Focused ultrasound with microbubbles induces sterile inflammatory response proportional to the blood brain barrier opening: Attention to experimental conditions

Kovács, Zsófia; Burks, Scott R.; Frank, Joseph A.

doi:10.7150/thno.24181

Cited by 58 publications

(62 citation statements)

References 17 publications

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“…Optison TM and Definity ® have an intravascular half-life (T 1/2 ) of 1.3 min in 21% O 2, which is shortened by ~40% to 0.72 min when animals inhale 100% O 2 71 - 73 . MB perfluorocarbon gas is eliminated through the lungs and its clearance rate is governed by first-order principles 20 . Pharmacokinetic modeling would indicate that the infusion rate, initial concentration of injected MB, plasma concentration of MB, T 1/2 , volume of distribution, and oxygenation status all contribute to the numbers of MB exposed to pFUS PNP over the sonication period used to cause BBBD 20 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the upregulation of genes associated with NFkB pathways, which induce SIR, was not observed with the infusion of 10 µL/kg Definity ® and pFUS with passive cavitation detection (PCD) feedback six hours post treatment 4 , 5 . These results suggested that pFUS+10 µL/kg Definity ® -induced BBBD did not lead to elevations in genes associated with SIR; however, the lack of sampling of tissues at multiple or earlier time points does not preclude that existing baseline levels of cellular mRNA could have resulted in proteomic changes in the targeted tissues 20 .…”

Section: Introductionmentioning

confidence: 93%

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MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

Kovács

Sundby

et al. 2018

Theranostics

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Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound (pFUS) combined with microbubbles (MB) contrast agent infusion has been shown to transiently disrupt the blood-brain barrier (BBBD), increasing the delivery of neurotherapeutics to treat central nervous system (CNS) diseases. pFUS interaction with the intravascular MB results in acoustic cavitation forces passing through the neurovascular unit (NVU), inducing BBBD detected on contrast-enhanced MRI. Multiple pFUS+MB exposures in Alzheimer's disease (AD) models are being investigated as a method to clear amyloid plaques by activated microglia or infiltrating immune cells. Since it has been reported that pFUS+MB can induce a sterile inflammatory response (SIR) [1-5] in the rat, the goal of this study was to investigate the potential long-term effects of SIR in the brain following single and six weekly sonications by serial high-resolution MRI and pathology.Methods: Female Sprague Dawley rats weighing 217±16.6 g prior to sonication received bromo-deoxyuridine (BrdU) to tag proliferating cells in the brain. pFUS was performed at 548 kHz, ultrasound burst 10 ms and initial peak negative pressure of 0.3 MPa (in water) for 120 s coupled with a slow infusion of ~460 µL/kg (5-8×107 MB) that started 30 s before and 30 s during sonication. Nine 2 mm focal regions in the left cortex and four regions over the right hippocampus were treated with pFUS+MB. Serial high-resolution brain MRIs at 3 T and 9.4 T were obtained following a single or during the course of six weekly pFUS+MB resulting in BBBD in the left cortex and the right hippocampus. Animals were monitored over 7 to 13 weeks and imaging results were compared to histology.Results: Fewer than half of the rats receiving a single pFUS+MB exposure displayed hypointense voxels on T2*-weighted (w) MRI at week 7 or 13 in the cortex or hippocampus without differences compared to the contralateral side on histograms of T2* maps. Single sonicated rats had evidence of limited microglia activation on pathology compared to the contralateral hemisphere. Six weekly pFUS+MB treatments resulted in pathological changes on T2*w images with multiple hypointense regions, cortical atrophy, along with 50% of rats having persistent BBBD and astrogliosis by MRI. Pathologic analysis of the multiple sonicated animals demonstrated the presence of metallophagocytic Prussian blue-positive cells in the parenchyma with significantly (p<0.05) increased areas of activated astrocytes and microglia, and high numbers of systemic infiltrating CD68+ macrophages along with BrdU+ cells compared to contralateral brain. In addition, multiple treatments caused an increase in the number of hyperphosphorylated Tau (pTau)-positive neurons containing neurofibrillary tangles (NFT) in the sonicated cortex but not in the hippocampus when compared to contralateral brain, which was confirmed by Western blot (WB) (p<0.04).Conclusions: The repeated SIR following multiple pFUS+MB treatments could contribute to changes on MR imaging including persistent BBBD, co...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

Kovács

Sundby

et al. 2018

Theranostics

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“…at the target site, an inflammatory response that subsided after 24 h. Activated astrocytes and microglia were still present six days after the study. On the other hand, McMahon et al 45 showed that SIR is dependent on MB dose, sparking an important debate over the role of MBs in BBBD and SIR 46 , 92 , and highlighting the importance of aforementioned considerations detailed in this review.…”

