Determining the Role of Microbubbles in Sonoporation through Numerical Simulations

For over 100 years the damaging capabilities of collapsing bubbles and cavities have been known. Originally, the focus of research was on maritime applications, but today the fields of interest are far more wide ranging. In recent years, there has been a great deal of interest in sonoporation - the process of increasing cell permeability through the application of ultrasound to enable the delivery of large molecules, such as genes and drugs, to cells for the purposes of gene therapy or cancer treatment. A number of benefits over other therapeutic techniques have been proposed, and, consequently, a large body of experimental research (both in vitro and in vivo) continues to make progress in understanding and developing the procedure. It is well-known that the presence of microbubbles in the treatment region greatly enhances the efficacy of the procedure. However, the precise role of the microbubbles is poorly understood. Indeed, a detailed study of the interaction of multiple bubbles with adjacent cellular matter is extremely difficult to perform experimentally, especially within in vivo environments. To aid a complete understanding of the fluid mechanical processes involved, a computational modelling tool is needed to provide accurate simulations which can be controlled in a precise and cost-effective manner unavailable to experiment. However, the complexity of these processes is such that many of the popular computational and mathematical modelling approaches fall short in providing accurate predictions of the dynamics. With this in mind, this research project will develop a computational modelling tool capable of providing robust and accurate quantitative predictions of bubble dynamics relevant to the sonoporation process (specifically, multi-bubble dynamics near a deformable biological surface). This work will extend a pre-existing mathematical model and numerical method developed by the author and collaborators for solving multiphase viscoelastic flow problems. The overall aim is to ascertain (in a quantitative sense) the relative importance of the various fluid mechanical mechanisms that occur during microbubble-enhanced sonoporation. This investigation addresses the dearth of mathematical and computational research in this area, and will facilitate a complete understanding of the sonoporation process. The important insights and output from this project will play a fundamental role in the long-term development of a viable clinical procedure.

The long-term aim of this research is clear: to inform the development of a viable clinical procedure through a complex modelling capability that provides accurate and robust numerical simulations of in vivo scenarios. Given the proposed benefits of sonoporation in providing cost effective, non-invasive, and targeted cancer and gene therapy treatments, the potential long-term societal and economic benefits (that would result from the improved quality of life and health of citizens) are great. The beneficiaries and impact pathways directly arising from this project, which are crucial to the long-term aim, are outlined below.
Academic beneficiaries: Academic impact activities are critical in the short term to achieve longer term economic and societal impact. Biomedical scientists/engineers will benefit directly from the findings of the proposed research, which will inform the development of experimental methodologies and sonoporation techniques and thereby accelerate the development of viable clinical procedure. In addition to dissemination through bioscience journals and conferences, the impact of this research will be promoted through the forging of new collaborative links with experimental biomedical scientists/engineers in the UK. This will likely result in cross-disciplinary research partnerships that will serve to increase the UK's competitiveness and reputation as a world-leader in sonoporation research. It is also possible that the output from this project will eventually stand alongside other computational tools and form part of a virtual clinical trial capability on whole organ/body systems, for use by researchers and clinicians.
Commercial beneficiaries: The findings of this project will be of interest to the commercial developers of ultrasound contrast agents (UCAs). UCAs are in clinical use and enhance the images produced following ultrasound procedures. Commercial companies manufacturing UCAs (such as GE Healthcare) will be interested in the output of this project (including the software), which can offer insights into their research and development of improved UCAs for imaging and targeted drug delivery applications. The PI will work closely with the Research and Knowledge Exchange department (an MMU organisation dedicated to supporting the transition of academic enterprises into the commercial, public, and third sector) to explore and initiate potential commercial opportunities. A one day workshop will also be organised towards the end of this project to which the relevant commercial and academic parties will be invited. Besides fostering external collaboration, this event will explore the potential commercial exploitation and clinical benefit of the project output.
The General Public: The PI undertakes several outreach and public engagement activities a year, both independently and in his role as a committee member of the North-West branch of the Institute of Mathematics and its Applications (IMA). The economic and societal impact of inspiring young people to become scientists/mathematicians arguably outweighs all other impact pathways. Based on previous years, impact activities will likely include IMA-endorsed public and school presentations on the PI's research into bubble dynamics (including the output from this project), and CPD seminars for secondary school science teachers. These activities will be complemented by the ongoing online dissemination and feedback via social networking sites, Twitter, Facebook, and YouTube, in addition to the research group homepage.