Miniature High-Intensity Focussed Ultrasound Arrays for Targeted Drug Delivery

Lead Research Organisation: University of Strathclyde
Department Name: Electronic and Electrical Engineering

Abstract

There exists a wide range of therapeutic agents, including genetic material, proteins, and chemotherapeutic agents, whose function can only be fulfilled if they are deployed into specific location of the body. Thus, a targeted delivery approach would enhance the drug effectiveness. There is a spectrum of ultrasonic assistance methods for delivery of such agents, with this research project specifically concentrating on the design and implementation of a high intensity focussed array integrated into a needle assembly.

The PhD will encompass a broad range of technical challenges, with the primary objective to develop a prototype high power ultrasound (HPUS) needle fully characterised and evaluated using medical phantoms. The key work packages of the PhD research programme are:

1. Design and fabrication of the high power ultrasonic devices
2. Miniaturisation of the HPUS transducers
3. Integration of the transducers into needle assembly
4. Characterisation and evaluation of targeted delivery though imaging the area within a medical phantom
5. Maximizing the efficiency of the process while keeping the power output within appropriate medical safety limits

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509760/1 30/09/2016 29/09/2021
1859405 Studentship EP/N509760/1 30/09/2016 29/09/2020 Alexandru Corneliu Moldovan
 
Description I have designed, optimized, manufactured, characterized and tested in-vitro a series of miniature-sized ultrasonic transducers aimed to promote drug delivery to the surrounding tissues, potentially through sonoporation. The transducer dimensions were reduced so they could be incorporated into a capsule or catheter to perform therapy intracorporeally. One potential aim of the catheter transducer is to increase the uptake of chemotherapeutic drugs in solid liver tumors close to large blood vessels, which is difficult to achieve with a larger external transducer due to the liver position inside the rib cage. The transducer is a phased array capable of focusing the ultrasonic beam at various steering angles and depths in the targeted tissue. The sonicated area is thus increased compared to a single element transducer and the mechanical motion (and procedure invasiveness) of the catheter is reduced due to the steering capability of the array. The miniature arrays were incorporated in two different packages: the initial package was designed for in-vitro experiments, while the later package was designed as a capsule connected to a tether cable, intended for in-vivo trials on living pigs. Both types of transducers have been characterized in a scanning tank, with satisfactory results for therapeutic purposes. The in-vitro experiments on human colorectal cancer cells proved the transducer's ability to induce and control tissue damage/ decrease in barrier function, potentially through sonoporation. The in-vivo experiments, preceded by ex-vivo experiments are scheduled in the near future. The in-vivo experiments focus on targeted drug delivery in the small intestine.
Exploitation Route Academic: the transducers that I have developed can be used for in-vitro and in-vivo targeted drug delivery trials. Bio-medical industry: If the technology is patented, the capsule could be used for targeted drug delivery in the intestine.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Collaboration with Glasgow University 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been actively collaborating with the Medical & Industrial Ultrasonics research cluster at Glasgow University. I have manufactured a single element composite transducer for a BBSRC funded PhD student at Glasgow University for sonoporation purposes. I have also been offering support to the researcher with regards to transducer characterization, control and pressure/ power measurement. I have also taken part in a cavitation project with Dr Paul Prentice, lecturer at University of Glasgow which resulted in the submission of a paper to 'Ultrasound in Medicine and Biology'. The paper is currently under further revision by the journal editors.
Collaborator Contribution I have been co-supervised by Prof Sandy Cochran, who has kindly allowed me access to their transducer manufacturing capabilities, which has eased my transducer manufacturing process. I have also received invaluable training in using various pieces of equipment by staff working in Medical & Industrial Ultrasonics research cluster.
Impact A transducer manufactured and characterized by me for a BBSRC funded PhD student at Glasgow University for sonoporation research. I am co-author on a paper about acoustic emissions from microbubbles which is currently under review by 'Ultrasound in Medicine and Biology' journal.
Start Year 2016
 
Title Miniature Ultrasonic Phased Array for Internal Sonoporation 
Description I have manufactured a Miniature Ultrasonic Array for Internal Sonoporation, which can be potentially improved for performing internal hepatic sonoporation. This involved the development of a finite element analysis model to design and optimize composite piezoelectric transducer arrays for the purpose of therapeutic ultrasound. I then manufactured the phased array transducers using the traditional dice and fill technique and fitted them in two different packages: one for in-vitro experiments (designed to fit ThinCert cell wells), and the other one in form of a capsule transducer for in-vivo experiments in the porcine small bowel. I characterized the transducers' performance, with satisfactory results in terms of focusing, power output, and low self-heating. The in-vitro transducer was successfully tested in-vitro, while the in-vivo tests with the capsule transducer are scheduled to start next month. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2020
Development Status Under active development/distribution
Impact This device is intended to increase the absorption of various drugs in harder to reach tissues/ tumors like hepatic cancer by use of sonoporation. The ultrasound transducer is designed to ultimately fit into an 8-Fr catheter. The invasiveness of the procedure is reduced due to the phased array design of the transducer that allows to electronically steer and focus the ultrasonic beam. This in turn allows for greater tissue coverage than achieved with a single-element ultrasonic transducer, without the requirement of mechanical motion of the catheter, and better targeting of the tumor, while sparing the healthy tissue around. We performed an in-vitro trial that proved the miniature-sized phased array could control tissue damage/ the decrease in barrier function (potentially through sonoporation), not just produce it. Afterwards, I designed a capsule phased array transducer, connected to a tether cable, aimed for drug delivery in the small bowel.