Focused Ultrasound Combined with Microbubbles for Inducing Blood-Brain Barrier Opening: Cavitation Monitoring and Control

doi:10.26599/AUDT.2026.250050

Abstract

Abstract:

Focused ultrasound (FUS) represents an emerging non-invasive technique capable of achieving reversible and targeted opening of the blood-brain barrier (BBB) when combined with microbubbles (MBs), significantly enhancing drug permeability. This technology demonstrates considerable potential in preclinical studies for diagnosing and treating neurological disorders. Ensuring safe and effective BBB opening while preventing tissue injuries such as red blood cell extravasation remains a critical translational challenge. This review examines the mechanisms of FUS combined with MBs induced BBB opening, key influencing factors, and recent advances in strategies for monitoring and controlling in vivo cavitation activity, providing foundational insights for future research.

Key words: Focused ultrasound; Microbubbles; Blood-brain barrier; Control; Cavitation; Monitoring

Li Na, Li Fan. Focused Ultrasound Combined with Microbubbles for Inducing Blood-Brain Barrier Opening: Cavitation Monitoring and Control. Advanced Ultrasound in Diagnosis and Therapy, 2026, 10(1): 51-58.

Figures/Tables 2

Figure 1

Table 1

Research Basis Information for Cavitation Monitoring Controllers"

Study	Model	Ultrasound parameters	Focus area	Microbubble	Monitoring target	Control type	Sonication termination
O'reilly (2012)	Rats	Frequency: 551.5 kHz RPF: 2 Hz Pulse duration: 10 ms Total treatment time: 2 min	The top of the cranium	Denity 0.02 mL/kg⁻¹	1.5f₀ and 2.5f₀ ultraharmonics	Open-loop	Stop with ultraharmonics
Tsai (2016)	Rats	dual-frequency FUS transducer: 0.55 MHz and 1.1 MHz Pulse duration: 10 ms PRF = 1 Hz Total treatment time: 90 s power range: 2-7 W	The top of the cranium	SonoVue 0.1 ml/kg⁻¹	Subharmonics dose (threshold method)	Open-loop	Sub-harmonics dose reached 0.55 MHz
Huang (2017)	Pigs	Frequency: 230 kHz RPF: 2 Hz Total sonication time: 50 s Power range: 3-10 W	The porcine brain	Denity 4 ml/kg⁻¹	Spectral integration of the subharmonic (threshold method)	Open-loop	Dual-Threshold Consecutive Trigger
Kamimur (2019)	Monkeys	Frequency: 500 kHz PRF: 5 Hz Pulse length: 10 ms Total treatment time: 2 min	Targe1: Hippocampus Target 2: 2 cm caudal offset Target 3: 2 cm rostral offset	SonoVue 0.3 ml/kg⁻¹	The SCD and ICD (threshold method)	Open-loop	End of duration
Sun (2017)	Rats	Frequency: 274.3 kHz PRF: 1 Hz/4 Hz Pulse duration: 32.3 ms	Striatum and hippocampus.	Optison 300 μl/kg⁻¹	harmonic emission (HE) and broadband emission (BE)	Open-loop	Detected BE/HE threshold reached
Robin (2021)	Mice	Frequency: 1.5 MHz PRF: 2 Hz Pulse length: 10 ms	The left striatum	Definity 0.1 µL/g⁻¹	the 3rd to 9th harmonic frequencies.	Open-loop	Reach the preset target value
Bing (2018)	Rats	Frequency: 0.5 MHz PRF: 1 Hz Pulse length: 10 ms Total treatment time: 125 s	Hippocampus on both sides	Optison: 30 μl/kg⁻¹ Denity: 6 μl/kg⁻¹ Nanobubble: 737 μl/kg⁻¹	AUC by summing at sub- or ultra- harmonics amplitudes within ± 0.05 MHz bandwidth	Real-time closed-loop	End of duration
Çavuşoğlu (2019)	Mice	frequency: 650 KHz PRF: 1 Hz Pulse duration: 10 ms Total treatment time: 5 min	The top of the cranium	BG8235 1.1-1.2 μl/kg⁻¹	the broadband response	Real-time closed-loop	End of duration
McDannol (2020)	Rats	Frequency: 660 kHz PRF: 1.1 Hz Pulse duration: 5 ms Power range: 0.16-0.39 W Total treatment time: 55 s	Most of the right hemisphere of the brain	Denity: 20 μl/kg⁻¹ BG8774: 20 μl/kg⁻¹ MSB4: 20 μl/kg⁻¹	subharmonic and bandwidth	Real-time closed-loop	End of duration
Chien (2022)	Mice	Frequency: 1.5 MHz\| Pulse length: 6.7 ms	The brainstem	Denity 8 × 10⁸ Mbs/ml	SC level: sum spectrum magnitude at the third harmonic IC level: sum spectrum magnitude at 3.3 ± 0.02 MHz	Real-time closed-loop	End of duration
Chien (2022)	Pigs	Frequency: 2.25 MHz PRF: 1 Hz Pulse length: 10 ms Total treatment time: 180 s	The cortical brain region	Denity 10 μl/kg⁻¹	SC level: sum spectrum magnitude at the fourth harmonic IC level: sum spectrum magnitude at 2.1 ± 0.02 MHz	Real-time closed-loop	End of duration
Lee (2022)	Mice	Frequency: 1.64 MHz PRF: 1 Hz Pulse length: 10 ms	The entire tumor and its periphery	Denity/10 μl/kg⁻¹	The third harmonic level	Real-time closed-loop	End of duration

