Experimental study on high-frequency subharmonic scattering characteristics of ultrasound contrast agent microbubbles under low ambient pressure_Journal of Biomedical Engineering

Authors：

LU Huimin ^1,2 , WANG Yun ^2,3 , HUANG Laixin ² , XU Gang ⁴ , ZHOU Juan ² ,  YU Wenkui ¹ ,  LI Fei ²

1. Department of Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, P. R. China;
2. Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, P. R. China;
3. Department of Ultrasound, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China;
4. Liver Transplant Center, Organ Transplant Center, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

YU Wenkui, Email: yudrnj2@163.com; LI Fei, Email: fei.li@siat.ac.cn

Keywords：

Traumatic brain injury; Intracranial pressure; Ultrasound contrast agent microbubbles; Subharmonic scattering; Subharmonic aided pressure estimation

DOI：

10.7507/1001-5515.202304012

Video：

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Correlation between nonlinear subharmonic scattering of ultrasound contrast agent microbubbles and ambient pressure is expected to be used for local brain tissue pressure monitoring. Although high-frequency ultrasound has achieved high-resolution imaging of intracranial microvessels, the research on high-frequency subharmonic scattering characteristics of microbubbles is insufficient at present, which restricts the research progress of estimating local brain tissue pressure based on high-frequency subharmonic scattering of microbubbles. Therefore, under the excitation of 10 MHz high-frequency ultrasound, the effects of different acoustic pressures and ambient pressures on the high-frequency subharmonic scattering characteristics of three different ultrasound contrast agents including SonoVue, Sonazoid and Huashengxian were investigated in this in vitro study. Results showed that the subharmonic scattering amplitudes of the three microbubbles increased with the increase of ambient pressure at the peak negative acoustic pressures of 696, 766 and 817 kPa, and there was a favorable linear correlation between subharmonic amplitude and ambient pressure. Under the above three acoustic pressures, the highest correlation coefficient of SonoVue was 0.948 (P = 0.03), the highest sensitivity of pressure measurement was 0.248 dB/mm Hg and the minimum root mean square error (RMSE) was 2.64 mm Hg. Sonazoid's highest correlation coefficient was 0.982 (P < 0.01), the highest sensitivity of pressure measurement was 0.052 dB/mm Hg and the minimum RMSE was 1.51 mm Hg. The highest correlation coefficient of Huashengxian was 0.969 (P = 0.02), the highest sensitivity of pressure measurement was 0.098 dB/mm Hg and the minimum RMSE was 2.00 mm Hg. The above in vitro experimental results indicate that by selecting ultrasound contrast agent microbubbles and optimizing acoustic pressure, the correlation between high-frequency subharmonic scattering of microbubbles and ambient pressure can be improved, the sensitivity of pressure measurement can be upgraded, and the measurement error can be reduced to meet the clinical demand for local brain tissue pressure measurement, which provided an important experimental basis for subsequent research in vivo.

Citation： LU Huimin, WANG Yun, HUANG Laixin, XU Gang, ZHOU Juan, YU Wenkui, LI Fei. Experimental study on high-frequency subharmonic scattering characteristics of ultrasound contrast agent microbubbles under low ambient pressure. Journal of Biomedical Engineering, 2023, 40(6): 1209-1216. doi: 10.7507/1001-5515.202304012 Copy

