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SYNTOH Report Summary

Project ID: 655888
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - SYNTOH (Synthetic Optical Holography)

Reporting period: 2016-01-11 to 2018-01-10

Summary of the context and overall objectives of the project

Microscopy is an indispensable tool in research, medicine and industry that enables the inspection of objects that are otherwise too small to see with the naked eye. But detailed view on biological objects, for example, is tremendously important: Microscopy allows to identify structure within cells and tissues, which made it a vital instrument for modern molecular and cell biology. The 2014 Nobel price award to Betzig, Moerner and Hell for super-resolved fluorescence microscopy is a clear signal that continuous development in the field of microscopy is recognized and essential for research that relies on microscopy.

This project, SYNTOH, seeks to develop and facilitate phase imaging, an emerging imaging modality in microscopy with applications in biology, medicine and manufacturing. In a typical microscopy application, contrast is generated by light absorption in the sample, which however requires staining to reveal structure in biological specimen. But light also experiences subtle shifts in the light wave’s phase as it passes the specimen. This yields rich information on the sample, which, however, is typically lost in recording process. The phase information can be retrieved by interferometry, and research has shown that this opens up new avenues in biological imaging. For example, cell structure can be revealed similar to images in fluorescence microscopy, the gold standard of imaging modalities in biology, without the need for time-consuming staining of the samples. However, current methods of phase imaging are slow or expensive.

Synthetic optical holography is the core technology being developed in this project. It provides a fast, technological simple and cost effective way to perform phase imaging in confocal microscopy. The goal is to verify our technology by imaging relevant biological specimen, and to develop and demonstrate a concept of an add-on module for existing microscope setups. To this end, we will also work on the theory of our technology to develop new algorithms and to solve current limitations.

Furthermore, we will investigate a particular application of phase imaging: How can phase imaging contribute to cancer research and diagnostics. An estimated 3.7 million new cases of cancer will be diagnosed in Europe each year. Higher precision in prediction of clinical outcomes are needed for more effective decision making. This project will investigate how phase imaging can provide a new view in microscopy-based investigation of cancer. For this purpose, we will develop and test novel instrumentation and apply it to a current problem in cancer research.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the outgoing phase we have developed a universal system extension based on synthetic optical holography. With a minimal number of components, we have achieved to implement phase imaging in existing confocal microscopes. Importantly, this implementation does not require the instrument to be opened or modified, which is typically not allowed by service contracts set in place by the microscope manufactures. Instead, our solution is a drop-in add-on. Having validated our idea in Matlab simulations first, we proceeded to test our idea in practice. To this end, we reached out to imaging centers on campus at the University of Illinois at Urbana-Champaign, the partner organization of this project. We also contacted major manufacturers of confocal microscopes and obtained a demo microscope to test our technology with. We imaged several samples, ranging from biological samples (human cheek cells, cancer cells and stem cells) to semiconductors (photodiode). The results validated our technology and will be published in a scientific journal.

We furthermore implemented our technology in a homebuilt microscope to implement a time-resolved phase imaging. We applied this modality to measure vibration modes in microelectromechanical systems (MEMS) devices, which are found in many electronic devices that we use everyday ranging from smartphones to printers. In comparison to state-of-the art, our technology provides a full characterization in frequency and mode profiles of the out-of-plane vibration modes, which in principle can access up to GHz frequencies. We envision fast routine characterization of MEMS devices as an application.

Extensive work has also been performed in regard to using phase imaging for cancer research. We built a prototype microscope in our laboratory. First, we fabricated resolution test targets to test our microscope. We then proceeded to imaged breast tissue micro array (TMA). TMAs are a collection of tissue section from a multitude of patients on a single glass slide, containing both normal and malignant tissue, which makes TMAs an excellent test sample for validating our microscope method. First data shows that we are able to resolve the different cell types in the breast tissue sections. Importantly, human interpretation of the data is not required, but is done in an automated fashion on a computer using statistical analysis.

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)

A result of this project is the development of a universal system extension based on synthetic optical holography that enables phase imaging in existing confocal microscopes. Only few off-the-shelf components are needed that will be added to the confocal microscope. In our opinion, this solution is significantly cheaper in comparison to established phase resolving microscopes which are usually stand-alone systems rather than a system extension. Also, being based on confocal microscopy, our method does not suffer from image artifacts pertaining to typical wide-field phase imaging setups (formation of halos around objects is avoided). The prospect of a reduced price together with improved image quality can be expected to help establishing phase imaging in laboratories and thus contribute to the development and promotion of this technology which is still in its emerging phase. Our technology has potential for commercialization.

Furthermore, we are currently working with an imaging center on campus with the goal to make our technology available to users. This is an ongoing effort. Our goal until the end of this project is to have identified potential users of our technology and to have applied our technology to solve an imaging problem in biology in collaboration with the users.

We will also continue to develop phase imaging for cancer research. We are currently working on analyzing data to provide a final validation of our method. The potential impact of our method is that in the future it could provide automated histologic segmentation in a clinical setting. With this goal, our method follows the lines of other research based on automated histopathologic recognition of cancer, to remove time consuming sample preparation and to avoid human error in interpretation of image data. In comparison to existing instrumentation, however, our method is potentially cheaper, faster and requires less sample preparation, although this is still subject of current research and we hope for validation until the end of this project.

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