Table 1

References 54

[1]	Knox EG, Aburto MR, Clarke G, Cryan JF, O'Driscoll CM. The blood-brain barrier in aging and neurodegeneration. Mol Psychiatry 2022; 27: 2659-2673. doi: 10.1038/s41380-022-01511-z
[2]	Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell 2015; 163: 1064-1078. doi: 10.1016/j.cell.2015.10.067
[3]	Zhao P, Wu T, Tian Y, You J, Cui X. Recent advances of focused ultrasound induced blood-brain barrier opening for clinical applications of neurodegenerative diseases. Adv Drug Deliv Rev 2024; 209: 115323. doi: 10.1016/j.addr.2024.115323
[4]	Keiser MS, Chen YH, Davidson BL. Techniques for intracranial stereotaxic injections of adeno-associated viral vectors in adult mice. Curr Protoc Mouse Biol 2018; 8: e57. doi: 10.1002/cpmo.57
[5]	D'Amico RS, Aghi MK, Vogelbaum MA, Bruce JN. Convection-enhanced drug delivery for glioblastoma: a review. J Neurooncol 2021; 151: 415-427. doi: 10.1007/s11060-020-03408-9
[6]	Tan JS, Jaffar Ali MNB, Gan BK, Tan WS. Next-generation viral nanoparticles for targeted delivery of therapeutics: Fundamentals, methods, biomedical applications, and challenges. Expert Opin Drug Deliv 2023; 20: 955-978. doi: 10.1080/17425247.2023.2228202
[7]	Saksena J, Hamilton AE, Gilbert RJ, Zuidema JM. Nanomaterial payload delivery to central nervous system glia for neural protection and repair. Front Cell Neurosci 2023; 17: 1266019. doi: 10.3389/fncel.2023.1266019
[8]	Rao R, Patel A, Hanchate K, Robinson E, Edwards A, Shah S, et al. Advances in focused ultrasound for the treatment of brain tumors. Tomography 2023; 9: 1094-1109. doi: 10.3390/tomography9030090
[9]	Liu HL, Yang HW, Hua MY, Wei KC. Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status. Neurosurg Focus 2012; 32: E4.
[10]	Memari E, Khan D, Alkins R, Helfield B. Focused ultrasound-assisted delivery of immunomodulating agents in brain cancer. J Control Release 2024; 367: 283-299. doi: 10.1016/j.jconrel.2024.01.034
[11]	Schoen S Jr, Kilinc MS, Lee H, Guo Y, Degertekin FL, Woodworth GF, et al. Towards controlled drug delivery in brain tumors with microbubble-enhanced focused ultrasound. Adv Drug Deliv Rev 2022; 180: 114043. doi: 10.1016/j.addr.2021.114043
[12]	Scott K, Klaus SP. Focused ultrasound therapy for Alzheimer's disease: exploring the potential for targeted amyloid disaggregation. Front Neurol 2024; 15: 1426075. doi: 10.3389/fneur.2024.1426075
[13]	Rezai AR, Ranjan M, Haut MW, Carpenter J, D'Haese PF, Mehta RI, et al. Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes. J Neurosurg 2022; 139: 275-283.
[14]	Jahangiri S, Yu F. Fundamentals and applications of focused ultrasound-assisted cancer immune checkpoint inhibition for solid tumors. Pharmaceutics 2024; 16: 411. doi: 10.3390/pharmaceutics16030411
[15]	Gorick CM, Breza VR, Nowak KM, Cheng VWT, Fisher DG, Debski AC, et al. Applications of focused ultrasound-mediated blood-brain barrier opening. Adv Drug Deliv Rev 2022; 191: 114583. doi: 10.1016/j.addr.2022.114583
