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Overcoming the Limits of Diffraction with Superresolution Lighting on a Chip

Periodic Reporting for period 1 - ChipScope (Overcoming the Limits of Diffraction with Superresolution Lighting on a Chip)

Reporting period: 2017-01-01 to 2018-12-31

The physical laws of diffraction generally limit the spatial resolution of optical systems, being about 250 nm for light in the visible range. That is the reason why we usually cannot directly observe virus, single proteins or molecules with conventional optical microscopes. Attempts to overcome this limit have led to “super-resolution” techniques, like STED, STORM, PALM, NSOM, etc., all of them based on bulky optical systems and complex sample preparations.
The principle of ChipScope is different. Instead of using optical elements to obtain superresolution, in ChipScope we will use a set of light sources so small that are well below the diffraction limit. In ChipScope we will develop arrays of semiconductor nanoLEDs with a pixel-to-pixel spacing of less than the diffraction limit that can be turned on independently. This will be a leap forward in extreme miniaturisation.
ChipScope will revolutionize optical microscopes with superresolution capabilities, making them chip-sized, simple, affordable and ubiquitously available, not only for laboratories working in manifold research fields, but also in everyday life.
The first challenge of ChipScope is downscaling the size of existing technology on GaN LEDs by a factor ~100, in order to address the problem of sub-diffraction resolution. The second challenge is operating these nanoLED arrays at a high refresh rate, in full synchronization with a CMOS light sensor capable of detecting one single photon, in order to produce ‘real time’ images of molecular and biological events. Finally, the third challenge deals with the advanced theoretical studies regarding the fundamental physics of light-matter interaction at such small scale that will serve us to better understand the further potential and limitations of the ChipScope approach.
Within the project, the first chip-sized ‘Chip-Scopes’ will be developed, tested, calibrated and compared with state-of-the-art microscopy systems. ChipScope will prove the concept by using a real-time imaging device to study the in-cell mechanisms in a wide-spread disease called Idiopathic Pulmonary Fibrosis (IPF), a chronic age-related lung disease killing 0.5 Million people each year worldwide.
WP1. NanoLED array realization
TUBS has successfully fabricated, characterized, and demonstrated a prototype of 8 x 8 microLED array with pixel size of 5µm (Led1), and achieved progress for ongoing fabrication of the 16 x 16 LED array of 400 nm (Led2) employing photo- and e-beam lithography, respectively.

WP2. Theoretical modelling and image reconstruction
UNITOV formulated the design guidelines for the nanoLEDs based on the electrical models and optical simulations with TUBS. Also, UNITOV has made simulation of the similar realistic setups of the whole integrated system, as well as simulation of pinhole LEDs, and emission optimized structures to address the cross-talk between pixels in order to improve the device designs.
YMAGING starts their work on image processing for object reconstruction from the simulation results provided by UNITOV.

WP3. Microscope system integration
First generation of the driving electronics integrated using FPGA technology with existing CMOS SPAD (ASIC) from UB (Det1) were developed by UB. Additionally, the second generation of the driving electronics for Det2 was and is being tested. UB designed and fabricated additional integrated detectors as well.
The first version of the microscope setup (Mic1), composed by Det1 + Led1 has begun to be assembled and tested at UB facilities. In parallel, YMAGING designed the first version of the graphic user interface, with calibration and image reconstruction capabilities, and started to test the software (Sof1) with the microscope hardware (Mic1).

WP4. Microscope test and calibration
Novel test samples based on DNA origami are being developed by LMU, in order to adapt the size and structures of DNA origami nanorulers for the needs ChipScope, improving the brightness of DNA origami reference samples.

WP5. Proof-of-concept application: real-time imaging of living tissues
First design for setting up a fully automated microfluidic handling system for in vitro cultivation of biological cells by AIT. In parallel, MUW studied the influence of light emitting diode (LED) generated light on living cells which were cultivated in common cell culture microtiter plates integrated withLED array TUBS, and have also tested bio-compatiblity of different surfaces conditions presents in ChipScope microscope.

WP6. Exploitation, Dissemination and Communication
The decision structures were established during the kickoff meeting.
The Dissemination and Exploitation Plan was established and numerous communication activities have been done led by FSRM, taking in care the Intellectual Property.
Two public workshops have been organized by FSRM, a Interdisciplinary Workshop, during the kickoff meeting in Barcelona (Spain) and 'European Initiatives for the Next Generation of Nanoscopies in Biosciences Workshop' in the frame of the international conference Eurosensors2018 in Graz (Austria).
Also, the Industry Advisory Board has been established, which includes 8 members from industrial companies and research institutes.

WP7. Coordination and Management
The management of ChipScope has gone as expected, with the partners working actively on the project, centralizing all the documentation and meeting regularly.
The First Project Document and Open Research Data Database has been established, as well as the Data Management Plan.
The ChipScope approach to superresolution based on nanoLED arrays has, to our knowledge, 100% novelty. The viability of the ChipScope concept can only be studied and proven if a sufficiently small array of independently addressable light sources is fabricated, which is the key breakthrough to address in this project. In addition, we require to have video in ‘real time’ video capabilities. For that reason, ChipScope needs fast control of individual nanoLEDs, a major challenge considering the small sizes of the nanoLEDs with a pixel-to-pixel spacing of less than the diffraction limit.
The interplay between sub-wavelength nanoLEDs with nanoscale objects under investigation, as well as the interplay between far-field and near-field patterns, and their influence on the performance of the ChipScope approach is not known yet. This is fundamental problem that must be investigated in the theoretical activities of the project.
The intrinsic risk of the ambitious challenges ahead. However, the high risk is counterbalanced by the huge impact on our society if optical microscopy with would become massively available as a chip, even if we do not achieve superresolution. Due to the possibility of a high volumehigh-volume production based on semiconductor technology, ChipScope will open the door to widespread usage of sub-diffraction optical technology in every laboratory and also in everyday life, e.g. for personal health monitoring or point-of-care detection of pathogens for disease diagnostics and monitoring. In the future, this kind of analysis can revolutionize how medical diagnosis and drug development are carried out, e.g. making possible direct imaging and analysis of damaged tissues or pathogens in the point-of-care or even at home. All this without forgetting that numerous additional novel applications can already be envisaged in diverse fields like nanofabrication, optical computing, and communications, etc.
Basic principle of the ChipScope approach