Periodic Reporting for period 4 - MIB (Multi-modal, Endoscopic Biophotonic Imaging of Bladder Cancer for Point-of-Care Diagnosis) Berichtszeitraum: 2020-07-01 bis 2021-12-31 Zusammenfassung vom Kontext und den Gesamtzielen des Projekts In the Western World bladder cancer is among the most expensive diseases in terms of treatment costs – each medical intervention requires days of hospitalisation and the recurrence rate is high (50%). New optical methods combined with knowledge of tissue and disease are now able to meet these challenges. The MIB objective was to enable a step-change in point-of-care diagnostics of bladder cancer through robust, easy-to-use, cost-effective optical methods with high sensitivity and specificity. The concept relied on combining optical methods – optical coherence tomography (OCT), multi-spectral opto-acoustic tomography (MSOT), Raman spectroscopy (RS), and multiphoton microscopy (MPM) – providing structural, biochemical and functional information. The target was to use four different modalities during examination. With this combination, quick and accurate diagnosis of bladder cancer is enabled, leading to an earlier onset of treatment. The step-change is that this hybrid concept is provided through cystoscopy (an endoscopic procedure inserting a device into the human body) examining the bladder. The consortium developed technology, including documentation and completed a first validation in a trial with patients successfully. Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse WP2 aimed to develop customised laser sources for the RS and MPM systems. The key results are a compact Ti:S mode-locked laser and Y-branch lasers for the Raman applications. The compact, tuneable source has been designed and undergoes final test before being deployed in the imaging application (MPM). WP3 aimed to design a rigid, angled endoscope with an integrated working channel as a cystoscope, and to design two in vivo fibre-probes of which one combines OCT, RS, and MSOT, and the second uses MPM for in vivo analysis of bladder tumours. A rigid cystoscope was developed. MIB decided to change the approach for the light delivery and imaging to piezo-tube based scanners, and to develop a piezo tube-based scanning unit for image acquisition. Through careful design the scanning probe was developed and being prepared for validation in clinical settings. Moreover, a probe for MPM was developed. The design was completed and first tests of the MEMS-based distal probe head scanning demonstrates the expected performance. WP4 aimed to combine the modalities and prepare an imaging platform of the different modalities of OCT, RS, MSOT, and MPM. The goal was to combine the modalities in a common and mobile platform; to perform in-vitro and ex-vivo testing; and to develop image co-registration algorithms. For all biopsies the histopathology report was available allowing a first statistical analysis of the performance: It was documented that OCT served for distinguishing early stage tumor from normal tissue and Raman served for distinguishing low grade from high grade tumor tissue. The results are predicative for developing multimodal probes and to co-register and correlate the complementary structural and molecular information. The RS and OCT platforms has been finalized and are ready to be used as mobile systems in a clinical setting. The other modalities, MSOT and MPM, critically depend on the probe development in WP3. It has proved to be a challenge to integrate our photoacoustic sensing method into the confined optical probe housing. Finally, while designing the clinical platforms for OCT and RS a considerable effort has been put into documenting the adherence to the Medical Device Regulations (MDR). WP5 concerns the clinical testing and clinical relevance. The preclinical protocol has been approved by the local ethical committee and data protection agreements signed. Biobanks with frozen biopsies from bladder tumour patients and healthy controls for in vitro studies have been established and first validation was successfully completed. The Raman system was approved by authorities and successfully deployed in a clinical study.In WP6, focus has been on completing The Technical Product Documentation (TPD) for the imaging platform, to ensure the legal framework for testing on humans. MIB decided to focus on preparing in vivo testing of the most mature methods.Several probes and imaging platforms are developed and available; OCT and RS will be further deployed in bladder cancer detection as well as the MPM probe. Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts) In current medical diagnostic procedures, biopsy and observing abnormal changes in tissue remain the golden standard; however, information needed for diagnosis takes days to obtain. Combining optical imaging and diagnostics offer great promise to address unmet clinical needs. A non-invasive optical imaging approaches enable earlier onset of treatment, reduced therapy costs, reduced recurrence rates and less patient discomfort. Up to now, the 4 optical methods at play were applied as standalone techniques, each targeting one biomarker. However, recently it has been shown that the clinical diagnosis is significantly improved by this multimodal biomedical imaging which comes closer to identifying how diseased tissue has developed, and at what stage it is in. And when it comes to cancer, or cellular-level functional imaging, it is being considered the next generation technology within diagnostics.By introducing new multi-modal optical imaging, the overarching vision is that MIB improves the diagnostic performance of bladder cancer allowing earlier onset of treatment and thereby reducing the recurrence rate by at least 10%, which currently is 50% after 12 months follow-up. Due to the currently high recurrence rate, there is a need for a high number of expensive follow-up procedures. By improving diagnosis and, therefore, reducing recurrence rate, the need for follow-up procedures is reduced, and patient quality of life will improve drastically.The project relies on the development of new compact light sources, high-speed imaging systems, and novel probes for endoscopes being combined and applied clinically. The consortium comprises world-leading academic organisations in a strong, unique partnership with innovative SMEs and clinical end-users. Although requiring further development, MIB has made significant progress in the technical development of the imaging platform, and, in addition, completed first steps towards validation with lab tests prior to the planned animal and human testing. The consortium conducted a clinical study successfully with patients using the developed technology. Combined OCT and Raman spectroscopy of human bladder tissue. OCT and Raman racks readied for clinical testing. RS: Back-end system, probe, nephroscope, and clinical study. MIB Impact.