MEMS-enabled miniaturised multimodal microscopy through pulsed structured illumination

The build-up of antimicrobial resistance is developing to become one of the biggest modern health challenges, one that has emerged over the last decade and places a significant threat on modern day medical treatments. While fantastic research in deciphering build-up and interaction mechanisms between cells and micro-organisms that lead to drug resistance are ongoing, tool-kits to evaluate, image and visualise these interactions in real-time 3D environments and with subcellular resolution are limited to very well-funded research labs and central facilities. While access to these is enabled in the UK through time requests in grant applications, the possibility to have systems in situ and in an environment that fosters biological development would present a significant potential to leverage further research momentum and invention to tackle this wide ranging significant health challenge.

In this proposal, miniaturised 3D imaging systems with super-resolution capability will be developed, allowing to resolve samples beyond the physical diffraction limit based on active optical microsystems and 3D-printing. This will allow the creation of small scale and portable systems which could drastically alter the access gap and costs currently present in state-of-the art subcellular biomedical imaging systems, both in research as well as in pre-clinical settings. We seek to address this by combining fluorescence and acoustic based imaging modalities, enabling high-throughput investigations through multi-modal parallel systems which can show new insights in the behaviour of microbial-cell interactions and antimicrobial resistance development.

By creating fluorescence and acoustic super-resolution imaging systems in a combined small-scale form factor, the complimentary information content from both imaging techniques will be characterised and evaluated. From initial system designs an iterative improvement process with feedback from biomedical researchers will be followed to have multiple cycles of development, design, fabrication and test to create a targeted miniaturised super-resolution system that can significantly help solving problems of antimicrobial resistance build-up.

The primary objective is a centimetre scale 3D super-resolution system with active micro-optics for full digital control of the imaging content, with the research also looking at novel resolution and information fusion potentials of the complementary imaging modalities, generating real-time process information for end-users. The outcome of this research project will advance significantly the availability of state-of-the-art biomedical imaging systems in environments on national and international level, specifically for large scale parallel investigations and lower funded labs, as present in many developing countries.

The proposed research will develop miniaturised multimodal 3D super-resolution biomedical imaging systems utilising 3D-printing and active micro-optics, which will significantly increase the functionality and capability of light-sheet based biomedical imaging techniques through complimentary signal contrast detection and drastically reduce the costs of state-of-the-art techniques through the mentioned cost-effective micro-optics and 3D-printing.

The usefulness of the developed systems will be demonstrated with trials including Leishmaniasis parasite-host interaction pathways investigations and further antimicrobial resistance scenario investigations, creating multiple impacts by leveraging the use of a portable, cost-effective, dual modality imaging system that is tailored for the envisaged investigations and can be used with commonly used sample preparation techniques in biomedical sciences. Anticipated results will directly benefit the international academic community in biomedical imaging research, end-users who are investigating cell-scale dynamics with long-term interaction processes, and have a potential for industry benefit through leveraging the industrial exploitation of the novel approach to super-resolution small-package system design.

The project goal of generating an imaging system with subcellular resolution and multiple contrast mechanisms has direct application potential across a wide range of biomedical science, plant science and developmental biology research areas, harnessing access to the technology for insight into subcellular dynamics/interactions, which leverages impact on the UK society through addressing healthcare challenges. It also raises the development potential into applying the systems for research questions looking into neglected infectious diseases which disproportionally affect developing countries.

Further beneficiaries on the academic side are anticipated through the multidisciplinary approach to benefit both engineering and biomedical research communities in the form of the development of a super-resolution concept with simultaneous feature evaluation and adaptable sample excitation through the use of active micro-optics, allowing for a significant reduction of data storage requirements by automatically classifying and recording of only sample areas of interest. This has the potential to further cross-fertilise the associated disciplines, raising the potential to use the developed systems in new environments through the miniaturisation, with future potential for pre-clinical and clinical applications.

All staff involved (PI, post-doc, students, and collaborators) will gain knowledge and a significant skills improvement on aspects ranging from microscope system design and miniaturisation, miniaturised optics integration, image processing techniques, and 3D-printed hardware design, all the way to system application tests. By engaging with collaborators in developing countries through this proposal and the PI's framework of a RAEng Engineering for Development Research Fellowship, the system deployment and exposure in an international context will be addressed with an additional significant impact on the developing partners research landscape.