Competition Between Acoustic Radiation Forces and Hydrodynamic Drag in Short-Pulsed-Ultrasound-Driven Microbubble Cluster Dynamics in Microfluidic Channel
摘要
Microbubble dynamics under short-pulse ultrasound in flowing environments are governed by the interplay between acoustic radiation forces and hydrodynamic drag, yet their coupled effects remain insufficiently understood. Here, we investigate microbubble cloud behaviour in a vessel-mimicking microfluidic channel under short-pulse ultrasound (1.125 MHz) and controlled laminar flow (37.5–150 µL/min). High-speed visualization reveals two distinct regimes: an actively interacting regime characterized by clustering and coalescence, and a ‘frozen’ regime in which microbubbles exhibit minimal displacement despite continued ultrasound excitation. A theoretical model incorporating lift force, Bjerknes forces, wall-induced hydrodynamic interaction, and hydrodynamic drag with wall correction captures the transition between actively moving and frozen states, confirming that both a low flow rate and short-pulse ultrasound sequences promote the development of ‘frozen’ bubble nearby the wall, and demonstrating that microbubble cloud dynamics under short-pulse excitation is determined by a dynamic competition between acoustic radiation forces and near-wall hydrodynamic drag, with flow rate and pulse duration acting as coupled control parameters.
参考文献
[1] O'reilly M A. Exploiting the mechanical effects of ultrasound for noninvasive therapy[J]. Science, 2024,385(6714):eadp7206.
[2] Sboros V. Response of contrast agents to ultrasound[J]. Advanced drug delivery reviews, 2008, 60(10):1117-1136.
[3] Faez T, Emmer M, Kooiman K, et al. 20 years of ultrasound contrast agent modeling[J]. IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 2012,60(1):7-20.
[4] Coussios C C, Roy R A. Applications of acoustics and cavitation to noninvasive therapy and drug delivery[J]. Annu Rev Fluid Mech, 2008, 40(1): 395-420.
[5] Cattaneo M, Guerriero G, Shakya G,et al. Cyclic jetting enables microbubble-mediated drug delivery[J].Nature Physics,2025,21(4):590-598.
[6] Chen H, Kreider W, Brayman A A, et al. Blood vessel deformations on microsecond time scales by ultrasonic cavitation[J]. Physical review letters, 2011, 106(3): 034301.
[7] Fan Y, Ohl C-D. Perforation of thin-membrane-covered soft matter induced by cavitation-initiated extreme mechanics[J]. Physical Review Applied, 2025, 23(2): 024052.
[8] Ohl C-D, Arora M, Ikink R, et al. Sonoporation from jetting cavitation bubbles[J]. Biophysical journal,2006,91(11):4285-4295.
[9] Li F, Yang C, Yuan F,et al. Dynamics and mechanisms of intracellular calcium waves elicited by tandem bubble-induced jetting flow[J]. Proc Natl Acad Sci U S A, 2018, 115(3): E353-e362.
[10] Maeda K, Colonius T. Bubble cloud dynamics in an ultrasound field[J]. Journal of fluid mechanics, 2019,862:1105-1134.
[11] Maeda K, Maxwell A D. Controlling the dynamics of cloud cavitation bubbles through acoustic feedback[J]. Physical Review Applied,2021, 15(3): 034033.
[12] Fan Y, Li H, Zhu J, et al. A simple model of bubble cluster dynamics in an acoustic field[J]. Ultrasonics Sonochemistry,2020,64:104790.
[13] Fan Y, Li H, Fuster D. Time-delayed interactions on acoustically driven bubbly screens[J]. The Journal of the Acoustical Society of America, 2021, 150(6): 4219-4231.
[14] Mettin R, Akhatov I, Parlitz U, et al. Bjerknes forces between small cavitation bubbles in a strong acoustic field[J]. Physical review E, 1997, 56(3): 2924.
[15] Louisnard O. A simple model of ultrasound propagation in a cavitating liquid. Part II: Primary Bjerknes force and bubble structures[J]. Ultrasonics sonochemistry,2012,19(1):66-76.
[16] Lanoy M, Derec C, Tourin A, et al. Manipulating bubbles with secondary Bjerknes forces[J]. Applied Physics Letters,2015,107(21).
[17] Gumerov NA, Akhatov I S. Modes of self-organization of diluted bubbly liquids in acoustic fields: One-dimensional theory[J]. The Journal of the Acoustical Society of America, 2017, 141(2): 1190-1202.
[18] Fan Y, Li H, Xu C, et al. Influence of bubble distributions on the propagation of linear waves in polydisperse bubbly liquids[J]. The Journal of the Acoustical Society of America, 2019, 145(1): 16-25.
[19] Postema M, Marmottant P, Lancée C T, et al. Ultrasound-induced microbubble coalescence[J].Ultrasound in medicine& biology,2004,30(10):1337-1344.
[20] Rychak J J,Klibanov AL, Hossack J A. Acoustic radiation force enhances targeted delivery of ultrasound contrast microbubbles: in vitro verification[J]. IEEE transactions on ultrasonics, ferroelectrics, and frequency control,2005,52(3):421-433.