[16]	Hughes A, Khan DS, Alkins R. Current and emerging systems for focused ultrasound-mediated blood-brain barrier opening. Ultrasound Med Biol 2023; 49: 1479-1490. doi: 10.1016/j.ultrasmedbio.2023.02.017
[17]	Mondou P, Mériaux S, Nageotte F Vappou J Novell A Larrat Larrat. State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound. Phys Med Biol 2023; 68:.
[18]	Ching-Hsiang Fan, Chih-Kuang Yeh. Microbubble-enhanced focused ultrasound-induced blood–brain barrier opening for local and transient drug delivery in central nervous system disease. Journal of Medical Ultrasound 2014; 22: 183-193. doi: 10.1016/j.jmu.2014.11.001
[19]	McDannold N, Vykhodtseva N, Hynynen K. Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity. Phys Med Biol 2006; 51: 793-807. doi: 10.1088/0031-9155/51/4/003
[20]	Apfel RE, Holland CK. Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound. Ultrasound Med Biol 1991; 17: 179-185. doi: 10.1016/0301-5629(91)90125-G
[21]	Bader KB, Holland CK. Gauging the likelihood of stable cavitation from ultrasound contrast agents. Phys Med Biol 2013; 58: 127-144. doi: 10.1088/0031-9155/58/1/127
[22]	Jin Q, Kang ST, Chang YC, Zheng H, Yeh CK. Inertial cavitation initiated by polytetrafluoroethylene nanoparticles under pulsed ultrasound stimulation. Ultrason Sonochem 2016; 32: 1-7. doi: 10.1016/j.ultsonch.2016.02.009
[23]	Chen H, Kreider W, Brayman AA, Bailey MR, Matula TJ. Blood vessel deformations on microsecond time scales by ultrasonic cavitation. Phys Rev Lett 2011; 106: 034301. doi: 10.1103/PhysRevLett.106.034301
[24]	Tung YS, Marquet F, Teichert T, Ferrera V, Konofagou EE. Feasibility of noninvasive cavitation-guided blood-brain barrier opening using focused ultrasound and microbubbles in nonhuman primates. Appl Phys Lett 2011; 98: 163704. doi: 10.1063/1.3580763
[25]	Rigollet S, Rome C, Ador T, Dumont E, Pichon C, Delalande A, et al. FUS-mediated BBB opening leads to transient perfusion decrease and inflammation without acute or chronic brain lesion. Theranostics 2024; 14: 4147-4160. doi: 10.7150/thno.96721
[26]	Gao Y, Gao S, Zhao B, Zhao Y, Hua X, Tan K, et al. Vascular effects of microbubble-enhanced, pulsed, focused ultrasound on liver blood perfusion. Ultrasound Med Biol 2012; 38: 91-98. doi: 10.1016/j.ultrasmedbio.2011.09.018
[27]	Izhar M, Thakur A, Park DJ, Chang SD. Ultrasound mediated blood-brain barrier opening increases brain tumor biomarkers: A review of preclinical and clinical trials. J Liq Biopsy 2024; 6: 100277. doi: 10.1016/j.jlb.2024.100277
[28]	Jung O, Thomas A, Burks SR, Dustin ML, Frank JA, Ferrer M, et al. Neuroinflammation associated with ultrasound-mediated permeabilization of the blood-brain barrier. Trends Neurosci 2022; 45: 459-470. doi: 10.1016/j.tins.2022.03.003
