The use of ultrasound contrast agents (UCAs) for estimating portal pressure has recently gained attention due to its clinical promise, yet variability in acoustic amplitude poses challenges. UCAs contain microbubbles (1–10 µm in diameter), and understanding their acoustic response is essential to address this variability. However, systematic exploration of factors influencing microbubble behavior remains limited in current literature. This paper introduces a novel finite element analysis-based framework for portal pressure estimation, bridging key gaps. Developed in two stages, the model first captures the subharmonic response of a single bubble to an acoustic excitation of 50 kPa at 4 MHz, highlighting the influence of bubble size on resonance frequency. In the second stage, single-bubble responses are extended to analyze how microbubble population, size, and spatial distribution affect portal pressure estimation. For the first time, this study elucidates the experimental scatter in pressure measurements through a comprehensive consideration of these variables, offering new directions for UCA-based clinical pressure estimation in applications such as portal and cardiac pressure assessment.
SanyalAJBoschJBleiA, et al. Portal hypertension and its complications. Gastroenterology2008; 134: 1715–1728.
2.
DaveJKHalldorsdottirVGEisenbreyJR, et al. Investigating the efficacy of subharmonic aided pressure estimation for portal vein pressures and portal hypertension monitoring. Ultrasound Med Biol2012; 38: 1784–1798.
XuGLiFMaoY.Portal pressure monitoring—state-of-the-art and future perspective. Ann Transl Med2019; 7: 583.
5.
FairbankWMScullyMO.A new noninvasive technique for cardiac pressure measurement: resonant scattering of ultrasound from bubbles. IEEE Trans Biomed Eng1977; 24: 107–110.
6.
HökB.A new approach to noninvasive manometry: Interaction between ultrasound and bubbles. Med Biol Eng Comput1981; 19: 35–39.
7.
ShankarPMChapelonJYNewhouseVL.Fluid pressure measurement using bubbles insonified by two frequencies. Ultrasonics1986; 24: 333–336.
8.
MiwaH.Pressure measuring system with ultrasonic wave. Patent 4483345, USA, 1984.
9.
BouakazAFrinkingPJde JongN, et al. Noninvasive measurement of the hydrostatic pressure in a fluid-filled cavity based on the disappearance time of micrometer-sized free gas bubbles. Ultrasound Med Biol1999; 25: 1407–1415.
10.
SunTJiaNZhangD, et al. Ambient pressure dependence of the ultra-harmonic response from contrast microbubbles. J Acoust Soc Am2012; 131: 4358–4364.
11.
WuJFanTXuD, et al. Overpressure dependence of sub-harmonic generation from contrast agent SonoVue microbubbles. Acta Acust United Acust2015; 101: 55–61.
12.
LiuSWuJGuY, et al. Ambient pressure evaluation through sub-harmonic response of chirp-sonicated microbubbles. Ultrasound Med Biol2017; 43: 332–340.
13.
ZomackMLohseD.Response of bubbles to diagnostic ultrasound: a unifying theoretical approach. Eur Phys J B1998; 4: 247–255.
14.
ZhengHBarkerAShandasR.Predicting backscatter characteristics from micron- and submicron- scale ultrasound contrast agents using a size-integration technique. IEEE Trans Ultrason Ferroelectr Freq Control2006; 53: 639–644.
15.
KatiyarASarkarKForsbergF.Modeling subharmonic response from contrast microbubbles as a function of ambient static pressure. J Acoust Soc Am2011; 129: 2325–2335.
16.
HuangBZhengH-RZhangD.Asymmetric oscillation and acoustic response from an encapsulated microbubble bound within a small vessel. Chinese Phys Lett2010; 27: 064302.
17.
HosseinkhahNHynynenK.A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels. Phys Med Biol2012; 57: 785–808.
18.
ShenYWangTChinC, et al. Interaction between microbubble and elastic microvessel in low frequency ultrasound field using finite element method. Chinese Sci Bull2013; 58: 291–298.
19.
ChenCGuYTuJ, et al. Microbubble oscillating in a microvessel filled with viscous fluid: a finite element modeling study. Ultrasonics2016; 66: 54–64.
20.
RiJPangNBaiS, et al. Three-dimensional numerical analysis of wall stress induced by asymmetric oscillation of microbubble trains inside micro-vessels. Phys Fluids2023; 35: 011904.
21.
MaedaKColoniusT.Bubble cloud dynamics in an ultrasound field. J Fluid Mech2019; 862: 1105–1134.
22.
ShiWForsbergFRaichlenJ, et al. Pressure dependence of subharmonic signals from contrast microbubbles. Ultrasound Med Biol1999; 25: 275–283.
23.
NioAQFaraciAChristensen-JeffriesK, et al. Optimal control of SonoVue microbubbles to estimate hydrostatic pressure. IEEE Trans Ultrason Ferroelectr Freq Control2020; 67: 557–567.
24.
LiFLiDYanF.Improvement of detection sensitivity of microbubbles as sensors to detect ambient pressure. Sensors2018; 18: 4083.
25.
