MEMS-enabled miniaturised multimodal microscopy through pulsed structured illumination

抗菌素耐药性的积累正在发展成为现代健康面临的最大挑战之一，这一挑战在过去十年中出现，并对现代医学治疗构成重大威胁。虽然在破译导致耐药性的细胞和微生物之间的积聚和相互作用机制方面的出色研究正在进行中，但在实时3D环境中以亚细胞分辨率评估，成像和可视化这些相互作用的工具包仅限于资金充足的研究实验室和中央设施。虽然在英国，通过拨款申请中的时间要求可以获得这些系统，但在原位和促进生物发展的环境中拥有系统的可能性将为利用进一步的研究动力和发明来应对这一广泛的重大健康挑战提供巨大的潜力。在这项提案中，将开发具有超分辨率能力的三维成像系统，允许基于主动光学微系统和3D打印来解析超出物理衍射极限的样品。这将允许创建小规模和便携式系统，这可以大大改变目前在研究和临床前环境中最先进的亚细胞生物医学成像系统中存在的访问差距和成本。我们试图通过结合基于荧光和声学的成像模式来解决这个问题，通过多模式并行系统实现高通量研究，这些系统可以显示微生物-细胞相互作用行为和抗菌素耐药性发展的新见解。通过在组合的小规模形状因子中创建荧光和声学超分辨率成像系统，将对来自两种成像技术的补充信息内容进行表征和评估。从最初的系统设计开始，将遵循一个根据生物医学研究人员反馈的迭代改进过程，进行多个开发、设计周期，制造和测试，以创建一个目标明确的超分辨率系统，可以显着帮助解决抗菌素耐药性的建立问题。主要目标是一个厘米级的3D超分辨率系统，具有主动微，该研究还着眼于互补成像模式的新分辨率和信息融合潜力，为最终用户生成实时过程信息。该研究项目的成果将大大提高国家和国际环境中最先进的生物医学成像系统的可用性，特别是对于大规模并行研究和低资金实验室，如许多发展中国家。

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.