Periodic Reporting for period 2 - MetaboliQs (Leveraging room temperature diamond quantum dynamics to enable safe, first-of-its-kind, multimodal cardiac imaging)
Periodo di rendicontazione: 2020-04-01 al 2022-03-31
The MetaboliQs project combines diamond-based quantum sensing and medical imaging, two areas of European excellence, to fundamentally change the molecular understanding and personalized care of cardiovascular diseases. The project resulted in the translation of two key technologies from quantum sensing and polarization for the metabolic analysis of cells and patients:
1. A hyperpolarized “metabolic microscope” - Leveraging the unprecedented sensitivity of NV centres to detect NMR signal and hyperpolarized metabolites on the microscopic scale, potentially down to the single cell level. This is a “holy grail” application for cell analysis, where the current state of the art with hyperpolarized NMR spectroscopy requires 10,000-100,000 cells. The project then focussed on enabling microscopic metabolic analysis using the diamond chip as the NMR sensor.
2. A “quantum polarizer” - using parahydrogen-based quantum technologies was developed by the project partner NVIS. Using this polarizer, we utilized the significantly improved detection methods to demonstrate for the first time a room-temperature quantum-based polarizer in preclinical pathological detection.
These two breakthrough technologies will enable previously unachievable, highly sensitive quantification of metabolic activity, paving the way for precision diagnostics and better-personalized treatment of cardiovascular diseases and other related pathologies.
1. A hyperpolarized “metabolic microscope” - Leveraging the unprecedented sensitivity of NV centres to detect NMR signal and hyperpolarized metabolites on the microscopic scale, potentially down to the single cell level. This is a “holy grail” application for cell analysis, where the current state of the art with hyperpolarized NMR spectroscopy requires 10,000-100,000 cells. The project then focussed on enabling microscopic metabolic analysis using the diamond chip as the NMR sensor.
2. A “quantum polarizer” - using parahydrogen-based quantum technologies was developed by the project partner NVIS. Using this polarizer, we utilized the significantly improved detection methods to demonstrate for the first time a room-temperature quantum-based polarizer in preclinical pathological detection.
These two breakthrough technologies will enable previously unachievable, highly sensitive quantification of metabolic activity, paving the way for precision diagnostics and better-personalized treatment of cardiovascular diseases and other related pathologies.
1.1 Main achievements in the first project period:
(1) Metabolic microscope
• Achieved homogeneous layers of ultra-shallow NV centres with excellent coherence time and sensing / polarization efficiency.
• Optimized µm-thick nitrogen-rich CVD growth and activation to achieve controllable high NV concentration with coherence times exceeding state of the art diamonds (HPHT/CVD).
• Developed etching techniques for nanostructuring dense nanopillar arrays with <400 nm pitch and >15 aspect ratio; Pillar side-walls were demonstrated to have very good surface properties by NV detection of external spins.
• Realized the first nitrogen-overgrown activated NV layers in nanostructures by combining thin-layer nitrogen-rich overgrowth with nanostructuring. Thus, the optimized properties of grown-nitrogen NV centres can be combined with higher surface area.
• Developed the smallest high-aspect nanostructures (less than 30 nm feature width) by combining e-beam lithography with a dewetting process.
• Demonstrated for the first time a detection of external molecules from a thin-layer nitrogen overgrowth opening the way to localized polarization and detection
• Developed a microfluidic-integrated diamond chip for microscale NMR of metabolites, utilizing the grown and optimized diamonds
• Achieving ~10 µm resolution for the detection of hyperpolarized metabolites by combination of flowing hyperpolarized metabolites with a diamond-chip microscale NMR sensor
see fig- 1
Hyperpolarized MRI
• Improved imaging sensitivity X7-fold by integration of novel 13C cryo-coil for preclinical imaging
• Developed new imaging acquisition sequences for capturing 3D hyperpolarized images and applied said sequences on metabolic imaging applications
• Developed comprehensive simulation framework for synthesizing HP MRI data. The volume of data generated enables applying novel data analysis schemes such as machine learning algorithms
• Polarized and detected hyperpolarized molecules using the best-in-class ultra-thin NV layer optimized in the project
• Conducted pivotal preclinical experiments with the PHIP quantum polarizer, demonstrating the option of polarizing 13C-pyruvate with the polarizer and achieving similar signal to noise ratio to the state of the art (dDNP) at the fraction of the time, complexity and cost.