1.	Yang C, Ma Y, Xie L, et al. Intracranial pressure monitoring in the intensive care unit for patients with severe traumatic brain injury: analysis of the CENTER-TBI China registry. Neurocrit Care, 2022, 37(1): 160-171.
2.	Smith M. Monitoring intracranial pressure in traumatic brain injury. Anesth Analg, 2008, 106(1): 240-248.
3.	Cremer O L. Does ICP monitoring make a difference in neurocritical care?. Eur J Anaesthesiol Suppl, 2008, 42: 87-93.
4.	Shi W T, Forsberg F, Raichlen J S, et al. Pressure dependence of subharmonic signals from contrast microbubbles. Ultrasound Med Biol, 1999, 25(2): 275-283.
5.	Halldorsdottir V G, Dave J K, Leodore L M, et al. Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions. Ultrason Imaging, 2011, 33(3): 153-164.
6.	Dave J K, Halldorsdottir V G, Eisenbrey J R, et al. Noninvasive estimation of dynamic pressures in vitro and in vivo using the subharmonic response from microbubbles. IEEE Trans Ultrason Ferroelectr Freq Control, 2011, 58(10): 2056-2066.
7.	Dave J K, Halldorsdottir V G, Eisenbrey J R, et al. Noninvasive LV pressure estimation using subharmonic emissions from microbubbles. JACC Cardiovasc Imaging, 2012, 5(1): 87-92.
8.	Dave J K, Halldorsdottir V G, Eisenbrey J R, et al. Investigating the efficacy of subharmonic aided pressure estimation for portal vein pressures and portal hypertension monitoring. Ultrasound Med Biol, 2012, 38(10): 1784-1798.
9.	Andersen K S, Jensen J A. Impact of acoustic pressure on ambient pressure estimation using ultrasound contrast agent. Ultrasonics, 2010, 50(2): 294-299.
10.	Frinking P J, Brochot J, Arditi M. Subharmonic scattering of phospholipid-shell microbubbles at low acoustic pressure amplitudes. IEEE Trans Ultrason Ferroelectr Freq Control, 2010, 57(8): 1762-1771.
11.	Li F, Li D, Yan F. Improvement of detection sensitivity of microbubbles as sensors to detect ambient pressure. Sensors, 2018, 18(12): 4083.
12.	Nio A Q X, Faraci A, Christensen-Jeffries K, et al. Optimal control of SonoVue microbubbles to estimate hydrostatic pressure. IEEE Trans Ultrason Ferroelectr Freq Control, 2020, 67(3): 557-567.
13.	Halldorsdottir V G, Dave J K, Marshall A, et al. Subharmonic-aided pressure estimation for monitoring interstitial fluid pressure in tumors: calibration and treatment with paclitaxel in breast cancer xenografts. Ultrasound Med Biol, 2017, 43(7): 1401-1410.
14.	向恒, 阳锐, 邹远文等. 超声亚谐波无创评估门静脉压力的体外实验研究. 生物医学工程学杂志, 2020, 37(6): 1073-1079.
15.	Xu G, Lu H, Yang H, et al. Subharmonic scattering of SonoVue microbubbles within 10-40 mmHg overpressures in vitro. IEEE Trans Ultrason Ferroelectr Freq Control, 2021, 68(12): 3583-3591.
16.	Lu H, Xu G, Wang Y, et al. Correlation between portal vein pressure and subharmonic scattering signals from SonoVue microbubbles in canines. Ultrasound Med Biol, 2023, 49(1): 203-211.
17.	Zheng S, Zhang Y, Cheng L, et al. Noninvasive assessment of intracranial pressure using subharmonic-aided pressure estimation: an experimental study in canines. J Trauma Acute Care Surg, 2022, 93(6): 882-888.
18.	Wang Y, Lu H, Huang L, et al. Noninvasive estimation of tumor interstitial fluid pressure from subharmonic scattering of ultrasound contrast microbubbles. Biosensors (Basel), 2023, 13(5): 528.
19.	Xu G, Wang Y, Lu H, et al. Portal vein pressure estimation and portal hypertension discrimination based on subharmonic scattering of ultrasound contrast agent microbubbles. IEEE Trans Biomed Eng, 2023, PP. DOI: 10.1109/TBME.2023.3293952.
20.	Mace E, Montaldo G, Osmanski B F, et al. Functional ultrasound imaging of the brain: theory and basic principles. IEEE Trans Ultrason Ferroelectr Freq Control, 2013, 60(3): 492-506.
21.	Tanter M, Fink M. Ultrafast imaging in biomedical ultrasound. IEEE Trans Ultrason Ferroelectr Freq Control, 2014, 61(1): 102-119.
22.	Errico C, Pierre J, Pezet S, et al. Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. Nature, 2015, 527(7579): 499-502.
23.	Couture O, Hingot V, Heiles B, et al. Ultrasound localization microscopy and super-resolution: A state of the art. IEEE Trans Ultrason Ferroelectr Freq Control, 2018, 65(8): 1304-1320.
24.	Gupta I, Eisenbrey J, Stanczak M, et al. Effect of pulse shaping on subharmonic aided pressure estimation in vitro and in vivo. J Ultrasound Med, 2017, 36(1): 3-11.
25.	Goertz D E, de Jong N, van der Steen A F W. Attenuation and size distribution measurements of Definity™ and manipulated Definity™ populations. Ultrasound Med Biol, 2007, 33(9): 1376-1388.
26.	Goertz D E, Cherin E, Needles A, et al. High frequency nonlinear B-scan imaging of microbubble contrast agents. IEEE Trans Ultrason Ferroelectr Freq Control, 2005, 52(1): 65-79.
27.	Goertz D E, Needles A, Burns P N, et al. High-frequency, nonlinear flow imaging of microbubble contrast agents. IEEE Trans Ultrason Ferroelectr Freq Control, 2005, 52(3): 495-502.
28.	Marmottant P, van der Meer S, Emmer M, et al. A model for large amplitude oscillations of coated bubbles accounting for buckling and rupture. J Acoust Soc Am, 2005, 118(6): 3499-3505.
29.	Sarkar K, Katiyar A, Jain P. Growth and dissolution of an encapsulated contrast microbubble: effects of encapsulation permeability. Ultrasound Med Biol, 2009, 35(8): 1385-1396.
30.	何蒙娜, 姜玉新, 吕珂. 超声造影剂Sonazoid与SonoVue的物理特征及临床特点比较. 中国医学影像技术, 2015, 31(2): 306-309.
31.	van Hoeve W, de Vargas Serrano M, Te Winkel L, et al. Improved sensitivity of ultrasound-based subharmonic aided pressure estimation using monodisperse microbubbles. J Ultrasound Med, 2022, 41(7): 1781-1789.

