Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - COEXIST (Confined, Optically Enhanced, X-ray Imaging Source for Tomography)
Teaser
Personalized medicine, which identifies effective treatments via the sub-cellular characterization of disease and its response to treatments, has been identified as key approach to improving clinical treatment effectiveness, quality of care, and reduce the financial burden. A...
Summary
Personalized medicine, which identifies effective treatments via the sub-cellular characterization of disease and its response to treatments, has been identified as key approach to improving clinical treatment effectiveness, quality of care, and reduce the financial burden. A significant barrier to mainstream personal medicine is rising research cost in drug discovery. The average R&D cost of pre-clinical drug discovery has recently risen to over $1 billion. A resource intensive, yet critical step, in pre-clinical R&D is imaging of a pharmaceutical’s sub-cellular effect on in-vitro biological cells. Sub-cellular imaging is traditionally performed using Transmission Electron Microscopy (TEM) and/or Visible Microscopy, but these techniques have been complimented with Cryo-TEM, Super-Resolution Fluorescence Microscopy (SRFM) and the newly emerging cryogenic Soft X-ray Tomography (Cryo-SXT). State-of-the-art Cryo-SXT is capable providing high-contrast, high-resolution, whole cell, natural (hydrated) 3D images of biological samples.
Two distinct soft X-ray (SXR) sources are presently available to researchers; (1) high brilliance synchrotron sources - which can provide 3D images within minutes, but require the submission and approval of proposals months in advance and (2) Nitrogen laser plasma sources - relatively compact user systems, but rely on bespoke complex laser system making commercial deployment extremely challenging. SiriusXT is currently developing a commercial, table-top, high brightness, laser-plasma based, SXR source capable of delivering high-resolution 3D images in 10s of minutes. Such a source effectively shrinks the capabilities of a synchrotron into the footprint and cost of a traditional user microscope systems (e.g. TEM).
The COEXIST project identified scope to enhance the imaging capabilities of table-top SXT. The primary scientific goal of COEXIST was to leverage fundamental research to develop innovative enhancements for SiriusXT’s soft X-ray commercial microscope beyond state-of-the-art. These enhancements aimed to considerably reduce image acquisition times and strengthen SiriusXT’s soft X-ray microscope’s position as a powerful tool for scientific research, thus narrowing the performance gap between synchrotron and table-top sources.
The COEXIST research succeeded in developing, integrating, and validating light-source and system enhancements for SiriusXT’s SXT. These R&D enhancements were instrumental in the delivery of the first SXR images from SiriusXT’s prototype system. In addition, exploratory research conducted as part of COEXIST project discovered avenues to deliver further SXT system improvements. As a whole, the COEXIST project delivered significant improvements to a state-of-the-art imaging platform, with the potential to benefit and accelerate whole sectors of research which utilize imaging, these include, but are not limited to; drug discovery, disease treatment/prevention and applied/industrial microbiology.
Work performed
The development of a proof-of-concept system into a stable, commercial system requires the surmounting of considerable scientific and engineering challenges, merging innovative research with industrial product development. A crucial requirement of a commercially viable system is the delivery a system capable of 40 hours of continuous imaging time between servicing. Three developmental phases were planned and implemented to achieve these goals: i) source development, ii) system development, and iii) system validation and demonstration.
Within the source development phase, three key-developmental ‘pain-points’ were identified and addressed. These technical challenges limited the intensity of soft x-ray (SXR) light delivered to illuminate a biological sample and the continuous operation time which the system could generate usable imagery. For this phase, the COEXIST project delivered a 46% increase in laser power density on target, with a similar increase in SXR emission. In addition, innovative operational and mechanical source improvements increased the mean time between service, successfully achieving the required commercial milestone. These source enhancements strengthened SiriusXT’s corporate knowledge, further developed their intellectual-property technology, and will provide a foundation/pathway for further research in generating additional IP in the near future.
The system development work delivered fundamental improvements to SiriusXT’s SXT system as a whole. Experimental research uncovered developed optical improvements and uncovered potentially exploitable IP to further mitigating plasma debris impinging on SXR optics. Similar fundamental research produced technical insights into the SXR optical-system as a whole, providing optimised designs and processes. The cumulative output of this technical program delivered an updated system design capable of delivering in-specification SXR photon densities at the imaging plane for over 40 hours.
The final developmental phase validated the system and process enhancements during normal operation of the SXT system. This validation phase confirmed the commercially required system operation of 40 hours and delivered the first enhanced soft X-ray generated images with high resolution. The experimental knowledge gained from these developmental and validation phases are already being exploited into an upgraded SXT microscope system. The fundamental research from the COEXIST project will form a foundation for subsequent performance improvements in the delivery of SXR tomographic imagery.
The high-resolution imagery obtained from SiriusXT’s COEXIST-enhanced SXT system will be disseminated to the microscopy community via presentations at forthcoming international microscopy conferences, and via open-access publication in two high-impact journals. This targeted dissemination will be complimented by a series of seminars aimed at introducing a broader scientific community to the obtained results. The combined dissemination and communication strategy aims to maximise the reach and impact of the COEXIST results.
Final results
The COEXIST project delivered significant enhancements to SiriusXT’s commercial soft X-ray tomogram (SXT) via improvements in SXR photon output and system stability. Successfully delivering the majority of project goals and objectives, the COEXIST project’s most notable results are:
• 46% increase laser power density delivered to target
• 40% improvement target stability and repeatability
• 40% increase in target longevity
• First 40-hour continuous operation validation benchmark
• First high-resolution SXR images
These enhancements have been demonstrated via the delivery of the first SXR high-resolution imagery, and the knowledge gained from fundamental research is being exploited further in the form of system hardware upgrades.
The technological and process improvements generated within the COEXIST project have demonstrably increased the technology readiness level of SiriusXT’s expertise and accelerated the development of the first commercially viable, table-top SXT. These technological enhancements have strengthened SiriusXT’s position at the forefront of commercial SXT research and development.
The potential of a relatively low cost, laboratory based, SXT imaging modality for fundamental scientific research could accelerate whole sectors of research ranging from drug discovery, disease treatment and industrial microbiology.