Periodic Reporting for period 3 - SURE (3-D Super resolution Ultrasound Real time imaging of Erythrocytes)
Periodo di rendicontazione: 2023-03-01 al 2024-08-31
The SURE project: ”3-D Super resolution Ultrasound Real time imaging of Erythrocytes” seeks to develop and research a new super resolution ultrasound imaging method potentially capable of resolving 3-D capillary flow in the human body. The approach tracks the motion of the individual red blood cells (erythrocytes) in a three-dimensional volume for a full visualization of anatomy, flow, and perfusion in a volume down to 13 cm at 20 volumes per second. The SURE imaging approach can potentially yield a paradigm shift in the scientific study, diagnoses, and treatment of cancer, diabetes, and vascular diseases at the capillary level, as it can enable volumetric visualization of capillary perfusion in real-time at frame rates above 20 Hz without injection of contrast agents. Imaging is performed using ultrasound at normal diagnostic levels with no known adverse effects and can, thus, be used on a wide range of the population from newborns to the elderly for both diagnosis and repeated screening. The super resolution imaging is performed without using contrast agents and is thereby thousands of times faster than current methods. The method potentially has an isotropic resolution of 50 μm in all directions, and the smallest details visible is thereby 100-400 times smaller volumetrically than current state-of-the-art 3-D ultrasound imaging. Using deep learning can further advance detection of targets making a resolution of 10 μm possible in flow measurements. These highly ambitious goals can only be attained in a synergistic research effort, and therefore the SURE project combines knowledge from four research groups. The scientific project includes breakthroughs in silicon row-column probes with 1 million elements, advanced synthetic aperture ultrafast coded imaging, deep learning for detecting and tracking of cells, pressure gradient estimation, and visualization and quantification of several hundreds of Gbytes volumetric data. The research finally entails clinical trials conducted on rodents and humans for studying the changes in perfusion for diabetes and cancer and reveal the efficacy of SURE.
The ERC funded project “3-D Super resolution Ultrasound Real time imaging of Erythrocytes” - SURE develops ultrasound methods for visualizing the flow in the smallest vessel in the human body. Current experimental super resolution imaging uses small micro bubbles injected into a vein to visualize the flow in the human body. The method is invasive and takes several minutes for yielding satisfactory images. This can be avoided using our newly developed SURE method, which employs the red blood cells for imaging. Here a ultrasound research scanner is used for acquiring data for only 3 seconds to yield images with a resolution of 25 micrometers without any preparation of the patient. This has recently been demonstrated on the kidney of a Sprague-Dawley rat, which was scanned using a Verasonics research scanner, and the SURE processing program. It shows that super resolution imaging with a resolution of 25-40 micrometers can be attained in 3 seconds, orders of magnitude faster than current super resolution imaging with contrast agents, which takes 3-10 minutes to acquire. The SURE images need no contrast agents, and the patients can be directly scanned by a conventional ultrasound probe. This makes translation into the clinic easy. The images were compared to micro-CT scans acquired over 11 hours, and the vasculature of the SURE images were compared to the micro-CT scans. Selected vessels with a size between 55 to 85 micrometers agreed within 10 micrometers. Tracking can now also be used in the SURE processing, making it possible to quantify the flow velocity in the micro-vasculature and characterize arterioles and venules. Mice with an implanted tumor has also be scanned and the micro-vasculature of the tumor can be seen. Early studies indicate a radically different flow pattern than for healthy tissue. Further studies with be conducted to reveal the growth of tumors and their characterization.
The SURE method has now been translated to human clinical use and several clinical protocols have been submitted and approved by the authorities. Trials on the lymph nodes, tendons, kidney, and the breast are on-going. Early indications are that previously unseen flow in tendons and their vasculature can be revealed with SURE. This has also been seen for selected lymph nodes.
A study on non-invasive pressure gradient estimations in the carotid artery has also been initiated using the same ultrasound sequence as for SURE imaging. It has been shown that the method can measure gradients with a ten times higher precision than current invasive pressure catheters. This makes it possible to make screening of the carotid artery for a much wider patient group. A clinical study has been approved and is now on-going on both volunteers and patients.
