Periodic Reporting for period 4 - MicroMOUPE (Microscopy - Making optimal use of photons and electrons) Reporting period: 2022-09-01 to 2023-08-31 Summary of the context and overall objectives of the project MICROMOUPE stands for ‘Microscopy – Making Optimal Use of Photons and Electrons’. The project aims at enhancing both light and electron microscopy, with a focus on interferometric microscopy techniques. In light optics, such techniques are typically used to study the morphology of cells. More recently it has been advanced to the detection and characterization of single proteins. In electron optics, interferometric techniques are used in cryogenic electron microscopy, one of the most successful techniques for the determination of the atomic structure of proteins. MICROMOUPE aims at enhancing the sensitivity of such techniques. Specifically, we want to maximize the information content obtained per interaction between the specimen under study and a probing particle (electron or photon). This would reduce the dose that is needed to achieve the required measurement accuracy, enabling faster, more accurate, or less damaging imaging of sensitive samples.We will develop an information theoretical description of interferometric imaging techniques. This will enable us to quantitatively compare existing interferometric microscopy techniques, and to predict optimized techniques that increase the information content per dose. Two experimental tools that are expected to enable such advances are adaptive optics, and cavity-enhanced measurements. We will explore such techniques experimentally, both with electrons and with photons as probe particles. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Major results of the project MICROMOUPE:1. We advanced the theoretical understanding of interferometric microscopy techniques: We have analyzed phase microscopy techniques based on the information-theoretical concepts of (Quantum) Fisher Information and (Quantum) Cramér-Rao Bounds (Q-CRB). The CRB enabled a quantitative comparison of the measurement precision that is possible using existing imaging techniques, such as phase contrast microscopy, holography, phase-stepping interferometry, interferometric scattering microscopy, coherent bright-field imaging, or darkfield microscopy. The Q-CRB gives an upper limit on the achievable precision and yields a gauge against which all techniques can be compared. Our results can be found in (Maestre et al., Phys. Rev. Appl., 15(2), 024047 (2021)), and in (Dong et al., J. Phys. D.: Appl. Phys., 54,39 (2021)). 2. We demonstrated reconfigurable quantum networks (S. Leedumrongwatthanakun, Nature Photonics, 14, pages139–142(2020).): In collaboration with Prof. Gigan (ENS Paris), we could show that wavefront shaping, in combination with the complex coupling provided within multimode fibers, can enable reconfigurable quantum networks. Specifically, we showed that specific quantum states can be realized at the output of a multimode fiber if the wavefront at the input was shaped appropriately. 3. We demonstrated ponderomotive electron beam shaping (Mihaila et al, Phys. Rev. X 12, 031043 (2022)): In light optics, advanced wavefront shaping techniques have enabled applications in imaging, astronomy, and quantum engineering (see above). In electron optics, on the other hand, wavefront shaping techniques are still in a proof-of-principle state. Within MICRMOUPE, we could show that an electron pulse can be shaped using intense laser pulses. Shaping the laser pulses prior to the interaction with the electrons allowed us to realize programmable, almost arbitrary electron beam shaping. Importantly, electron-light interaction is fully elastic and lossless, which sets it apart from other approaches to wavefront shaping. This realizes new degrees of freedom in electron optics, potentially enabling aberration correction, phase plates for phase microscope, or probe-engineering for ptychography. Note, that wavefront shaping is crucial to achieve the sensitivity limits described in point 1 above. 4. We envisioned a novel microscopy technique, which we call Optical Near-field Electron Microscopy (R. Marchand et al., Phys. Rev. Applied 16, 014008 (2021)). The technique is based on the photo-electric effect and combines the non-invasiveness of light microscopy with the spatial resolution enabled by electron optics. The idea we proposed is now pursued in an EIC-funded project (ONEM, ID 101017902), which we coordinate. The first experimental results already show the potential of the technique for label- and damage-free super-resolution microscopy. 5. We have contributed to designs for the world’s first Multi-pass Transmission Electron Microscope (MPTEM, M. Mankos et al., Advances in Imaging and Electron Physics, 212, 71-86 (2019)). MPTEM promises to reduce the dose-induced damage in electron microscopy by a factor of ~4, which could potentially enable the imaging of single alpha helices using electron microscopy. The prototype we designed is currently manufactured and will soon be installed in the lab of our collaborator Prof. Kasevich (Stanford University).6. We have developed a setup for fast and efficient fluorescent lifetime microscopy: Our work on optical multi-pass microscopy led to the development of electro-optic crystals that can be used to gate an image with nanosecond resolution. Based on this development we applied for an ERC proof-of-principle grant in order to develop super-resolution fluorescent lifetime imaging. The grant (EOFLIM) is still ongoing, but the first super-resolved FLIM data have been obtained and will be published soon. The technique improves the speed of FLIM by orders of magnitude, and thus also enables volumetric imaging and video-rate live-cell imaging. We believe that this technique provides exciting opportunities for the life sciences and for diagnostics. 7. We have also engaged in an outreach project that communicates science in an artistic way (E de Dios Rodríguez et al, Leonardo, 1-7 (2020)). Our work uses modern technology to image light propagating across everyday objects. Our work was shown in public talks, public installations, and outreach events. 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) MICROMOUPE led to advances in our understanding of microscopy (see #1 above), to technological advances (see #2, #3, #5, and #6 above) that enable microscopy techniques at unprecedented speed and sensitivity, and to a novel idea for label- and damage-free super-resolution microscopy (see #4 above). We are convinced that these developments will have an impact in physics, chemistry, and the life sciences. We will pursue several of these topics in follow-up projects after the end of MICROMPOUPE. capture_en.png
