Determining the Role of Microbubbles in Sonoporation through Numerical Simulations

Lead Research Organisation: University of Manchester
Department Name: Mechanical Aerospace and Civil Eng

Abstract

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.

Planned Impact

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.

Publications


10 25 50
 
Description We have developed a predictive software tool that calculates the flow and deformation associated with bubble and biological cell interaction.
This work has provided initial insight into the response of cells to nearby bubble dynamics. For example, the cell 'blebbing' phenomenon may result principally from non-local hydrodynamic response in the cell due to adjacent bubble dynamics, rather than from internal cell biochemistry.
Exploitation Route Findings may be used by experimentalists, developers and practitioners to further understand and eventually optimise the behaviour of microbubbles in the human body for robust and effective targeted drug delivery.
Sectors Pharmaceuticals and Medical Biotechnology
URL http://www.sciencedirect.com/science/article/pii/S0301932216301975
 
Title Bubble data set 
Description Results from bubble modelling software 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact No impact yet. 
 
Title bubble computational model 
Description Computational model for viscoelastic bubble dynamics 
Type Of Material Computer model/algorithm 
Year Produced 2016 
Provided To Others? Yes  
Impact No impact yet. 
 
Description Leeds Microbubble Consortium 
Organisation University of Leeds
Department School of Electronic and Electrical Engineering Leeds
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Developing modelling tool for microbubble dynamics
Collaborator Contribution Provision of experimental data for validation
Impact No outputs yet
Start Year 2014
 
Title bubble open source code 
Description software for predicting bubble dynamics in multiphase viscoelastic fluids 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact No impact yet. 
URL https://github.com/bubbles-manchester
 
Description AERC (Nantes) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Dissemination of latest project developments.
Year(s) Of Engagement Activity 2015
 
Description Applied Maths Conference (China) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Interesting discussion with audience members and subsequently links formed with colleagues in Beijing University.
Year(s) Of Engagement Activity 2015
 
Description Invited lecture at Leeds Microbubble Symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Dissemination of work on numerical modelling to experimentalists and industry users/practitioners, with attendees from all over the world. Keynote talk given and poster presented. Fruitful discussions took place potentially opening avenues to collaboration on future projects.
Year(s) Of Engagement Activity 2016
URL http://www.microbubbles.leeds.ac.uk/home/news/news-item/article/annual-microbubble-symposium.html
 
Description Invited talk to Cardiff fluids group/discussion with Prof TN Phillips 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Dissemination of research developments to Cardiff University fluids group. Active discussion following talk. Separate discussion undertaken with Prof Phillips on future collaboration and related research opportunities.
Year(s) Of Engagement Activity 2016