nervous System Disorders;Label;Laboratories;Lead;Length;Malignant Neoplasms;Malignant Tumor;Mammals, Rats;Marketing;Medical;Medical Imaging, Ultrasound;Medication;Methods;Methods And Techniques;Methods, Other;Metric;Microbubbles;Modeling;Names;Needles;Neoplasms Of Neuroglia;Nervous System Diseases;Nervous System, Brain;Neuroglial Neoplasm;Neuroglial Tumor;Neurologic Disorders;Neurological Disorders;Outcome;Patients;Pb Element;Penetration;Performance;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Physiologic Pulse;Position;Positioning Attribute;Pressure;Pressure- Physical Agent;Principal Investigator;Prognosis;Pulse;Rat;Rattus;Research;Sbir;Sbirs (R43/44);Shapes;Signal Transduction;Signal Transduction Systems;Signaling;Site;Skull;Small Business Innovation Research;Small Business Innovation Research Grant;Spottings;System;System, Loinc Axis 4;Techniques;Technology;Testing;Therapy (Focused Us);Time;Tissues;Transducers;Treatment Efficacy;Tumors Of Neuroglia;Ultrasonic Imaging;Ultrasonogram;Ultrasonography;Ultrasound Test;Ultrasound, Medical;Base;Biological Signal Transduction;Cranium;Diagnostic Ultrasound;Disease/Disorder;Drug/Agent;Experiment;Experimental Research;Experimental Study;Glioblastoma Multiforme;Heavy Metal Pb;Heavy Metal Lead;Improved;In Vivo;Malignancy;Nano Particle;Nanoparticle;Neoplasm/Cancer;Nervous System Disorder;Neurological Disease;New Technology;Outcome Forecast;Pre-Clinical;Preclinical;Pressure;Public Health Relevance;Research Study;Response;Sonogram;Sonography;Sound Measurement;Spongioblastoma Multiforme;Therapeutic Efficacy;Therapeutically Effective;Therapy Outcome;Time Use;Tissue Trauma;Tumors In The Brain;Ultrasound;Ultrasound Imaging;Ultrasound Scanning