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Holographic super-resolution micro-endoscopy for in-vivo applications

Periodic Reporting for period 3 - LIFEGATE (Holographic super-resolution micro-endoscopy for in-vivo applications)

Reporting period: 2020-11-01 to 2022-04-30

Microscopy can nowadays facilitate immensely detailed observations in living matter, but only in very limited depths. This is due to overwhelmingly complex organization of living matter, which makes tissues of all higher order organisms opaque. A variety of endoscopes can reach much deeper, the imaging quality is however always compromised and their usage in sensitive tissues such as the brain structures is often responsible for extensive tissue damage. Both life sciences - particularly neuroscience, as well as health-care would benefit immensely, if detailed observations are made possible through miniature endoscopes retaining the imaging capacity of the best light-based microscopes.
Funded by the European Research Council (ERC), LIFEGATE is a 5-years-project aiming to develop hair-thin endoscopic devices which can efficiently funnel a variety of advanced microscopic techniques through. They operate on entirely different principle when compared to standard endoscopes: Instead of quidding the image pixel-by-pixel in flexible fibre bundles or reforming the image periodically by single or multiple narrow lenses, they deliver the image information via a single optical fibre acting as a light quidding pipe. The light signals propagating through are entirely scrambled so they leave the fibre as randomly spatially distributed signals. The use of digital holography can control and reverse this randomizing process and enable delivery of light to the object under investigation in pure, unscrambled way. This relaxes many limitations in the construction of endoscopic imaging devices including the otherwise unavoidable compromises between the instrument’s footprint, working distance and the ability to see the detail. This however comes with several new challenges which must be addressed before this perspective concept becomes practical, a burden which LIFEGATE took on as its overarching objective.
Perhaps the largest impact of the ERC grant will be the successful implementation of holographic endoscopy which will bring about several new opportunities in the investigation of the complex processed of life matter as well as its impairments. Particularly in the domain of neuroscience, it will provide a new, minimally invasive window into fundamental processes behind sub-cellular-scale functional connectivity of neurons and onset of common disabling neuronal disorders such as Alzheimer’s disease. Separately in health-care environment, it will bring a new technological basis for keyhole clinical diagnostics, enabling intra-operative live histology and microsurgery, reaching currently inaccessible regions of the human body, while sending back images with sub-cellular resolution in-situ.
LIFEGATE is organized along four objectives. The first focuses on pushing the technological basis to its current limits, including finding and employment of the best holographic modulators and optical fibres, devising the most stable and compact optical geometries and compiling the computer control algorithms with the most efficient numerical approaches. The second objective extends the fundamental basis particularly by replacing complex calibration procedures by highly accurate modelling of light transport and crucially making the imaging performance immune to degradation caused by bending or twisting the optical fibre. The third aims to construct the first holographic endoscope suitable for the use in clinical environments and test its benefits in relevant conditions. The last objective aims to translate the holographic endoscopy into neuroscience providing imaging in large depths of sensitive structures of nervous system of living and fully functioning animal model.
Since the beginning of the project, we have constructed a number of optical geometries optimized for the variety of tasks proposed in LIFEGATE, featuring the fastest and the most accurate holographic modulators available on the market. We have developed the first version of a common programing basis utilizing the full extent of reachable performance in terms of speed and resolution, while paying a large attention to enabling translation and usage by non-specialists. Our fundamental research has identified several perspective approaches how to limit complex calibration procedures required by using every new segment of optical fibre and find previously unknown ways of making imaging performance immune to fibre deformation. We have constructed a compact holographic endoscope for clinical applications with the highest-ever speed and pixel-resolution, ready to be tested in relevant conditions. Finally, we have completed the first series of in-vivo observations in animal models visualizing neurons and their connectivity in neuronal circuits, thus confirming that the applicability of holographic endoscopy in in-vivo neuroscience is indeed feasible.
From the technological perspective, to the best of our knowledge we have already explored and deployed the best currently available technologies, particularly that of holographic light modulation and computing. Our light-shaping ability now reaches fidelity required even for highly demanding approaches of modern microscopy including super-resolution techniques. Our fundamental progress has reached the point, where constructions of holographic endoscopes tolerate bending deformations to a very large extent and so we envisage that after suitable engineering we will be able to apply holographic endoscopy even in motile animal models. The ERC project therefore reaches an intensive translational phase in both healthcare applications and in-vivo Neuroscience, where we no longer see any severe technological nor fundamental obstructions standing in the way. We have already identified a spectrum of the most suitable studies to be conducted, where the unique features of holographic endoscopy, making the largest difference upon to the state of the art will be exemplified.