[29]	Chen M, Peng C, Wu H, Huang CC, Kim T, Traylor Z, et al. Numerical and experimental evaluation of low-intensity transcranial focused ultrasound wave propagation using human skulls for brain neuromodulation. Med Phys 2023; 50: 38-49. doi: 10.1002/mp.16090
[30]	Gerstenmayer M, Fellah B, Magnin R, Selingue E, Larrat B. Acoustic transmission factor through the rat skull as a function of body mass, frequency and position. Ultrasound Med Biol 2018; 44: 2336-2344. doi: 10.1016/j.ultrasmedbio.2018.06.005
[31]	Fletcher SP, Zhang Y, Chisholm A, Martinez S, McDannold N. The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening. Phys Med Biol 2024; 69:.
[32]	Carpentier A, Stupp R, Sonabend AM, Dufour H, Chinot O, Mathon B, Ducray F, Guyotat J, Baize N, Menei P, de Groot J, Weinberg JS, Liu BP, Guemas E, Desseaux C, Schmitt C, Bouchoux G, Canney M, Idbaih A. Repeated blood-brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial. Nat Commun 2024; 15: 1650. doi: 10.1038/s41467-024-45818-7
[33]	Wasielewska JM, White AR. "Focused ultrasound-mediated drug delivery in humans - a path towards translation in neurodegenerative diseases". Pharm Res 2022; 39: 427-439. doi: 10.1007/s11095-022-03185-2
[34]	Olumolade OO, Wang S, Samiotaki G, Konofagou EE. Longitudinal motor and behavioral assessment of blood-brain barrier opening with transcranial focused ultrasound. Ultrasound Med Biol 2016; 42: 2270-2282. doi: 10.1016/j.ultrasmedbio.2016.05.004
[35]	Shin J, Kong C, Cho JS, Lee J, Koh CS, Yoon MS, et al. Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters. Neurosurg Focus 2018; 44: E15.
[36]	Parks TV, Szuzupak D, Choi SH, Alikaya A, Mou Y, Silva AC, et al. Noninvasive disruption of the blood-brain barrier in the marmoset monkey. Commun Biol 2023; 6: 806. doi: 10.1038/s42003-023-05185-3
[37]	Martinez PJ, Song JJ, Castillo JI, DeSisto J, Song KH, Green AL, et al. Effect of microbubble size, composition, and multiple sonication points on sterile inflammatory response in focused ultrasound-mediated blood-brain barrier opening. ACS Biomater Sci Eng 2024; 10: 7451-7465. doi: 10.1021/acsbiomaterials.4c00777
[38]	O'Reilly MA, Huang Y, Hynynen K. The impact of standing wave effects on transcranial focused ultrasound disruption of the blood-brain barrier in a rat model. Phys Med Biol 2010; 55: 5251-5267. doi: 10.1088/0031-9155/55/18/001
[39]	Choi JJ, Feshitan JA, Baseri B, Wang S, Tung YS, Borden MA, et al. Microbubble-size dependence of focused ultrasound-induced blood-brain barrier opening in mice in vivo. IEEE Trans Biomed Eng 2010; 57: 145-154. doi: 10.1109/TBME.2009.2034533
[40]	Arvanitis CD, Livingstone MS, Vykhodtseva N, McDannold N. Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring. PLoS One 2012; 7: e45783. doi: 10.1371/journal.pone.0045783
[41]	de Jong N, Emmer M, van Wamel A, Versluis M. Ultrasonic characterization of ultrasound contrast agents. Med Biol Eng Comput 2009; 47: 861-873. doi: 10.1007/s11517-009-0497-1
