The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice.
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ABSTRACT:
SUBMITTER: Tung YS
PROVIDER: S-EPMC3248062 | biostudies-other | 2011 Nov
REPOSITORIES: biostudies-other
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Project description:Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.
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Project description:Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62-1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.
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Project description:Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood-brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood-brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.
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Project description:Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.
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Project description:Burst-mode focused ultrasound (FUS) induces microbubble cavitation in the vasculature and temporarily disrupts the blood-brain barrier (BBB) to enable therapeutic agent delivery. However, it remains unclear whether FUS-induced BBB opening is accompanied by neuromodulation. Here we characterized the functional effects of FUS-induced BBB opening by measuring changes in somatosensory evoked potentials (SSEPs) and blood-oxygen-level dependent (BOLD) responses. Rats underwent burst-mode FUS (mechanical index (MI) of 0.3, 0.55 or 0.8) to the forelimb region in the left primary somatosensory cortex to induce BBB opening. Longitudinal measurements were followed for up to 1 week to characterize the temporal dynamics of neuromodulation. We observed that 0.8-MI FUS profoundly suppressed SSEP amplitude and prolonged latency, and this effect lasted 7 days. 0.55-MI FUS resulted in minimal and short-term suppression of SSEP for less than 60 minutes and didn't affect latency. BOLD responses were also suppressed in an MI-dependent manner, mirroring the effect on SSEPs. Furthermore, repetitive delivery of 0.55-MI FUS every 3 days elicited no accumulative effects on SSEPs or tissue integrity. This is the first evidence that FUS-induced BBB opening is accompanied by reversible changes in neuron responses, and may provide valuable insight toward the development of FUS-induced BBB opening for clinical applications.
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Project description:Glioblastoma is the most common type of brain tumor. Due to the presence of the blood-brain barrier, the effects of chemotherapy have been unsatisfactory. The combination of focused ultrasound and microbubbles to reversibly open the blood-brain barrier is now considered a key factor in improving treatment outcomes of glioblastoma. In this study, we developed bionic drug delivery microbubbles, which in combination with focused ultrasound had an obvious inhibitory effect on glioblastoma. We extracted the brain microvascular cell membranes, combined them with lipid components, and loaded them with superparamagnetic iron oxide and doxorubicin to prepare biomimetic drug delivery microbubbles (FeDOX@cellMBs). We demonstrated that FeDOX@cellMBs retained the intrinsic properties of loading, such as magnetic properties and drug toxicity, both in vitro and in vivo. FeDOX@cellMBs exhibited good tumor targeting and uptake under the combined action of magnetic and focused ultrasound. Importantly, the FeDOX@cellMBs demonstrated excellent internal stability and effectively inhibited tumor growth in orthotopic glioblastoma mice. Finally, organ H&E staining confirmed that FeDOX@cellMBs were safe for use. In conclusion, FeDOX@cellMBs successfully penetrated the blood-brain barrier and effectively inhibited glioblastoma growth under the combined effects of focused ultrasound and magnetic stimulation. These results provide a new approach for the treatment of glioblastoma, with implications for future clinical translation.
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Project description:Focused Ultrasound (FUS) combined with microbubbles (FUS+MB) to transiently open the blood brain barrier (BBB) has shown promise as an immunotherapeutic in models of neurodegenerative disorders - resulting in significantly reduced pathological load and improved cognition. Preliminary histology and bulk tissue analysis of FUS+MB have indicated brain macrophage changes as a potential mechanism of the immunotherapy. However, prior to this study the temporal effect of FUS+MB on the two dominant brain macrophage populations - microglia and central nervous system associated macrophages (CAM) has not been reported. In this study, we establish that FUS+MB triggers a biphasic process involving both microglia and CAM. In the Phase I, 24h after treatment, microglia and resident CAM exhibit an early response signature, characterized by the upregulation of recruitment-associated chemokine and cytokines. In Phase II, 72h after treatment, CAM population size increases dramatically and both cell types exhibit a late response signature, characterized by upregulation of interferon genes indicative of cellular activation and immune response. Next, cell cycle analysis and immunohistochemistry indicate that microglia exhibit increased proliferation across both phases but CAM do not. Finally, the brain macrophage population size is correlated with the ultrasound-induced cavitation dose, indicating a dose-dependent response to treatment. The findings presented herein not only provide insight into the mechanism of the FUS+MB immunomodulatory effects but also into a mechanism of brain macrophage response that is capable of ameliorating neurological disease.
2023-06-17 | GSE198707 | GEO
Project description:Focused ultrasound (FUS) in combination with systemically injected microbubbles can be used to non-invasively open the blood-brain barrier (BBB) in targeted regions for a variety of therapeutic applications. Over the past two decades, preclinical research into the safety and efficacy of FUS-induced BBB opening has proven this technique to be transient and efficacious, propelling FUS-induced BBB opening into several clinical trials in recent years. However, as clinical trials further progress, the neuroinflammatory response to FUS-induced BBB opening needs to be better understood. In this study, we provide further insight into the relationship of microbubble cavitation and the resulting innate immune response to FUS-induced BBB opening. By keeping ultrasound parameters fixed (i.e. frequency, pressure, pulse length, etc.), three groups of mice were sonicated using a real-time cavitation controller until a target cavitation dose was reached (1 x 107 V2•s, 5 x 107 V2•s, 1 x 108 V2•s). The change in relative gene expression of the mouse inflammatory cytokines and receptors were evaluated at three different time-points (6 h, 24 h, and 72 h) after FUS. At both 6 and 24 h time-points, significant changes in relative gene expression of inflammatory cytokines and receptors were observed across all cavitation groups. However, the degree of changes in relative expression levels and the number of genes with significant changes in expression varied across the cavitation groups. Groups with a higher cavitation dose exhibited both greater changes in relative expression levels and greater number of significant changes. By 72 h post-opening, the gene expression levels returned to baseline in all cavitation dose groups, signifying a transient inflammatory response to FUS-induced BBB opening at the targeted cavitation dose levels. Furthermore, the real-time cavitation controller was able to produce consistent and significantly different BBB permeability enhancement volumes across the three different cavitation dose groups. These results indicate that cavitation monitoring and controlling during FUS-induced BBB opening can be used to potentially modulate or limit the degree of neuroinflammation, further emphasizing the importance of implementing cavitation controllers as FUS-induced BBB opening is translated into the clinic.
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Project description:The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.
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