The blood-brain barrier is the primary obstacle to efficient intracerebral drug delivery. Focused ultrasound, in conjunction with microbubbles, is a targeted and non-invasive way to disrupt the blood-brain barrier. Many commercially available ultrasound contrast agents and agents specifically designed for therapeutic purposes have been investigated in ultrasound-mediated blood-brain barrier opening studies. The new generation of sono-sensitive agents, such as liquid-core droplets, can also potentially disrupt the blood-brain barrier after their ultrasound-induced vaporization. In this review, we describe the different compositions of agents used for ultrasound-mediated blood-brain barrier opening in recent studies, and we discuss the challenges of the past five years related to the optimal formulation of agents.

Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.

Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood-brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [¹⁸F]2-fluoro-2-deoxy-sorbitol ([¹⁸F]FDS) was evaluated as a small-molecule (paracellular) marker of blood-brain barrier (BBB) integrity. [¹⁸F]FDS was straightforwardly produced from chemical reduction of commercial [¹⁸F]2-deoxy-2-fluoro-D-glucose. [¹⁸F]FDS and the invasive BBB integrity marker Evan’s blue (EB) were i.v. injected in mice after an optimized FUS protocol designed to generate controlled hemispheric BBB disruption. Quantitative determination of the impact of FUS on the BBB permeability was determined using kinetic modeling. A 2.2 ± 0.5-fold higher PET signal (n = 5; p < 0.01) was obtained in the sonicated hemisphere and colocalized with EB staining observed post mortem. FUS significantly increased the blood-to-brain distribution of [¹⁸F]FDS by 2.4 ± 0.8-fold (V_T; p < 0.01). Low variability (=10.1%) of V_T values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [¹⁸F]FDS PET provides a readily available, sensitive and reproducible marker of BBB permeability to noninvasively monitor the extent of BBB disruption induced by FUS in vivo.

Objective. Cavitation dose monitoring plays a key role in ultrasound drug delivery to the brain. The use of capacitive micromachined ultrasonic transducer (CMUT) technology has a great potential for passive cavitation detection (PCD). Approach. Here, a circular (diameter 7 mm) CMUT centered at 5 MHz was designed to be inserted into a therapeutic transducer (1.5 MHz) used for ultrasound-induced blood–brain barrier (BBB) disruption on mice. CMUT-based real-time cavitation detection was performed during the ultrasound procedure (50 μl intravenous injection of SonoVue microbubbles, frequency 1.5 MHz, PNP 480 kPa, duty Cycle 10%, PRF 10 Hz, duration 60 s). BBB disruption were confirmed by contrast-enhanced 7T-MRI. Main results. The CMUT device has a fractional bandwidth of 140%, almost twice a conventional piezocomposite PCD transducer. As expected, the CMUT device was able to detect the occurrence of harmonic, subharmonic and ultraharmonic frequencies as well as the increase of broadband signal indicating inertial cavitation in a wide frequency range (from 0.75 to 6 MHz). Signal-to-noise ratio was high enough (>40 dB) to perform ultrafast monitoring and follow the subtle intrapulse variations of frequency components at a rate of 10 kHz. Significance. This first in vivo proof of concept demonstrates the interest of CMUT for PCD and encourages us to develop devices for PCD in larger animals by integrating an amplifier directly to the CMUT front-end to considerably increase the signal-to-noise ratio.

Microbubble-mediated focused ultrasound is a promising strategy for transient and localized blood-brain barrier (BBB) permeabilization, enabling drug delivery to the brain. Optimizing microbubble stability and acoustic response is essential to maximize treatment efficiency and minimize potential damage. This study introduces an innovative microbubble formulation with a phospholipid-fluoropolymer shell (LIP-POL), designed to enhance circulation persistence while maintaining a low cavitation threshold. The physicochemical and acoustic properties of LIP-POL microbubbles were systematically compared with phospholipid-shell microbubbles (LIP) and the commercial agent SonoVue®. Both SonoVue and LIP-POL microbubbles have similar concentrations and sizes (approximately 5 × 10⁸ bubbles/mL, mean size of 2.5-2.7 µm), whereas LIP microbubbles are around 100 times more concentrated (7.3 × 10¹⁰ bubbles/mL) and slightly smaller (1.9 µm). In vitro, ultra-harmonics appeared at 120 kPa for LIP, 150 kPa for LIP-POL, and 200 kPa for SonoVue (fc = 1 MHz, PRF = 10 kHz, 40 cycles). Consistent with microbubbles' acoustic signature, the BBB opening threshold (fc = 1.5 MHz) occurred at lower Mechanical Indices (MI) for LIP and LIP-POL microbubbles (MI = 0.16) compared to SonoVue (MI = 0.20). Stability of circulating microbubbles was assessed using BBB permeabilization protocol at various time points post microbubble-injection. LIP-POL microbubbles remained effective for up to 15 min post-injection, compared to 7.5 min for LIP and 5 min for SonoVue (2 × 10⁷ microbubbles injected). The prolonged efficacy of LIP-POL microbubbles (three times longer than SonoVue) opens the possibility for extended ultrasound treatments, particularly for BBB permeabilization across larger areas in large animal models or humans.

As differential exposure to airport-generated aerosols may affect employee lung function, the main objective of this study was to longitudinally evaluate spirometry measures among Air France employees. In addition, an exploratory exposure assessment to airport aerosol was performed in a small cohort of workers using personal monitoring devices. Change in lung function over a ~6.6-yr period was documented for office workers (n = 68) and mechanics (n = 83) at Paris-Roissy airport, France and terminal (n = 29), or apron (n = 35) workers at Marseille airport, France. Overall, an excessive decline in lung function was found for 24.75% of airport workers; excessive decline occurred more often for terminal workers (44.83%) as compared to mechanics (14.47%; P = 0.0056), with a similar tendency for apron workers (35.29%) as compared to mechanics (P = 0.0785). Statistically significant differences/tendencies were detected among the yearly rates of change for %-predicted values of forced expiratory volume in 1 s, forced vital capacity, peak expiratory flow, and from 25% to 75% forced expiratory flow. For the latter variables, the terminal and/or apron workers at Marseille generally had significantly faster lung function decline as compared to office workers and/or mechanics in Paris, although the latter were exposed to a higher level of elemental carbon. No relation between lung function decline and exposure to airport tarmac environments was evidenced. Multivariate exploration of individual variables representing sex, smoking, atopy, respiratory disease, residential PM_2.5 pollution, the peak size of particles in lung exhalates or exhaled carbon monoxide at the time of follow-up failed to explain the observed differences. In conclusion, this study documents the first evidence of excessive lung function decline among certain airport workers in France, although the identification of emission sources (environmental factors, aircraft exhaust, etc) remains challenging.