[42]	Pouliopoulos AN, Kwon N, Jensen G, Meaney A, Niimi Y, Burgess MT, et al. Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates. Sci Rep 2021; 11: 15043. doi: 10.1038/s41598-021-94188-3
[43]	O'Reilly MA, Hynynen K. Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology 2012; 263: 96-106. doi: 10.1148/radiol.11111417
[44]	Tsai CH, Zhang JW, Liao YY, Liu HL. Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers. Phys Med Biol 2016; 61: 2926-2946. doi: 10.1088/0031-9155/61/7/2926
[45]	Huang Y, Alkins R, Schwartz ML, Hynynen K. Opening the blood-brain barrier with mr imaging-guided focused ultrasound: preclinical testing on a trans-human skull porcine model. Radiology 2017; 282: 123-130. doi: 10.1148/radiol.2016152154
[46]	Kamimura HA, Flament J, Valette J, Cafarelli A, Aron Badin R, Hantraye P, et al. Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance. J Cereb Blood Flow Metab 2019; 39: 1191-1203. doi: 10.1177/0271678X17753514
[47]	Ji R, Karakatsani ME, Burgess M, Smith M, Murillo MF, Konofagou EE. Cavitation-modulated inflammatory response following focused ultrasound blood-brain barrier opening. J Control Release 2021; 337: 458-471. doi: 10.1016/j.jconrel.2021.07.042
[48]	Sun T, Zhang Y, Power C, Alexander PM, Sutton JT, Aryal M, et al. Closed-loop control of targeted ultrasound drug delivery across the blood-brain/tumor barriers in a rat glioma model. Proc Natl Acad Sci U S A 2017; 114: E10281-E10290.
[49]	Bing C, Hong Y, Hernandez C, Rich M, Cheng B, Munaweera I, et al. Characterization of different bubble formulations for blood-brain barrier opening using a focused ultrasound system with acoustic feedback control. Sci Rep 2018; 8: 7986. doi: 10.1038/s41598-018-26330-7
[50]	McMahon D, Lassus A, Gaud E, Jeannot V, Hynynen K. Microbubble formulation influences inflammatory response to focused ultrasound exposure in the brain. Sci Rep 2020; 10: 21534. doi: 10.1038/s41598-020-78657-9
[51]	Chien CY, Yang Y, Gong Y, Yue Y, Chen H. Blood-brain barrier opening by individualized closed-loop feedback control of focused ultrasound. BME Front 2022; 2022: 9867230. doi: 10.34133/2022/9867230
[52]	Chien CY, Xu L, Pacia CP, Yue Y, Chen H. Blood-brain barrier opening in a large animal model using closed-loop microbubble cavitation-based feedback control of focused ultrasound sonication. Sci Rep 2022; 12: 16147. doi: 10.1038/s41598-022-20568-y
[53]	Lee H, Guo Y, Ross JL, Schoen S Jr, Degertekin FL, Arvanitis C. Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade. Sci Adv 2022; 8: eadd2288. doi: 10.1126/sciadv.add2288
[54]	Shijie Lv, Huifeng Zheng, Runguang Yao, Yuebin Wang, Baoming Peng. Monitoring acoustic cavitation effects in tissues under the action of HIFU based on ultrasound images. Applied Acoustics 2024; 219: 109937. doi: 10.1016/j.apacoust.2024.109937