Section: Safety Considerationsmentioning

confidence: 91%

“…These variations make it extremely difficult to correlate the effects of FVD to the resulting measures of MB+FUS effects. Indeed, MB+FUS BBBD dosing parameters remain central to understanding the different presentations of sterile immune response (SIR) in the brain—a matter of some debate 45 , 46 , which centers on whether or not there is a therapeutic window between the microbubble concentration needed to induce BBBD and that which causes SIR. Even matching FVD and acoustic parameters, two studies using different UCA formulations will likely observe significant differences in results due to unequal microbubble concentration, size distribution, gas composition and shell chemistry 47 .…”

Section: Microbubble Parametersmentioning

confidence: 99%

State-of-the-art of microbubble-assisted blood-brain barrier disruption

2018

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Focused ultrasound with microbubbles promises unprecedented advantages for blood-brain barrier disruption over existing intracranial drug delivery methods, as well as a significant number of tunable parameters that affect its safety and efficacy. This review provides an engineering perspective on the state-of-the-art of the technology, considering the mechanism of action, effects of microbubble properties, ultrasound parameters and physiological variables, as well as safety and potential therapeutic applications. Emphasis is placed on the use of unified parameters, such as microbubble volume dose (MVD) and ultrasound mechanical index, to optimize the procedure and establish safety limits. It is concluded that, while efficacy has been demonstrated in several animal models with a wide range of payloads, acceptable measures of safety should be adopted to accelerate collaboration and improve understanding and clinical relevance.

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“…These findings are consistent with sterile inflammation (SI), an innate immune response. The potential for FUS to induce local SI has sparked discussion of the cellular implications of FUS, both where additional inflammation may be desirable (such as cancer or Alzheimer's) or undesirable (such as multiple sclerosis or stroke) [19][20][21][22]. Transcriptomic studies have shown that FUS induced SI is proportional to both microbubble dose and FUS acoustic pressure [23,24].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Response of Brain Tissue to Focused Ultrasound-Mediated Blood-Brain Barrier Disruption Depends Strongly on Anesthesia

Mathew

Gorick

Thim

et al. 2020

Preprint

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Focused ultrasound (FUS) mediated blood brain barrier disruption (BBBD) is a promising strategy for the targeted delivery of systemically-administered therapeutics to the central nervous system (CNS). Pre-clinical investigations of BBBD have been performed on different anesthetic backgrounds; however, the potential influence of the choice of anesthetic on the molecular response to BBBD is unknown, despite its potential to critically affect interpretation of experimental therapeutic outcomes. Here, using bulk RNA sequencing approaches, we comprehensively examined the transcriptomic response of both normal brain tissue and brain tissue exposed to FUS-induced BBBD in mice anesthetized with either isoflurane with medical air (Iso) or ketamine/dexmedetomidine (KD). In normal murine brain tissue, Iso alone elicited minimal differential gene expression (DGE) and repressed pathways associated with neuronal signaling. KD alone, however, led to massive DGE and enrichment of pathways associated with protein synthesis. In brain tissue exposed to BBBD (1 MHz, 0.5 Hz pulse repetition frequency, 0.4 MPa peak-negative pressure), we systematically evaluated the relative effects of anesthesia, microbubbles, and FUS on the transcriptome. Of particular interest, we observed that gene sets associated with sterile inflammatory responses and cell-cell junctional activity were induced by BBBD, regardless of the choice of anesthesia. Meanwhile, gene sets associated with metabolism, platelet activity, tissue repair, and signaling pathways, were differentially affected by BBBD, with a strong dependence on the anesthetic. We conclude that the underlying transcriptomic response to FUS-mediated BBBD may be powerfully influenced by anesthesia. These findings raise considerations for the translation of FUS-BBBD delivery approaches that impact, in particular, metabolism, tissue repair, and intracellular signaling.

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Focused ultrasound with microbubbles induces sterile inflammatory response proportional to the blood brain barrier opening: Attention to experimental conditions

Abstract: This editorial highlights the findings of McMahon [1] and demonstrates the need for careful attention to experimental conditions that influence microbubble concentration and pharmacokinetics contributed to focused ultrasound-induced blood brain barrier opening and sterile inflammation.

Cited by 58 publications

References 17 publications

MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

State-of-the-art of microbubble-assisted blood-brain barrier disruption

Transcriptomic Response of Brain Tissue to Focused Ultrasound-Mediated Blood-Brain Barrier Disruption Depends Strongly on Anesthesia

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