[21] Rychak J J,Klibanov AL, Ley K F,et al. Enhanced targeting of ultrasound contrast agents using acoustic radiation force[J]. Ultrasound in medicine& biology,2007,33(7): 1132-1139.
[22] Kovacs Z I, Kim S, Jikaria N, et al. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation[J]. Proceedings of the National Academy of Sciences, 2017, 114(1): E75-E84.
[23] Shin J, Kong C, Cho J S,et al. Focused ultrasound-mediated noninvasive blood-brain barrier modulation:preclinical examination of efficacy and safety in various sonication parameters[J]. Neurosurgical Focus,2018,44(2):E15.
[24] Pouliopoulos A N, Kwon N, Jensen G, et al. Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates[J]. Scientific reports,2021,11(1):15043.
[25] Jordo J F, Thévenot E, Markham-Coultes K, et al. Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound[J]. Experimental neurology,2013,248:16-29.
[26] Choi J J, Selert K, Vlachos F, et al. Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles[J]. Proceedings of the National Academy of Sciences, 2011, 108(40): 16539-16544.
[27] Lim Kee Chang W, Chan T G, Raguseo F, et al. Rapid short-pulses of focused ultrasound and microbubbles deliver a range of agent sizes to the brain[J]. Scientific Reports, 2023, 13(1): 6963.
[28] Morse S V, Mishra A, Chan T G, et al. Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles[J]. Journal of Controlled Release,2022,341:605-615.
[29] Morse S V, Pouliopoulos A N, Chan T G,et al. Rapid short-pulse ultrasound delivers drugs uniformly across the murine blood-brain barrier with negligible disruption[J]. Radiology, 2019, 291(2): 459-466.
[30] O'reilly M A, Waspe A C, Ganguly M, et al. Focused-ultrasound disruption of the blood-brain barrier using closely-timed short pulses: influence of sonication parameters and injection rate[J]. Ultrasound Med Biol,2011,37(4):587-594.
[31] Zhou Q,Tan C,Liu C,et al. Regulating microbubble clusters for improving temporal uniformity of stable cavitation intensity under rapid short-pulse ultrasound[J]. Ultrasonics Sonochemistry,2025: 107582.
[32] Memari E, Hui F, Yusefi H, et al. Fluid flow influences ultrasound-assisted endothelial membrane permeabilization and calcium flux[J]. J Control Release,2023,358: 333-344.
[33] Jain R K. Determinants of tumor blood flow: a review[J]. Cancer Res, 1988, 48(10): 2641-2658.
[34] Yuan F, Leunig M, Huang S K,et al. Microvascular permeability and interstitial penetration of sterically stabilized(stealth) liposomes in a human tumor xenograft[J]. Cancer Res, 1994, 54(13): 3352-3356.
[35] Scremin O U,Li M G, Scremin A M,et al. Cholinesterase inhibition improves blood flow in the ischemic cerebral cortex[J]. Brain Res Bull, 1997,42(1):59-70.
[36] Li C, Ma Y, Liu M, et al. Characteristics of flow fields in the gas-liquid mini-bubble columns with particle image velocimetry measurements[J]. AIChE Journal, 2022, 68(9): e17798.
[37] Sennoga CA, Seddon J M, Frueh J A,et al. Dynamics of targeted microbubble adhesion under pulsatile compared with steady flow[J]. Ultrasound in Medicine& Biology, 2014, 40(10): 2445-2457.
[38] Yan F, Li X, Jiang C, et al. A novel microfluidic chip for assessing dynamic adhesion behavior of cell-targeting microbubbles[J]. Ultrasound in Medicine& Biology,2014,40(1): 148-157.
[39] Acconcia C N, Leung B Y, Winch G, et al. Acoustic radiation force induced accumulation and dynamics of microbubbles on compliant surfaces[J]. Physics in Medicine& Biology, 2019, 64(13): 135003.
[40] Juang E K, De Cock I, Keravnou C, et al. Engineered 3D microvascular networks for the study of ultrasound-microbubble-mediated drug delivery[J]. Langmuir, 2018,35(31): 10128-10138.
[41] Pouliopoulos A N, Li C, Tinguely M, et al. Rapid short-pulse sequences enhance the spatiotemporal uniformity of acoustically driven microbubble activity during flow conditions[J]. The Journal of the Acoustical Society of America, 2016, 140(4): 2469-2480.
[42] De Maio A, Lin F-H, Stefanovic B, et al. Tissue-type Differences in Focused Ultrasound and Microbubble-mediated Drug Delivery to the Brain Exist at Vessel Level[J]. Theranostics, 2026, 16(4):1975.
[43] Zhang X, Huk D, Wang Q,et al. A microfluidic shear device that accommodates parallel high and low stress zones within the same culturing chamber[J]. Biomicrofluidics, 2014, 8(5).
[44] Park W, Choi M J, Lee J S, et al. Embedded 3D-Coaxial Bioprinting of Stenotic Brain Vessels with a Mechanically Enhanced Extracellular Matrix Bioink for Investigating Hemodynamic Force-Induced Endothelial Responses[J]. Advanced Functional Materials, 2025, 35(50): e04276.
