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Multimodal, Functional Bio-Photonic Imaging

Periodic Reporting for period 1 - FBI (Multimodal, Functional Bio-Photonic Imaging)

Reporting period: 2016-10-01 to 2018-09-30

FBI aims to train and educate 15 fellows on emerging multi-modal imaging modalities, translating these modalities from laboratory to clinical settings. The consortium, comprising 5 universities and 4 companies, is led by Technical University of Denmark and involves an outstanding group of academic and industrial partners in the early stage researcher’s training and forming of their skills. Pillars of this action are the interdisciplinary relations between industry, technical sciences and clinical end-users provided during the project, the high-quality training activities and the programme of intersectoral secondments, including to hospitals. The translation of technology into biomedical applications is specifically emphasised through the implementation of an entrepreneurship programme involving all ESRs and members, particularly SMEs.

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 the development of tunable femtosecond lasers.
*) implement multi-spectral opto-acoustic tomography (MSOT) into endoscopy, closely linked with integration into the imaging platform. The performance of MSOT is dependent on the ultrasound transducer and, therefore, its characterisation on spatial field resolution is crucial.
*) integrate several imaging modalities into a common platform and its validation. 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. This platform combines wide field, dark field and phase contrast imaging, with 4-point electrophysiological recordings, MPM and SHG. It allows studying detailed functional cell activity on model membrane systems or various cell lines in living culture in order to determine the relationship between optical signals and electrical, mechanical and structural changes, volumetric and metabolic activity.

FBI has the ambitious aim of transferring the research and development results into applications, preferably into commercialisation. Therefore, the ESRs receive training through a novel programme emphasising innovation and technology transfer.
The work is divided into 4 technical workpackages (2 – 5), one training workpackage (6) and one dissemination and exploitation workpackage (7). The achievements are:

WP2: Sources 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 and first tests carried out (ESR2). Pump sources based on semiconductor lasers are investigated (ESR3), which links with the development of tunable femtosecond lasers for imaging (ESR4).

WP3: Experimental imaging frameworks and novel algorithms for MSOT image improvement have been developed (ESR6). Construction of an endoscope-like bench top scanner for hybrid acoustic-resolution optoacoustic and optical coherence tomography (OCT) mesoscopy imaging, and an optical-resolution optoacoustic microscopy imaging system using a GRIN lens coupled to a single-mode fibre for light delivery have been obtained (ESR5). Good spatial resolutions of ultrasound transducers are demonstrated from preliminary measurements on excised mouse ears (ESR7).

WP4: The focus is on biomarkers and delivery probes. First data on a 1300 nm swept source-based OCT setup is reported and used with endoscope probes, manufactured and characterized in FBI (ESR8). Tomograms are presented showing ability to resolve different layered structures within biological tissue. First ex-vivo images are obtained taken from bladder biopsies. Our progress shows that the imaging platform is ready for an ex-vivo study to further evaluate and test diagnostic capability (ESR8). Initial results using a hybrid microscope combining Optical Coherence Microscopy (OCM) and Multi-Photon Microscopy (MPM) are presented, including spectrally resolved MPM detection. Preliminary data showing images of Zebrafish larvae has been demonstrated (ESR9). Initial results on a multimodal surgical microscope for neurosurgical guidance show great promise. OCT and Fluorescence lifetime imaging (FLIM) both enable real time acquisition and processing as demonstrated. These important results were obtained during a secondment at CZM, and ex vivo measurement on brain biopsies are planned (ESR10). Initial results on image and data analysis using deep learning techniques are obtained and additional efforts are planned to improve our automatic training algorithm. These new concepts may be applied to fuse different modalities (ESR11). First steps to develop a method for image fusion on endoscopic view aimed to improve neurosurgical procedures have been taken, based on existing Philips surgical navigation system. Preliminary tests are carried out and first investigations on image fusion using a skull phantom have been initiated (ESR12).

WP5: The combined MPM/SHG microscope for high-resolution imaging has been built and preliminary tests show fascinating results (ESR14,15), evidenced by a recent publication in the highly-ranked journal Science (ESR15). The microscope is further compacted by applying the novel ultrafast light source designed and developed (ESR13).

WP6 and WP7: ESRs have received training and been exposed to transferring their results into applications through a novel programme emphasising innovation and technology transfer. ESRs have taken part in seminars, technical meetings, and business-oriented activities, i.e. Summer School in entrepreneurship. For the remainder of FBI, these skills will be expanded through additional workshops, schools, and personal coaching, which would install entrepreneurial spirit and knowledge – leading to new medical devices benefitting health-care for patients.
FBI holds great promise that new scientific breakthroughs and methods will arise when combining technologies into new concepts. The specific research objectives of FBI are:
*) Develop novel, compact light sources and detection schemes fulfilling needs for adaptation into biological or clinical applications
*) Develop new multimodal imaging systems including special delivery probes for deep tissue imaging applications and ultra-high resolution, functional imaging applications including their validation
*) Unprecedented, non-invasive functional recording of cellular activity

The developed technology and systems furthermore facilitate the application of optical imaging in clinical settings, thus strongly improving capabilities within cancer diagnostics, and in biological applications advancing understanding of diseases, such as Alzheimer’s disease.
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