Dual-mode ultrasound transducer for image-guided interstitial thermal therapy.

International audienceDeep-seated tumors can be treated by minimally invasive interstitial ultrasound thermal therapy. A miniature transducer emitting high-intensity acoustic waves is placed in contact with the targeted area to induce local thermal necrosis. Accurate positioning of the probe and treatment monitoring must be achieved for the technique to be effective. A piezocomposite technology was used for obtaining both high-quality imaging and effective treatment with the same transducer. Prototypes were designed and built to be compatible with an endoscopic approach for treating cholangiocarcinomas in the biliary ducts. The transducer had dimensions of 2.5 x 7.5 mm(2), it was cylindrically focused at 10 mm and it was operated at a center frequency of 11 MHz. Transducer efficiency was measured at 71%, and the impulse response corresponded to an axial resolution of 0.2 mm. In-vitro tests were conducted on samples of pig liver in which lesions up to 10 mm in depth were induced. B-mode images were obtained by mechanically rotating the transducer. Treatments were monitored in three ways: (i) classical M-mode images, (ii) images of local deformation of ultrasound lines during heating and (iii) comparison of the displacements induced in the tissue by radiation force, before and after treatments. The successful use of piezocomposite materials to manufacture dual-mode transducers opens new perspectives for interstitial ultrasound thermal therapy

How High Concentrations of Proteins Stabilize the Amorphous State of Calcium Orthophosphate: A Solid-State Nuclear Magnetic Resonance (NMR) Study of the Casein Case

Understanding how proteins stabilize amorphous calcium <i>ortho</i>-phosphate (ACP) phases is of great importance in biology and for pharmaceutical or food applications. Until now, most of the former investigations about ACP–protein stability and equilibrium were performed under conditions where ACP colloidal nanoclusters are surrounded by low to moderate concentrations of peptides or proteins (15–30 g L^–1). As a result, the question of ACP–protein interactions in highly concentrated protein systems has clearly been overlooked, whereas it corresponds to actual industrial conditions such as drying or membrane filtration in the dairy industry for instance. In this study, the structure of an ACP phase is monitored in association with one model phosphorylated protein (casein) using solid-state nuclear magnetic resonance (ssNMR) under two conditions of high protein concentration (300 and 400 g L^–1). At both concentrations and at 25 °C, it is found that the caseins maintain the mineral phase in an amorphous form with no detectable influence on its structure or size. Interestingly, and in both cases, a significant amount of the nonphosphorylated side chains interacts with ACP through hydrogen bonds. The number of these interacting side chains is found to be higher at the highest casein concentration. At 45 °C, which is a destabilizing temperature of ACP under protein-free conditions, the amorphous structure of the mineral phase is partially transformed at a casein concentration of 300 g L^–1, while it remains almost intact at a casein concentration of 400 g L^–1. Therefore, these results clearly indicate that increasing the concentration of proteins favors ACP–protein interactions and stabilizes the ACP clusters more efficiently

Study of a dual-mode array integrated in a multi-element transducer for imaging and therapy of prostate cancer

International audienceThe development of endocavitary dual-mode probes is essential for the accurate treatment of many deep seated cancers which require a high imaging resolution and the capacity to selectively treat focal areas in the region of interest. The MULTIP project is aimed at using state-of-art piezoelectric technologies to design dual-mode ultrasonic probes for cancer-foci treatment and monitoring. In order to allow an efficient surgery planning, the technical study has been accompanied by a volume processing study permitting the design of the ultrasonic imaging/therapy process based on high-resolutionhigh-quality MRI images. Several prototypes were designed based on a simulation study and implemented: 1) two successive wide-band dual-mode transducer allowing imaging at high resolution (6 MHz) on a wide field of view, and therapy at 3 MHz with a good transduction efficiency (48% and 70%); 2) a therapy-only transducer matrix adapted to the desired curvature with a high transduction efficiency (70%). Finally, a registration study of MRI volumes on ultrasound volumes has shown that, because of the texture of the ultrasound images, it is more efficient to search at registering the surfaces of the volumes once they have been segmented in each modality, rather than trying to register the two data volumes directly