A major results is three-dimensional ultrasound imaging using specialized row-column probes. The project has demonstrated that our row-column technology can be used for both super resolution imaging, normal high quality anatomic imaging, and blood velocity imaging, where the blood velocity vector is found in all three directions within the full volume and with a high time resolution. The row-column array only need 128 measurement channels, whereas a similar matrix probe used in current commercial scanners would need 16,384 channels, yielding 128 times more data. The processing is, thus, 128 times faster with our approach. The new method makes it possible to fabricate probes that are larger, which can see deeper into the tissue, and use higher frequencies for a corresponding higher resolution. This has the potential to introduce very high quality 3-D imaging in medical ultrasound using current scanner hardware. A new beamfoming method has been developed where only a single plane is needed for each emission for extrapolating to the the full volume. This further reduces the calculation demand by a factor of 100 for a combined reduction of 12,000 times compared to full matrix probes. This has been implemented on a standard research scanner and GPU card . Real time full volumetric imaging can now be attained for hundred of volumes a second, making it possible to implement 3-D ultrasound imaging using standard, commercial hardware.
CMUT probes are also being fabricated in the project. They avoid the use of lead in ultrasound probes and are therefore more environmentally friendly. It has also been shown that CMUT probes can be used in combination with coded excitation for increased penetration depth or resolution to further increase imaging quality.
The SURE method has now been translated to human clinical use and several clinical protocols have been submitted and approved by the authorities. Trials on the lymph nodes, tendons, kidney, and the breast are on-going. Early indications are that previously unseen flow in tendons and their vasculature can be revealed with SURE. This has also been seen for selected lymph nodes.
A study on non-invasive pressure gradient estimations in the carotid artery has also been initiated using the same ultrasound sequence as for SURE imaging. It has been shown that the method can measure gradients with a ten times higher precision than current invasive pressure catheters. This makes it possible to make screening of the carotid artery for a much wider patient group. A clinical study has been approved and is now on-going on both volunteers and patients.
A major results is three-dimensional ultrasound imaging using specialized row-column probes. The project has demonstrated that our row-column technology can be used for both super resolution imaging, normal high quality anatomic imaging, and blood velocity imaging, where the blood velocity vector is found in all three directions within the full volume and with a high time resolution. The row-column array only need 128 measurement channels, whereas a similar matrix probe used in current commercial scanners would need 16,384 channels, yielding 128 times more data. The processing is, thus, 128 times faster with our approach. The new method makes it possible to fabricate probes that are larger, which can see deeper into the tissue, and use higher frequencies for a corresponding higher resolution. This has the potential to introduce very high quality 3-D imaging in medical ultrasound using current scanner hardware. A new beamfoming method has been developed where only a single plane is needed for each emission for extrapolating to the the full volume. This further reduces the calculation demand by a factor of 100 for a combined reduction of 12,000 times compared to full matrix probes. This has been implemented on a standard research scanner and GPU card . Real time full volumetric imaging can now be attained for hundred of volumes a second, making it possible to implement 3-D ultrasound imaging using standard, commercial hardware.
CMUT probes are also being fabricated in the project. They avoid the use of lead in ultrasound probes and are therefore more environmentally friendly. It has also been shown that CMUT probes can be used in combination with coded excitation for increased penetration depth or resolution to further increase imaging quality.
The future plans for the ERC SURE project is to translate the method to clinical studies on cancer patients. We have now demonstrated that super resolution can be obtained reliably in seconds for resolution down to 29 micrometers. Consistent images images are seen for the many rats already scanned and early indications of successful translation to human use is seen. The fast implementation of 3-D ultrasound imaging with row-column probes has also been demonstrated on commercial hardware and opens the avenue for fast and in-expensive high quality 3-D imaging. The hope is that cancer can be reliably detected, and that the evolution of the disease and treatment efficiency is quantifiable with SURE imaging. The development and use of row-column arrays for three-dimensional ultrasound imaging also looks quite promising. We hope to demonstrate that such arrays can be used in the clinic and will yield improved anatomic, flow and functional imaging, and that such imaging can be conducted in real time at the bed side. This could yield major benefits for studying the anatomy in 3-D and also ensure that complete data sets are obtained in few seconds. The medical doctors can then retrospectively, after the patient has left, study both anatomy, flow in major vessels, and perfusion in smaller vessels to aid the diagnoses of cancer and diabetes progression and treatment.