Periodic Reporting for period 1 - MicroflowLife (Whole-organ 3D ultrasound micro-flow imaging: from basics physics to clinical proof-of-concept on cardiac and cerebral diseases)
Reporting period: 2022-09-01 to 2025-02-28
Blood circulation is essential to organs’ functions and occurs through a complex network of vessels with diameters varying from several millimetres for large arteries to only a few microns for small capillaries. Dysfunctions in the microcirculation are early markers of many diseases, which are however diagnosed at later stage, when observable symptoms become visible at larger scales. Mapping blood flows across several spatial scales at depth in organs is therefore crucial for early diagnosis and monitoring of diseases, but it remains a major challenge in clinical medical imaging. Our laboratory Physics for Medicine Paris has introduced in 2015 ultrasound localization microscopy (ULM), a non-invasive method to map and quantify blood flows at depth in organs down to a micron scale resolution, opening avenues for medical imaging. However, 2D ULM is highly operator-dependent because probe positioning is critical to view the appropriate cross-section. Imaging the whole-organ in 3D is therefore crucial for clinical practice, and for a comprehensive investigation of organ’s functions. Capturing large 3D volumes through the bones such as the skull or the rib cage is a further challenge in ultrasound imaging: acoustic energy losses due to reflection and distortion of ultrasound waves at the bone interface significantly reduce the imaging sensitivity. The objective of MicroflowLife is to develop ultrasensitive 3D ULM for mapping the microcirculation of the whole organs such as the heart and the brain. Our approach relies on the development of novel ultrasonic multi-lens probes, combined with new acquisition sequences and processing methods. Our technology and methods will be first validated in vitro and in vivo, and then translated clinically in first-in-human studies. It has the potential to become a major tool to assess microcirculation in whole-organs in patients.
Assessing the blood flows across several spatial scales (down to the micron scale across the whole organ) is essential for early diagnosis and efficient therapeutic strategies, but remains a major challenge in clinical medical imaging. In MicroflowLife project, our main objective is to develop a new technological framework for achieving ultrasensitive 3D Ultrasound Localisation Microscopy to map the microflows of the whole-organs.
In the first two years, we have achieved three main objectives:
1. We successfully designed, built and characterize the first ultrasonic multi-lens probe adapted to whole-organ microcirculation assessment. We first developed a simplified prototype of 16 elements combined with lenses. We were able to show the feasibility of performing ultrasound localization microscopy (ULM) in vitro on a tube over a large volume. Based on this very important discovery, we, recently, were able to make a multi-lens probe with 256 elements. The probe aperture is 8 cm by 10 cm which represents an extremely large aperture compared to state of the art (generally 1cm by 1 cm). Next step includes : validating in vitro on tubes behind a skull and ribs. Next probe generations are also currently under study to add curvature and random position of elements to enhance energy transmission and reduce side lobes, respectively.
2. We successfully developed ultrasonic sequences to image flow at a high frame rate (>300 volumes/s). Post processing algorithms specific to the multi-lens framework were invented to take into account the effect of the lens to be able to build whole organ 3D vasculature map at a micrometer scale
3. We developed a realistic flow phantom to test our multi-lens prototypes in simulation and postprocessing methods. Human vasculature of the brain and the heart were retrieved from an open source atlas. Colonization algorithms were used to grow microcirculation. Particle flow was generated inside the vasculature. Particle positions were retrieved in an acoustic simulation software. Different probe and postprocessing algorithms were compared.
In the first two years, we have achieved three main objectives:
1. We successfully designed, built and characterize the first ultrasonic multi-lens probe adapted to whole-organ microcirculation assessment. We first developed a simplified prototype of 16 elements combined with lenses. We were able to show the feasibility of performing ultrasound localization microscopy (ULM) in vitro on a tube over a large volume. Based on this very important discovery, we, recently, were able to make a multi-lens probe with 256 elements. The probe aperture is 8 cm by 10 cm which represents an extremely large aperture compared to state of the art (generally 1cm by 1 cm). Next step includes : validating in vitro on tubes behind a skull and ribs. Next probe generations are also currently under study to add curvature and random position of elements to enhance energy transmission and reduce side lobes, respectively.
2. We successfully developed ultrasonic sequences to image flow at a high frame rate (>300 volumes/s). Post processing algorithms specific to the multi-lens framework were invented to take into account the effect of the lens to be able to build whole organ 3D vasculature map at a micrometer scale
3. We developed a realistic flow phantom to test our multi-lens prototypes in simulation and postprocessing methods. Human vasculature of the brain and the heart were retrieved from an open source atlas. Colonization algorithms were used to grow microcirculation. Particle flow was generated inside the vasculature. Particle positions were retrieved in an acoustic simulation software. Different probe and postprocessing algorithms were compared.
Our method effectively addresses key limitations of existing imaging modalities. Our use of a novel large-aperture multi-lens matrix array has resolved the limited field of view typically associated with classical ultrasonic matrix arrays. The non-invasive nature, high resolution, and real-time capabilities of our method make it a cost-effective and accessible alternative to existing techniques. Compared to CT angiography and 4D flow MRI, it significantly enhances anatomical visualization, flow dynamic assessment, and overall vascular analysis. Its potential is further envisioned by the simplicity of the underlying technology, making it highly accessible for widespread adoption in research laboratories and hospitals.