[45] Juste-Lanas Y, Hervas-Raluy S, Garcia-Aznar J M,et al. Fluid flow to mimic organ function in 3D in vitro models[J].APL bioengineering,2023,7(3).
[46] Li S, Liu X, Zhang L,et al. Integrated applications of microfluidics, organoids, and 3D bioprinting in in vitro 3D biomimetic models[J]. International Journal of Bioprinting,2025,11(3):115-153.
[47] Cai Y, Fan K, Lin J,et al. Advances in BBB on chip and application for studying reversible opening of blood-brain barrier by sonoporation[J]. Micromachines,2022,14(1):112.
[48] Li F, Yuan F, Sankin G,et al.A Microfluidic System with Surface Patterning for Investigating Cavitation Bubble(s)-Cell Interaction and the Resultant Bioeffects at the Single-cell Level[J].J Vis Exp,2017,(119).
[49] Squires T M, Quake S R. Microfluidics: Fluid physics at the nanoliter scale[J]. Reviews of modern physics,2005,77(3):977-1026.
[50] Van Der Kroon I, Quinto-Su PA, Li F, et al. Acoustically driven cavitation cluster collapse in planar geometry[J]. Phys Rev E Stat Nonlin Soft Matter Phys,2010,82(6 Pt 2):066311.
[51] Helfield B, Chen X, Watkins S C, et al. Biophysical insight into mechanisms of sonoporation[J]. Proceedings of the National Academy of Sciences, 2016, 113(36): 9983-9988.
[52] Qiao C, Luo S, Liu Z,et al. Tuning Endothelial Barrier Permeability with Ultrasound: A Pulse-Length-Dependent Interplay Between Bubble Dynamics and Cellular Bioeffects[J]. LangTaoSha Preprint Server,2026.
[53] Shen Y, Cai Y, Qiao C, et al. A bottom-up approach to understanding ultrasound mediated blood-brain barrier opening using long and short pulses[J]. bioRxiv, 2025: 2025.2006.2011.659100.
[54] Heiles B, Chavignon A, Hingot V, et al. Performance benchmarking of microbubble-localization algorithms for ultrasound localization microscopy[J]. Nature Biomedical Engineering, 2022, 6(5): 605-616.
[55] Bruus H. Theoretical microfluidics[M]. Oxford university press, 2007.
[56] Poelma C. Ultrasound imaging velocimetry: a review[J]. Experiments in Fluids, 2017, 58(1): 3.
[57] Zhang J,Yan S, Yuan D,et al. Fundamentals and applications of inertial microfluidics: a review[J]. Lab on a Chip, 2016, 16(1): 10-34.
[58] Blake J R. The Kelvin impulse: application to cavitation bubble dynamics[J]. The ANZIAM Journal,1988,30(2):127-146.
[59] Xu P, Li B, Ren Z,et al. Dynamics of a laser-induced buoyant bubble near a vertical rigid boundary[J]. Physical Review Fluids, 2023, 8(8): 083601.
[60] Supponen O, Obreschkow D, Tinguely M, et al. Scaling laws for jets of single cavitation bubbles[J]. Journal of Fluid Mechanics, 2016, 802: 263-293.
[61] Segers T, Versluis M. Acoustic bubble sorting for ultrasound contrast agent enrichment[J]. Lab on a Chip,2014,14(10):1705-1714.
[62] Goldmans A, Brenner H. Slow viscous motion of a sphere parallel to a plane wall-I Motion through a quiescent fluid[J]. Chemical Engineering Science, 1967, 22: 637651.
[63] Watanabe T, Kukita Y. Translational and radial motions of a bubble in an acoustic standing wave field[J]. Physics of Fluids A: Fluid Dynamics, 1993, 5(11): 2682-2688.
[64] Zeng L, Najjar F, Balachandar S,et al. Forces on a finite-sized particle located close to a wall in a linear shear flow[J]. Physics of fluids, 2009, 21(3).
[65] Nanayakkara S, Zhao J, Terrington S,et al. Effects of surface roughness on the drag coefficient of spheres freely rolling on an inclined plane[J]. Journal of Fluid Mechanics, 2024, 984: A13.
[66] Zhou Z, Jin G, Tian B,et al. Hydrodynamic force and torque models for a particle moving near a wall at finite particle Reynolds numbers[J]. International Journal of Multiphase Flow, 2017, 92: 1-19.
[67] Li F, Yang C, Yuan F,et al. Dynamics and mechanisms of intracellular calcium waves elicited by tandem bubble-induced jetting flow[J]. Proceedings of the National Academy of Sciences, 2018, 115(3): E353-E362.
[68] Lin J, Qiao C, Jiang H,et al. Reversible Ca2+ signaling and enhanced paracellular transport in endothelial monolayer induced by acoustic bubbles and targeted microbeads[J]. Ultrasonics Sonochemistry, 2025,112:107181.
[69] Li F, Park T H, Sankin G,et al. Mechanically induced integrin ligation mediates intracellular calcium signaling with single pulsating cavitation bubbles[J]. Theranostics, 2021, 11(12): 6090.
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