• Conducted in vivo studies with a novel metabolic agent, hyperpolarized 13C fumarate as a biocompatible agent with no cytotoxicity
• Demonstrated comparable and even better results with the quantum polarizer compared with the d-DNP setup.
• Developed a simulation framework that enables the generation of synthetic data for optimization of imaging components and for deep learning (i.e. training neural networks).
• Optimized a pig heart model as good preclinical model for cardiovascular disease
• Demonstrated experimentally the usefulness of HP MRI for detecting ischemia at 3 T and 1.5 T MRI scanners.
see fig. 2
1.2 Main achievements of interest outside the project
• The quantum-grade diamonds and the optimized ultra-thin NV layers used for polarization will have a clear advantage also for Diamond Quantum Sensors
• The very high polarization reached in 13C spins in diamonds could be utilized in nanodiamond tracers which combine optical and magnetic resonance imaging for multimodal imaging
• The comprehensive simulation framework developed for synthesizing HP MRI data can have significant applications in areas for machine learning and AI outside of hyperpolarized MRI, including other imaging modalities or even outside of healthcare applications
1.3 Dissemination and Exploitation of results
• Developed a dissemination and communication plan
• Setting up of a public homepage at the beginning of the project, which is updated regularly
• Published periodically a newsletter, to which interested persons can subscribe to
• Established channels on Twitter and LinkedIn
• Created a video about the project to make the content of the project available for a broad audience
• Published important events within the project by press releases
• To have an actual and comprehensive overview of the IP important for the project and generated during its duration, a Knowledge Portfolio was set up, which is updated regularly
• Participated in a summer school for interested students, organized jointly with the AsteriQs project
• Hosted a workshop hosted by the project consortium to which key people from science and industry were invited
1.4 Project Management
• Run by two coordinators to optimize the work
• Ensure progress by internal activities (telephone conference, video meetings of the executive board, general assemblies)
• Participate in the Steering Executive Board within the EC Quantum Flagship
• Defined a “Project Management Plan and Guidelines” at the beginning of the project
• Generated “Team‐Room” to store reports, deliverables, minutes and presentations given during Metaboliqs meetings.
(1) Metabolic microscope
• Achieved homogeneous layers of ultra-shallow NV centres with excellent coherence time and sensing / polarization efficiency.
• Optimized µm-thick nitrogen-rich CVD growth and activation to achieve controllable high NV concentration with coherence times exceeding state of the art diamonds (HPHT/CVD).
• Developed etching techniques for nanostructuring dense nanopillar arrays with <400 nm pitch and >15 aspect ratio; Pillar side-walls were demonstrated to have very good surface properties by NV detection of external spins.
• Realized the first nitrogen-overgrown activated NV layers in nanostructures by combining thin-layer nitrogen-rich overgrowth with nanostructuring. Thus, the optimized properties of grown-nitrogen NV centres can be combined with higher surface area.
• Developed the smallest high-aspect nanostructures (less than 30 nm feature width) by combining e-beam lithography with a dewetting process.
