Blood-Brain Barrier Disruption and Vascular Damage Induced by Ultrasound Bursts Combined with Microbubbles can be Influenced by Choice of Anesthesia Protocol

McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia

doi:10.1016/j.ultrasmedbio.2011.04.019

Cited by 54 publications

(44 citation statements)

References 47 publications

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“…In such methods the quantification of bound tMBs strongly depends on the injected dose, imaging system gain, and local perfusion [137]. In addition, the influence of inhaled gases in the anaesthetic protocols influences the MBs longevity [148][149][150][151]. These studies confirmed longer circulation times of in-house lipid-shell decafluorobutane-filled UCAs and commercially available UCAs such as Definity and Albunex when animals breathe medical air instead of pure oxygen as the carrier gas for the isoflurane anaesthetic.…”

Section: Contrast-specific Imaging Techniquesmentioning

confidence: 74%

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

Rooij

Daeichin

Skachkov

et al. 2015

International Journal of Hyperthermia

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Ultrasound contrast agents (UCAs) are used routinely in the clinic to enhance contrast in ultrasonography. More recently, UCAs have been functionalised by conjugating ligands to their surface to target specific biomarkers of a disease or a disease process. These targeted UCAs (tUCAs) are used for a wide range of pre-clinical applications including diagnosis, monitoring of drug treatment, and therapy. In this review, recent achievements with tUCAs in the field of molecular imaging, evaluation of therapy, drug delivery, and therapeutic applications are discussed. We present the different coating materials and aspects that have to be considered when manufacturing tUCAs. Next to tUCA design and the choice of ligands for specific biomarkers, additional techniques are discussed that are applied to improve binding of the tUCAs to their target and to quantify the strength of this bond. As imaging techniques rely on the specific behaviour of tUCAs in an ultrasound field, it is crucial to understand the characteristics of both free and adhered tUCAs. To image and quantify the adhered tUCAs, the state-of-the-art techniques used for ultrasound molecular imaging and quantification are presented. This review concludes with the potential of tUCAs for drug delivery and therapeutic applications.

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Section: Contrast-specific Imaging Techniquesmentioning

confidence: 74%

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

Rooij

Daeichin

Skachkov

et al. 2015

International Journal of Hyperthermia

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“…Measurements of MRI contrast enhancement indicated significantly higher contrast in the sonicated hemisphere, particularly in the cortex. Although this is not the first time BBB disruption has been achieved with an unfocused US, 15,23 to our knowledge, our study is the first that has tested a small unfocused US transducer that can be adapted for use as an implantable US device in a bur hole.…”

Section: Discussionmentioning

confidence: 93%

Opening of the blood-brain barrier with an unfocused ultrasound device in rabbits

Beccaria¹,

Canney

Goldwirt

et al. 2013

JNS

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Object The blood-brain barrier (BBB) is a major impediment to the intracerebral diffusion of drugs used in the treatment of gliomas. Previous studies have demonstrated that pulsed focused ultrasound (US) in conjunction with a microbubble contrast agent can be used to open the BBB. To apply the US-induced opening of the BBB in clinical practice, the authors designed an innovative unfocused US device that can be implanted in the skull and used to transiently and repeatedly open the BBB during a standard chemotherapy protocol. The goal of this preliminary work was to study the opening of the BBB induced by the authors' small unfocused US transducer and to evaluate the effects of the sonications on brain parenchyma. Methods Craniectomy was performed in 16 healthy New Zealand White rabbits; epidural application of a single-element planar ultrasonic transducer operating at 1 MHz was then used with a pulse-repetition frequency of 1 Hz, pulse lengths of 10–35 msec, in situ acoustic pressure levels of 0.3–0.8 MPa, and sonication for 60–120 seconds. SonoVue was intravenously injected during the US applications, and opening of the BBB was determined by detecting extravasation of Evans blue dye (EBD) in brain tissues, quantitative measurement of EBD with UV-visible spectrophotometry, and contrast enhancement after Gd injection in 4.7-T MRI. A histological study was performed to determine adverse effects. Results An opening of the BBB was observed over a large extent of the US beam in the brain corresponding to in situ pressures of greater than 0.2 MPa. The BBB opening observed was highly significant for both EBD (p < 0.01) and MRI Gd enhancement (p < 0.0001). The BBB opening was associated with minor adverse effects that included perivascular red blood cell extravasations that were less than 150 μm in size and not visible on MR images. Moderate edema was visible on FLAIR sequences and limited to the extent of the sonication field. Conclusions The results demonstrate that the BBB can be opened in large areas of the brain in rabbits with lowpower, pulsed, and unfocused US with limited damage to healthy tissue.

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“…and acoustic cavitation forces inducing stable MB oscillations that can be accompanied by shear stress and microstreaming (i.e., radiating forces originating from MB) or inertial cavitation with unstable oscillations and violent rapid collapse of MB at the endothelial surface resulting in decreased tight junction integrity (29,30). pFUS+MB has been reported to cause hemodynamic alterations in the brain associated with temporary vasoconstriction, as seen with BBBD (31,32).…”

Section: Significancementioning

confidence: 99%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

371

388

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MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1-7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells. The BBB consists of specialized endothelial cells connected through various tight junction proteins (TJP), astrocyte endplates, and a basement membrane. These components form part of the neurovascular unit (NVU) that is comprised of vessels, pericytes, microglia, astrocytes, and neurons along with the extracellular matrix (1,3,4,8). BBBD secondary to ischemia or trauma leads to increases in endothelial caveolae and down-regulation of TJP, transcytosis of plasma proteins (i.e., albumin), and vasogenic edema (1,6,(8)(9)(10)(11). The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12-15). The release of CCTFs and inte...

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Blood-Brain Barrier Disruption and Vascular Damage Induced by Ultrasound Bursts Combined with Microbubbles can be Influenced by Choice of Anesthesia Protocol

Cited by 54 publications

References 47 publications

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

Opening of the blood-brain barrier with an unfocused ultrasound device in rabbits

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

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