1. Yang C, Ma Y, Xie L, et al. Intracranial pressure monitoring in the intensive care unit for patients with severe traumatic brain injury: analysis of the CENTER-TBI China registry. Neurocrit Care, 2022, 37(1): 160-171.
2. Smith M. Monitoring intracranial pressure in traumatic brain injury. Anesth Analg, 2008, 106(1): 240-248.
3. Cremer O L. Does ICP monitoring make a difference in neurocritical care?. Eur J Anaesthesiol Suppl, 2008, 42: 87-93.
4. Shi W T, Forsberg F, Raichlen J S, et al. Pressure dependence of subharmonic signals from contrast microbubbles. Ultrasound Med Biol, 1999, 25(2): 275-283.
5. Halldorsdottir V G, Dave J K, Leodore L M, et al. Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions. Ultrason Imaging, 2011, 33(3): 153-164.
6. Dave J K, Halldorsdottir V G, Eisenbrey J R, et al. Noninvasive estimation of dynamic pressures in vitro and in vivo using the subharmonic response from microbubbles. IEEE Trans Ultrason Ferroelectr Freq Control, 2011, 58(10): 2056-2066.
7. Dave J K, Halldorsdottir V G, Eisenbrey J R, et al. Noninvasive LV pressure estimation using subharmonic emissions from microbubbles. JACC Cardiovasc Imaging, 2012, 5(1): 87-92.
8. Dave J K, Halldorsdottir V G, Eisenbrey J R, et al. Investigating the efficacy of subharmonic aided pressure estimation for portal vein pressures and portal hypertension monitoring. Ultrasound Med Biol, 2012, 38(10): 1784-1798.
9. Andersen K S, Jensen J A. Impact of acoustic pressure on ambient pressure estimation using ultrasound contrast agent. Ultrasonics, 2010, 50(2): 294-299.
10. Frinking P J, Brochot J, Arditi M. Subharmonic scattering of phospholipid-shell microbubbles at low acoustic pressure amplitudes. IEEE Trans Ultrason Ferroelectr Freq Control, 2010, 57(8): 1762-1771.
11. Li F, Li D, Yan F. Improvement of detection sensitivity of microbubbles as sensors to detect ambient pressure. Sensors, 2018, 18(12): 4083.
12. Nio A Q X, Faraci A, Christensen-Jeffries K, et al. Optimal control of SonoVue microbubbles to estimate hydrostatic pressure. IEEE Trans Ultrason Ferroelectr Freq Control, 2020, 67(3): 557-567.
13. Halldorsdottir V G, Dave J K, Marshall A, et al. Subharmonic-aided pressure estimation for monitoring interstitial fluid pressure in tumors: calibration and treatment with paclitaxel in breast cancer xenografts. Ultrasound Med Biol, 2017, 43(7): 1401-1410.
14. 向恒, 阳锐, 邹远文等. 超声亚谐波无创评估门静脉压力的体外实验研究. 生物医学工程学杂志, 2020, 37(6): 1073-1079.
15. Xu G, Lu H, Yang H, et al. Subharmonic scattering of SonoVue microbubbles within 10-40 mmHg overpressures in vitro. IEEE Trans Ultrason Ferroelectr Freq Control, 2021, 68(12): 3583-3591.
16. Lu H, Xu G, Wang Y, et al. Correlation between portal vein pressure and subharmonic scattering signals from SonoVue microbubbles in canines. Ultrasound Med Biol, 2023, 49(1): 203-211.