DaveJKHalldorsdottirVGEisenbreyJR, et al. On the implementation of an automated acoustic output optimization algorithm for subharmonic aided pressure estimation. Ultrasonics2013; 53: 880–888.
26.
LuHXuGWangY, et al. Correlation between portal vein pressure and subharmonic scattering signals from SonoVue microbubbles in canines. Ultrasound Med Biol2023; 49: 203–211.
27.
XuGLuHYangH, et al. Subharmonic scattering of SonoVue microbubbles within 10–40-mmHg overpressures in vitro. IEEE Trans Ultrason Ferroelectr Freq Control2021; 68: 3583–3591.
28.
GuptaIEisenbreyJRMachadoP, et al. Diagnosing portal hypertension with noninvasive subharmonic pressure estimates from a US contrast agent. Radiology2021; 298: 104–111.
29.
EisenbreyJRDaveJKHalldorsdottirVG, et al. Chronic liver disease: noninvasive subharmonic aided pressure estimation of hepatic venous pressure gradient. Radiology2013; 268: 581–588.
30.
TirumaniSHPrasad ShanbhogueAKVikramR, et al. Imaging of the porta hepatis: spectrum of disease. Radiographics2014; 34: 73–92.
31.
WeinrebJKumariSPhillipsG, et al. Portal vein measurements by real-time sonography. Am J Roentgenol1982; 139: 497–499.
32.
HannessonPHStridbeckHLundstedtC, et al. Intravascular ultrasound of the portal vein — normal anatomy. Acta radiol1995; 36: 388–392.
33.
FrinkingPSegersTLuanY, et al. Three decades of ultrasound contrast agents: a review of the past, present and future improvements. Ultrasound Med Biol2020; 46: 892–908.
34.
DaeichinVFaezTRenaudG, et al. Effect of self-demodulation on the subharmonic response of contrast agent microbubbles. Phys Med Biol2012; 57: 3675–3691.
35.
MastTD.Empirical relationships between acoustic parameters in human soft tissues. Acoust Res Lett Online2000; 1: 37–42.
36.
LiFWangLFanY, et al. Simulation of noninvasive blood pressure estimation using ultrasound contrast agent microbubbles. IEEE Trans Ultrason Ferroelectr Freq Control2012; 59: 715–726.
37.
Jiménez-FernándezJ.Nonlinear response to ultrasound of encapsulated microbubbles. Ultrasonics2012; 52: 784–793.
38.
TuJGuanJQiuY, et al. Estimating the shell parameters of SonoVue® microbubbles using light scattering. J Acoust Soc Am2009; 126: 2954–2962.
39.
TengXDGuoXSTuJ, et al. Nonlinear response of ultrasound contrast agent microbubbles: from fundamentals to applications. Chin Phys B2016; 25: 124308.
40.
PatilAVReynoldsPHossackJA.A non-linear three-dimensional model for quantifying microbubble dynamics. J Acoust Soc Am2010; 127: EL80–EL86.
41.
CowleyJMulhollandAJGachaganA.A nonlinear elasticity approach to modelling the collapse of a shelled microbubble. IMA J Appl Math2017; 82: 781–801.
42.
ChenAIBalterMLChenMI, et al. Multilayered tissue mimicking skin and vessel phantoms with tunable mechanical, optical, and acoustic properties. Med Phys2016; 43: 3117–3131.
43.
AzhariH.Basics of biomedical ultrasound for engineers. Hoboken, NJ: John Wiley & Sons, 2010.
44.
GummerJSchenkeSDennerF.Modelling lipid-coated microbubbles in focused ultrasound applications at subresonance frequencies. Ultrasound Med Biol2021; 47: 2958–2979.
45.
HanifSSultanMMiyazakiT.Effect of relative humidity on thermal conductivity of zeolite-based adsorbents: theory and experiments. Appl Therm Eng2019; 150: 11–18.
46.
SojahroodAJHaghiHKarshafianR, et al. Critical corrections to models of nonlinear power dissipation of ultrasonically excited bubbles. Ultrason Sonochem2020; 66: 105089.
47.
BanerjeeDKNasrTNDreherWR, et al. Heavy oil recovery using SF6 and RF heating. Patent 8,960,286, USA, 2015.
48.
KotopoulisSPopaMMayoral SafontM, et al. SonoVue® vs. SonazoidTM vs. OptisonTM: which bubble is best for low-intensity sonoporation of pancreatic ductal adenocarcinoma?Pharmaceutics2022; 14: 98.
49.
Abaqus Theory Guide, Dassault Systémes, SIMULIA Corp., Providence
50.
AndersenKSJensenJA.Impact of acoustic pressure on ambient pressure estimation using ultrasound contrast agent. Ultrasonics2010; 50: 294–299.
51.
NioAQFaraciAChristensen-JeffriesK, et al. The subharmonic amplitude of SonoVue increases with hydrostatic pressure at low incident acoustic pressures. In: IEEE international ultrasonics symposium, 6 September 2017, pp.1–4. New York: IEEE.
52.
RooversSSegersTLajoinieG, et al. The role of ultrasound-driven microbubble dynamics in drug delivery: from microbubble fundamentals to clinical translation. Langmuir2019; 35: 10173–10191.
