Periodic Reporting for period 2 - MOON (Multi-modal Optical Diagnostics for Ocular and Neurodegenerative Disease) Reporting period: 2018-05-01 to 2019-10-31 Summary of the context and overall objectives of the project According to the Photonics21 strategic roadmap1 for 2014-2018 demographic changes in Europe will have drastic consequences for European citizens and their healthcare system as increased life expectancy will lead to a dramatic increase of age-related diseases. Reviewing the prevalence of major retinal diseases as well as major neurodegenerative diseases we observe both Age-related Macula Degeneration (AMD) and Alzheimer’s Disease (AD) as those with highest number of people being affected in Europe. MOON will focus on the development of two step-changing diagnostic imaging systems: the first (MOON 1) combines Optical Coherence tomography (OCT) and non-invasive OCT Angiography (OCTA) with an unprecedented large field of view, and diagnostic imaging quality, targeting early retinal disease diagnostics. The second system (MOON 2) is a multi-band and multimodal functional imaging platform for in-depth diagnostics of ocular and neurodegenerative diseases on a molecular level combining the chemical specificity of Raman spectroscopy with the structural and functional sensitivity of OCT. For this task novel light source technology, advanced Raman spectrometers, and multimodal test eyes will be developed. The diagnosis with the MOON technology will be fully non-invasive and non-contact through a simple scan of the retina. An important step will be the validation of the system in vivo in a clinical setting by closely involving clinical collaborators. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The highlights of the first reporting period are the testing of the MOON akinetic laser technology in OCT systems on healthy retinas, the finalizing of the MOON 1 demonstrator and the setup of the Raman reference database of biomarkers, and the setting up of the fluorescence channel of the multimodal imaging platform MOON2. The measurements with the akinetic laser source demonstrate the huge potential of this technology for high quality retinal imaging and OCT angiography. Although a physical scan of 100nm will be challenging, it is expected that the actual axial resolution enabled by the laser will be sufficient for in-vivo retinal diagnosis based on OCT and OCTA. This technology feeds directly into the MOON 2 demonstrator.The MOON1 demonstrator has been finalized and shipped to MUW for clinical validation. The demonstrator exhibits unique performance features when compared to commercially available OCT platforms. It covers large field of view of up to 90deg, supports greater than 1MHz laser sweep rates, operates at 1060nm center wavelength, has an active tracking system, allows for dual transverse resolution settings, and features OCT angiography. A full list of chemical Raman biomarkers has been compiled and spectroscopically characterized. A Raman reference database is stepwise being compiled and serves as backbone for the chemometric analysis of more complex spectra.The developed fluorescence system is optimized to target curcumin fluorescence. This food additive attaches to plaques in the brain and the retina, that are characteristic for AD, and allows visualizing those plaques in-vivo. Model eyes have been built to be particularly used for multimodal platforms and the coregistration of the various channels. It contains features visible in Raman spectroscopy, fluorescence imaging, and OCT.During the second reporting period the key milestone achievement was to demonstrate, that Raman spectroscopy can be applied to the human eye, given the constraints on laser power as applied to the eye, as well as the measurement duration, that should not exceed 30seconds. By the end of the second reporting period, the MOON 2 platform has been finalized, incorporating now, in addition to the fluorescence and OCT channels, the specifically designed Raman channel, as well as a tracking capability. The co-registration of the signal channels is supported by a novel eye phantom, mimicking the human retina, and including fluorescent as well as Raman spectroscopic features. Another key milestone achievement was to obtain the ethics clearance for the MOON1 system, which is a worldwide unique retinal OCT and OCT angiography imaging system allowing wide field of view Imaging without image stitching, with a high signal quality and easy handling that meets the standards of clinical imaging. After clearance by the national authority, clinical studies have already been started at MUW. The first clinical cases demonstrate impressively the clinical potential of the MOON 1 technology. 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) The development of compact akinetic high-speed swept source technology in MOON already represents a significant step beyond state of the art. Fast and phase stable light sources especially at the longer wavelength of 1060nm with the potential to become cheaper at large numbers are the key elements for the next generation optical coherence tomography (OCT) platforms. Wide field OCT angiography over a large field of view, that was up to recent only possible with planar fundus imaging techniques, is now recorded in a few seconds in 3D, with diagnostic image quality. This can further minimize the need for invasive, laborious, and risky fluorescein angiography. The retinal periphery has gained large clinical interest today, as early onset of diseases such as diabetic retinopathy but also signs of age related macula degeneration may be seen only in such enlarged field of view settings. This has immediate implications on the socio-economic system, as pathologic changes can be treated early on. The most intriguing advancement through MOON is to pave the way for obtaining molecular fingerprinting in the living human retina by using Raman spectroscopy. Combining Raman spectroscopy with OCT will on the one hand provide highly sensitive morphological features with OCT, on the other hand it is possible to target specific disease biomarkers by Raman spectroscopy. So far, standard Raman spectroscopy has not been shown in the human eye. Identifying molecular biomarkers of the selected diseases and setting up the protocol for establishing a reference data base sets a standard operation procedure for clinical Raman spectroscopy, that can be followed by addressing other major diseases after MOON. The multimodal MOON 2 platform is supported by a multimodal eye phantom, that has been developed within the MOON project. This eye phantom is not only a key asset for the MOON project, but might be of value for various other ophthalmic imaging platforms on the market. Especially also in view of the strict medical device regulations, having a phantom mimicking the optical properties of the human eye, simulating as well ametropic eye conditions, allows for validation but also as reference of commercial imaging platforms.If successful, MOON provides diagnostic tools that are easy to operate, easy to access, cost-effective, and allow for early diagnosis of disease onset, before the quality of life has been already reduced, irreversible damages are done, and treatment becomes ineffective. Already by delaying the onset of wet AMD or hospitalization for dementia patients by early diagnosis based on MOON there is an enormous cost saving potential for the European economy.