Ultrasound-Induced Blood–Spinal Cord Barrier Opening in Rabbits

International audienceThe blood-spinal cord barrier (BSCB) considerably limits the delivery and efficacy of treatments for spinal cord diseases. The blood-brain barrier can be safely opened with low-intensity pulsed ultrasound when microbubbles are simultaneously administered intravenously. This technique was tested on the BSCB in a rabbit model in this work. Twenty-three segments of spinal cord were sonicated with a 1-MHz unfocused pulsed ultrasound device and compared with non-sonicated segments. BSCB disruption was assessed using Evan's blue dye (EBD) extravasation. Tolerance was assessed by histologic analysis. An increased EBD concentration indicating BSCB disruption was clearly observed in sonicated segments compared with controls (p = 0.004). On one animal, which received 10 sonications, repetitive BSCB disruptions revealed no evidence of cumulative toxicity. BSCB can be disrupted using an unfocused pulsed ultrasound device in combination with microbubbles without neurotoxicity even in case of repeated sonications

Temporary blood-brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma

International audienceINTRODUCTION: Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Few cytotoxic chemotherapies have been shown to be effective against GBM, due in part to the presence of the blood-brain barrier (BBB), which reduces the penetration of chemotherapies from the blood to the brain. Ultrasound-induced BBB opening (US-BBB) has been shown to increase the penetration of multiple chemotherapeutic agents in the brain in animal models. In the current study, the anti-tumor activity of carboplatin chemotherapy with and without US-BBB was investigated in several GBM mouse models.METHODS: First, the IC50 of two commercial (U87 and U251) and six patient-derived GBM cell lines (PDCL) to carboplatin was measured. Next, U87 was subcutaneously grafted to a nude mouse model to test the in vivo response of the tumor to carboplatin in the absence of the BBB. Lastly, nude mice bearing orthotopically xenografted GBM cell lines (U87 or a PDCL) were randomized to four experimental groups: (i) untreated, (ii) US-BBB alone, (iii) carboplatin alone and, (iv) carboplatin + US-BBB. Mice were treated once weekly for 4 weeks and monitored for toxicity, tumor growth, and survival.RESULTS: Carboplatin plus US-BBB enhanced survival (p = 0.03) and delayed tumor growth (p < 0.05) of GBM-bearing mice compared to carboplatin alone, with a 4.2-fold increase of carboplatin penetration in the brain, without evidence of significant neurological or systemic toxicity.CONCLUSIONS: Carboplatin efficacy was enhanced in GBM mouse models with US-BBB and appears to be a promising chemotherapy for this approach

Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood–brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A blood–brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10 µL/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly opened the BBB. BBB opening was confirmed visually and microscopically using Evans blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice’s survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome in order to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients

Pilot Study of Repeated Blood-Brain Barrier Disruption in Patients with Mild Alzheimer's Disease with an Implantable Ultrasound Device

International audienceBackground: Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer’s disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and the efficacy of this approach in patients with mild AD using an implantable ultrasound device. Methods: An implantable, 1 MHz ultrasound device (SonoCloud-1) was extradurally implanted under local anesthesia in the skull of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18 F-Florbetapir and 18 F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at four and eight months after initiation of sonications to monitor brain metabolism and amyloid levels along with cognitive evaluations. Evolution of cognitive and neuroimaging features were compared to that of a matched sample of control participants. Results: A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at four months of -6.6% (SD=7.2%) on 18 F-Florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in longitudinal change in glucose metabolism were observed compared to neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison to the ADNI participants as expected due to the small sample size and duration of the trial. Conclusions: These results demonstrate the safety of ultrasound-based BBB disruption and potential of this technology to be used as a therapy for AD patients. They support further research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease modifying drugs to further enhance the effects observed