• Demonstrated for the first time a detection of external molecules from a thin-layer nitrogen overgrowth opening the way to localized polarization and detection
• Developed a microfluidic-integrated diamond chip for microscale NMR of metabolites, utilizing the grown and optimized diamonds
• Achieving ~10 µm resolution for the detection of hyperpolarized metabolites by combination of flowing hyperpolarized metabolites with a diamond-chip microscale NMR sensor
see fig- 1
Hyperpolarized MRI
• Improved imaging sensitivity X7-fold by integration of novel 13C cryo-coil for preclinical imaging
• Developed new imaging acquisition sequences for capturing 3D hyperpolarized images and applied said sequences on metabolic imaging applications
• Developed comprehensive simulation framework for synthesizing HP MRI data. The volume of data generated enables applying novel data analysis schemes such as machine learning algorithms
• Polarized and detected hyperpolarized molecules using the best-in-class ultra-thin NV layer optimized in the project
• Conducted pivotal preclinical experiments with the PHIP quantum polarizer, demonstrating the option of polarizing 13C-pyruvate with the polarizer and achieving similar signal to noise ratio to the state of the art (dDNP) at the fraction of the time, complexity and cost.
• Conducted in vivo studies with a novel metabolic agent, hyperpolarized 13C fumarate as a biocompatible agent with no cytotoxicity
• Demonstrated comparable and even better results with the quantum polarizer compared with the d-DNP setup.
• Developed a simulation framework that enables the generation of synthetic data for optimization of imaging components and for deep learning (i.e. training neural networks).
• Optimized a pig heart model as good preclinical model for cardiovascular disease
• Demonstrated experimentally the usefulness of HP MRI for detecting ischemia at 3 T and 1.5 T MRI scanners.
see fig. 2
1.2 Main achievements of interest outside the project
• The quantum-grade diamonds and the optimized ultra-thin NV layers used for polarization will have a clear advantage also for Diamond Quantum Sensors
• The very high polarization reached in 13C spins in diamonds could be utilized in nanodiamond tracers which combine optical and magnetic resonance imaging for multimodal imaging
• The comprehensive simulation framework developed for synthesizing HP MRI data can have significant applications in areas for machine learning and AI outside of hyperpolarized MRI, including other imaging modalities or even outside of healthcare applications
1.3 Dissemination and Exploitation of results
• Developed a dissemination and communication plan
• Setting up of a public homepage at the beginning of the project, which is updated regularly
• Published periodically a newsletter, to which interested persons can subscribe to
• Established channels on Twitter and LinkedIn
• Created a video about the project to make the content of the project available for a broad audience
• Published important events within the project by press releases
• To have an actual and comprehensive overview of the IP important for the project and generated during its duration, a Knowledge Portfolio was set up, which is updated regularly
• Participated in a summer school for interested students, organized jointly with the AsteriQs project
• Hosted a workshop hosted by the project consortium to which key people from science and industry were invited
1.4 Project Management
• Run by two coordinators to optimize the work
• Ensure progress by internal activities (telephone conference, video meetings of the executive board, general assemblies)
• Participate in the Steering Executive Board within the EC Quantum Flagship
• Defined a “Project Management Plan and Guidelines” at the beginning of the project
• Generated “Team‐Room” to store reports, deliverables, minutes and presentations given during Metaboliqs meetings.
The original goal of the project was to fabricate a prototype for a diamond-based polarizer and demonstrate its profitableness for in vivo MRI studies. Figures of merit compared to the conventional dissolution DNP were to save preparation time by a factor of 40 as well as to omit cryogenic cooling and reduce costs. As the used quantum polarizer and the developed methods polarizes within 2 minutes instead of 2 hours, we have reduced preparation times by a factor of 60. In addition, the polarizer operates at room temperature and can be built for a fraction of the cost of a dissolution DNP polarizer. Thus, these figures of merit have been achieved with the introduced quantum polarizer.
In addition, observation of the high sensitivity of the high-quality diamond and further investigations lead to the unforeseen demonstration of NMR on the microscale, which after the project will be further developed to the prototype of a unique quantum microscope and goes, thus, beyond the expectations of the initial proposal.
In addition, observation of the high sensitivity of the high-quality diamond and further investigations lead to the unforeseen demonstration of NMR on the microscale, which after the project will be further developed to the prototype of a unique quantum microscope and goes, thus, beyond the expectations of the initial proposal.