17. Zheng S, Zhang Y, Cheng L, et al. Noninvasive assessment of intracranial pressure using subharmonic-aided pressure estimation: an experimental study in canines. J Trauma Acute Care Surg, 2022, 93(6): 882-888.
18. Wang Y, Lu H, Huang L, et al. Noninvasive estimation of tumor interstitial fluid pressure from subharmonic scattering of ultrasound contrast microbubbles. Biosensors (Basel), 2023, 13(5): 528.
19. Xu G, Wang Y, Lu H, et al. Portal vein pressure estimation and portal hypertension discrimination based on subharmonic scattering of ultrasound contrast agent microbubbles. IEEE Trans Biomed Eng, 2023, PP. DOI: 10.1109/TBME.2023.3293952.
20. Mace E, Montaldo G, Osmanski B F, et al. Functional ultrasound imaging of the brain: theory and basic principles. IEEE Trans Ultrason Ferroelectr Freq Control, 2013, 60(3): 492-506.
21. Tanter M, Fink M. Ultrafast imaging in biomedical ultrasound. IEEE Trans Ultrason Ferroelectr Freq Control, 2014, 61(1): 102-119.
22. Errico C, Pierre J, Pezet S, et al. Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. Nature, 2015, 527(7579): 499-502.
23. Couture O, Hingot V, Heiles B, et al. Ultrasound localization microscopy and super-resolution: A state of the art. IEEE Trans Ultrason Ferroelectr Freq Control, 2018, 65(8): 1304-1320.
24. Gupta I, Eisenbrey J, Stanczak M, et al. Effect of pulse shaping on subharmonic aided pressure estimation in vitro and in vivo. J Ultrasound Med, 2017, 36(1): 3-11.
25. Goertz D E, de Jong N, van der Steen A F W. Attenuation and size distribution measurements of Definity™ and manipulated Definity™ populations. Ultrasound Med Biol, 2007, 33(9): 1376-1388.
26. Goertz D E, Cherin E, Needles A, et al. High frequency nonlinear B-scan imaging of microbubble contrast agents. IEEE Trans Ultrason Ferroelectr Freq Control, 2005, 52(1): 65-79.
27. Goertz D E, Needles A, Burns P N, et al. High-frequency, nonlinear flow imaging of microbubble contrast agents. IEEE Trans Ultrason Ferroelectr Freq Control, 2005, 52(3): 495-502.
28. Marmottant P, van der Meer S, Emmer M, et al. A model for large amplitude oscillations of coated bubbles accounting for buckling and rupture. J Acoust Soc Am, 2005, 118(6): 3499-3505.
29. Sarkar K, Katiyar A, Jain P. Growth and dissolution of an encapsulated contrast microbubble: effects of encapsulation permeability. Ultrasound Med Biol, 2009, 35(8): 1385-1396.
30. 何蒙娜, 姜玉新, 吕珂. 超声造影剂Sonazoid与SonoVue的物理特征及临床特点比较. 中国医学影像技术, 2015, 31(2): 306-309.
31. van Hoeve W, de Vargas Serrano M, Te Winkel L, et al. Improved sensitivity of ultrasound-based subharmonic aided pressure estimation using monodisperse microbubbles. J Ultrasound Med, 2022, 41(7): 1781-1789.

Journal of Biomedical Engineering

Experimental study on high-frequency subharmonic scattering characteristics of ultrasound contrast agent microbubbles under low ambient pressure

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