Periodic Reporting for period 2 - FBI (Multimodal, Functional Bio-Photonic Imaging) Reporting period: 2018-10-01 to 2021-03-31 Summary of the context and overall objectives of the project FBI aims to train and educate 15 fellows on emerging multimodal imaging modalities, translating these modalities from laboratory to clinical settings. The training was undertaken by a consortium, comprising 5 universities and 4 companies, led by Technical University of Denmark and involved an outstanding group of academic and industrial partners, in the early stage researcher’s training and forming of their skills. Pillars of this action have been the interdisciplinary relations between industry, technical sciences and clinical end-users provided during the project, a focal point has been the high-quality training activities and the programme of intersectoral secondments to both industry and hospitals. The translation of technology into applications is specifically emphasised through the implementation of an entrepreneurship programme involving all ESRs and members, particularly SMEs. The goal is to promote innovation and entrepreneurship among the ESRs and provide novel instrumentation for society to the benefit of human beings.Optical imaging has potential to address unmet clinical needs by combining non-invasive and real-time capture of biomedical information; thus reduce costs, recurrence rates, and improve clinical outcomes. FBI targets to:*) develop light sources that either enable new imaging modalities or have the potential to disruptively reduce cost of the light source for existing modalities. Sources for multimodal imaging based on supercontinuum generation are developed. Integration of sources into small packages for high-resolution, high-speed imaging based on semiconductors are designed and developed. Addressing compactness, novel pump sources concepts involving semiconductor lasers are investigated, linked to development of tunable femtosecond lasers.*) integrate and validate several imaging modalities into a common platform, including endoscopy. Image and data analysis are integral parts of imaging systems. Novel deep learning techniques are developed in order to classify abnormal intestinal tissue located in the big bowel or colon.*) develop multimodal imaging that can image volumetric, metabolic, electrical and mechanical changes in living systems at the sub-cellular level label-free. FBI has the ambitious aim of transferring the research and development results into applications, preferably into commercialisation for the benefit the European industrial sector. Thus, the ESRs have received training through a novel programme emphasising innovation and technology transfer. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far WP2: A source for multimodal imaging based on supercontinuum generation are developed (ESR1). Integration of sources into small packages for high-resolution, high-speed imaging based on semiconductors are designed, fabricated and tested (ESR2). Pump sources based on semiconductor lasers are investigated (ESR3), which links with the development of femtosecond lasers (ESR4).WP3: Three imaging modalities (MSOT, OCT and ultrasound) were researched and in summary achieved: 1) The implementation of a hybrid MSOT/OCT endoscopic system including illumination and detection units, validated for ex-vivo rotation hybrid endoscopic imaging of upper GI track large animal samples, and its demonstration in 3D fusion-visualizations of MSOT and OCT (ESR5). 2) The hybrid microscopy and mesoscopy optoacoustic imaging implementation developed in reflection mode, enabling large area screening followed by small area high-resolution imaging of selected regions of interest, and validated in in-vivo studies. (ESR7). 3) The novel implementation of a hand-held linear and endoscopic radial ultrasound despeckling approach, enabling unprecedented image contrast and quality, and its demonstration with phantoms mimicking lymph nodes in the GI track (ESR7). 4) An advanced inversion approach developed to enhance reconstruction optoacoustic imaging accuracy, and its validation with multi-frequency fusion analysis in pre-clinical studies (ESR6).WP4: The focus was on biomarkers, multimodal imaging platforms and their clinical validation including the integration of MPM, OCT, ultrasound and Raman spectroscopy. The envisaged medical imaging platforms employ developed laser technology from WP2 to realize a multimodal, multi-scale, molecular sensitive imaging engine applied to specific and sensitive tumour sensing and characterization. The platforms were based on a modified commercial surgical microscope as well as a newly developed microscopes, endoscopes and cystoscopes. ESR 8 developed a 1300nm swept source based OCT setup that was used for testing various iterations of forward imaging probes. ESR 9 developed a hybrid microscope platform combining OCT and Multi-Photon Microscopy (MPM). ESR 10 developed a multimodal OCT and fluorescence lifetime (FLIM) microscope in close collaboration with Zeiss for neuro-surgery. ESR 11 developed advanced machine learning algorithms for medical diagnosis. ESR 12 investigated minimally invasive surgery including image fusion obtained by fusing the 3D medical images of the patients, such as CTs and MRIs, on the endoscopic field of view, in close collaboration with Philips.WP5: The multimodal imaging device that could image volumetric, metabolic, electrical and mechanical changes in living systems label-free was developed. This device combined wide field, dark field and phase contrast imaging, with 4-point electrophysiological recordings, MPM and SHG. The chemical, physical and optical processes that underlie neurological activity and perform experiments on model membrane systems, components of cells (e.g. microtubules), various living cell culture in order to determine the relationship between optical signals and electrical, mechanical and structural changes, volumetric and metabolic activity, were investigated (ESR14-15). The microscope was further compacted by applying the novel ultrafast light source designed and developed (ESR13).WP6 and WP7: ESRs have been exposed to transferring their results into applications through a novel programme emphasising innovation and technology transfer. ESRs have with great enthusiasm taken part in seminars, technical meetings, coaching on entrepreneurship, and business-oriented activities, i.e. Summer School in entrepreneurship. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) FBI delivered new scientific achievements of high value for industry and society.In summary, the main achievements are:*) Novel, compact light sources and detection schemes fulfilling needs for adaptation into biological or clinical applications.*) Multimodal imaging systems, including special delivery probes, and ultra-high resolution, functional imaging applications surgical microscope platforms.In both cases some are transferred to industrial collaborators for commercialisation.*) Multimodal imaging platform for non-invasive functional recording of cellular activity.The ESRs participated in a total of 16 secondments at industrial partners thus enhancing the technology transfer to industry and the hospital sector.FBI succeed in promoting innovation and entrepreneurial behavior currently there is already 2 ESR’s who are working in spinout companies within the biomedical field.The developed technology and systems facilitate the application of optical imaging in clinical settings, thus strongly improving capabilities within cancer diagnostics, and in biological applications advancing understanding of diseases at the cellular level. Examples of FBI developed devices and results FBI logo
