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Single-cell nuclear magnetic resonance spectroscopy with diamond quantum sensors

Periodic Reporting for period 2 - SingleCellQNMR (Single-cell nuclear magnetic resonance spectroscopy with diamond quantum sensors)

Reporting period: 2022-06-01 to 2023-11-30

The phenomena of biological processes such as drug resistance, cell development, and tumorigenesis are often attributed to individual events that occur at the single-cell level. However, the study of cell populations obscures these unique characteristics, necessitating the use of single-cell technologies to gain a comprehensive understanding of cell biology. Unfortunately, nuclear magnetic resonance (NMR) spectroscopy, a highly specific and non-invasive analytical tool, has been limited in its ability to study single cells due to its inherent low sensitivity.
In the SingleCellQNMR project, we aim to overcome this limitation using a novel approach that combines three key components: (i) highly sensitive quantum sensors for NMR detection, (ii) microfluidics, and (iii) advanced hyperpolarization methods. The innovative SingleCellQNMR project uses nitrogen-vacancy (NV) centers in diamond as atomic-sized magnetic quantum sensors. These defects are exceptionally well suited to detecting NMR signals from tiny sample volumes, such as those from a single cell. To meet the stringent technical requirements for single cell studies, a second generation quantum diamond spectrometer with integrated hyperpolarization capabilities will be developed. The project has two main aims:

a) Single cell metabolomics. The outstanding molecular specificity of NV-NMR will be employed for noninvasive analysis and quantification of metabolites at the individual cell level. By subjecting cells to external stimuli, such as drugs, we aim to observe and track their distinct metabolic responses over a period of time.

b) Single cell water diffusion and relaxation based contrast: This technique involves measuring water diffusion and proton relaxation at the single cell scale. This will allow us to probe microstructures and generate data to validate existing models of magnetic resonance imaging contrast

The SingleCellQNMR project aims to create a revolutionary, non-invasive tool that will usher in a new era of single cell studies. By providing early insights, this research effort will pave the way for future advances in our understanding of cellular behavior.
In the first funding period, we worked in three main directions. First, we designed and built a microscale NV-NMR experiment in a superconducting magnet. This experiment achieves state-of-the-art sensitivities (~ 20 pT/sqrt(Hz)) and the best reported chemical resolution to date of 0.2 ppm.

In a second step, the experiment was modified with magnetic field gradient coils developed in collaboration with the Zaitsev group in Freiburg. This setup allows for pulsed field gradient spin-echo experiments that can detect molecular diffusion on microscopic length scales - a key goal of the SingleCellQNMR project.

Thirdly, we have developed a fully integrated microfluidic platform for NV quantum sensing. This allows NMR spectroscopy to be performed on a chip and is a crucial step towards single-cell analysis.
The current results pave the way towards the ultimate goal of non-invasive single cell analysis. The microfluidic platform and the ability to perform diffusion measurements on microscopic length scales were key objectives within the SingleCellQNMR project. Building on this foundation, we are currently working on improving the sensitivity of the NV-NMR spectrometer, implementing hyperpolarisation methods and increasing the magnetic field at which our NV-NMR experiments are performed.
We would like to highlight our microscale diffusion NV-NMR results, which will have implications beyond single cell analysis, such as the microstructure analysis of tissues or the detection of ion diffusion in thin film materials for energy applications.