Optimising Magnetic Susceptibility Mapping to Enhance MRI of Microbubbles

Microbubbles (MBs) are an established ultrasound contrast agent but there has been significant recent interest in developing them as a contrast agent for Magnetic Resonance Imaging (MRI). MRI of MBs is useful because of its potential for combined applications in targeted imaging for monitoring and guidance of focused ultrasound therapies and drug and gene delivery. So far, MRI of synthesized MBs has been based on decreases in the MRI signal magnitude. Here, I propose to detect MBs using MRI magnetic susceptibility mapping which uses the phase of the complex MRI signal in gradient-echo MRI sequences. MBs have a different susceptibility than tissue; therefore the central idea here is that MBs present in an area of tissue will change its susceptibility so that it stands out as a bright or dark area in a MRI susceptibility map. I am one of the pioneers of susceptibility mapping: a new method which offers several advantages over conventional magnitude-based imaging. Susceptibility maps promise to enhance MRI of MBs because they are calculated from phase images which have higher contrast-to-noise ratios than standard magnitude images. The contrast in susceptibility maps directly represents the intrinsic magnetic susceptibility in an area and therefore has the potential to measure the MB concentration in that area. The susceptibility of MBs can be selected and tailored for different clinical applications so that MBs create bright (positive) contrast in susceptibility maps. All these advantages of MRI susceptibility mapping mean that it would improve the clinical applicability of MBs as a dual-modality contrast agent for MRI and ultrasound. Susceptibility mapping could also enhance MRI guidance and monitoring of MB-mediated drug and gene delivery and MB-enhanced focused-ultrasound surgery which is currently in use for treating uterine fibroids and is being developed to treat liver, bone, prostate and brain diseases. An EPSRC First Grant will be a springboard for a research programme which will ultimately lead to the development of a broad range of optimised MRI susceptibility-based techniques for diagnostic and therapeutic applications in preclinical models of disease and clinical imaging.

In addition to academic beneficiaries, this research will have an impact on healthcare in the long-term. Clinicians and patients will benefit because this work will increase the impact of microbubbles (MBs) as dual-modality (MRI-ultrasound (US)), and eventually multi-modality, contrast agents. It will enable the complementary advantages of US and susceptibility-mapping-(SM)-enhanced MRI to be combined for comprehensive clinical imaging as well as MRI-guided focused US and MRI of US-mediated targeted gene and drug delivery. A single injection of a MB dual-contrast agent will be more convenient for patients and clinicians and could also reduce healthcare costs. The impact of MBs in all these clinical applications will be increased through the key advantages of the MB-highlighting MRI susceptibility mapping techniques developed here over conventional magnitude-based MRI of MBs.

This research will also benefit industrial (pharmaceutical) partners because it opens the possibility for MB producers to tailor-make MBs with susceptibilities tuned for specific clinical applications. The ability to produce MB gas cores and shells with different susceptibilities will pave the way for MRI susceptibility-mapping-based monitoring of drug delivery via release of MB contents through US or magnetic-field induced MB destruction. Dr Stride will produce prototype tailored MBs and will help to identify and approach industrial partners. These activities are pathways to future commercial fabrication of MBs with specific susceptibility contrasts tuned for clinical applications.

MRI manufacturers could benefit from the image processing tools for MRI susceptibility mapping developed in the proposed research. Together with colleagues in the Department's Centre for Medical Image Computing (CMIC), I will develop and optimise a software tool for MRI susceptibility mapping. We will discuss the potential for commercialisation with UCL Business and approach MRI scanner manufacturers (e.g. at the ISMRM conference) regarding incorporation of susceptibility mapping software into their products. UCL Business (UCLB) is a subsidiary of UCL that offers assistance with technology development, including intellectual property licensing and the creation of spinout companies and joint ventures.

Starting with the scientific and technical ideas outlined in this proposal, I will take the following steps to maximise the impact of the new techniques developed through this research, translate them into clinical practice and facilitate industrial exploitation:
1. Development of MRI SM techniques for MB detection (with EPSRC first grant).
2. Preclinical MRI SM of MBs (with EPSRC first grant).
3. First steps towards clinical application by optimisation of SM in humans and imaging MBs in phantoms at 3 Tesla clinical field strength (with EPSRC first grant).
4. Human Pilot Study of MRI SM of MBs: with regulatory and ethical approval and in collaboration with clinicians at UCLH, imaging a small number of patients (<20) who have already been injected with MBs for other clinical purposes (e.g. US diagnostic imaging).
5. SM software package development in collaboration with CMIC colleagues and potential industrial partners.
6. Approach commercial MB manufacturers (through Dr Stride and UCLB) to develop MBs with susceptibilities tuned for selected clinical applications of MRI SM.
7. Preclinical studies a) applying optimised MRI SM techniques in disease models b) studying functionalised MBs for diagnostic molecular imaging and therapeutic applications using MRI SM.
8. Multi-modality MB imaging: Extend MRI SM applicability through development and testing of MBs for multi-modality imaging in partnership with departmental colleagues.
9. Clinical study: pending successful results from the human pilot study , and potentially in collaboration with a MB manufacturer, MRI SM of MBs for a selected clinical application in a large number of patients (>50).