Noninvasive and Localized Blood—Brain Barrier Disruption using Focused Ultrasound can be Achieved at Short Pulse Lengths and Low Pulse Repetition Frequencies

Choi, James J.; Selert, Kirsten; Gao, Zimeng; Samiotaki, Gesthimani; Baseri, Babak; Konofagou, Elisa E.

doi:10.1038/jcbfm.2010.155

Cited by 133 publications

(132 citation statements)

References 27 publications

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“…Recent studies have shown that larger microbubbles (4-5 and 6-8 μm) have a lower PRP threshold for BBB disruption than smaller bubbles (1-2 μm) (9, 20) when using PLs greater than 66.7 μs. Also, previous work, which analyzed concentrations of 0.01 to 0.25 μL∕g, did not show any significant differences in drug delivery concentration (16), which was in good agreement with other studies that used similar parameters (15).…”

Section: Discussionsupporting

confidence: 77%

“…In this paper, we demonstrated that BBB disruption may be achieved with as little as 5 pulses of 3.5 cycles (2.3 μs at 1.5 MHz) transmitted at a PRF of 100 kHz. Our previous work has demonstrated that 50 cycles (33 μs at 1.5 MHz) can induce BBB disruption (16). Increasing the number of emitted pulses, or the PL, increased the NOD.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, concerns remain with the dose and distribution of the agents delivered (14,17) and the safety associated with enhancing these characteristics (11). For instance, increased dose can be achieved with higher PRPs and PLs, but higher PRPs have been associated with cellular damage (11) and longer PLs have been associated with increased molecular accumulation at or near larger vessels, thus indicating off-target and inhomogeneous distribution (16,17). The short PL sequences used in this paper produced a more homogeneous distribution of molecular delivery throughout the targeted volume when compared to longer 20-ms PLs, especially for the 3-kDa dextran (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Exposure of tissues above, but near, the threshold has so far yielded the most promising results with molecular delivery without any associated damage, as assessed using histological analysis (11). Further increasing the PRP enhances the dose delivered, but is also associated with a highly heterogeneous distribution within the focal volume and the onset of erythrocyte extravasations, hemorrhage, and neuronal damage (11,16). Less understood is the effect different PLs have on delivery characteristics.…”

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confidence: 99%

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Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Choi¹,

Selert²,

Vlachos³

et al. 2011

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

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137

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Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood-brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 μs) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound.F ocused ultrasound (FUS) and microbubble-based drug delivery systems (DDSs) can increase the dose of an agent in a target volume and has potential in applications such as blood-brain barrier (BBB) disruption for the treatment of neurological diseases (1, 2), molecular and viral treatment of tumors (3), gene therapy for treating heart conditions (4), and enhancement of renal ultrafiltration (5). In each method, biologically inert and preformed microbubbles, with a lipid or polymer shell, a stabilized gas core, and a diameter less than 10 μm, are systemically administered and subsequently exposed to noninvasively delivered FUS pulses. Microbubbles within the target volume are "acoustically activated" in a complex range of behaviors known as acoustic cavitation. In stable cavitation, the microbubbles expand and contract with the acoustic pressure rarefaction and compression over several cycles (6). This activity has been associated with a range of bioeffects including displacement of the vessel wall through dilation and contractions (7,8). Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8). Each type and magnitude of cavitation activity results...

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Choi¹,

Selert²,

Vlachos³

et al. 2011

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

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137

145

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“…36,58 The observation of diffuse dye leakage along the length of the vessel was postulated to be due to transcellular passage compared to intense focal leakage, postulated to be due to paracellular transport. 36 Controlling the range of applied ultrasound pressure could be used to induce the different type of leakage following BBB disruption. Managing the leakage types, indicative of BBB disruption, may further improve drug delivery using FUS.…”

Section: ■ Cellular Mechanisms Of Fusmentioning

confidence: 99%

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

Burgess

Hynynen

2013

ACS Chem. Neurosci.

114

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Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer's disease. The requirements for clinical translation of FUS will be discussed. KEYWORDS:Focused ultrasound, blood-brain barrier, drug delivery B rain diseases, including psychiatric disorders, neurodegenerative diseases, and cancer, are among the most prevalent diseases worldwide. It has been estimated that 35% of all disease burden is attributable to brain disorders.1 Despite advancing research, which better understands the etiology and underlying mechanisms of disease, most of these diseases do not have effective treatments and essentially no cures exist.Designing therapeutic agents for the brain is very challenging. The brain is a well-protected organ, completely encased by the skull, making surgical access difficult and direct application of drugs impractical. However, perhaps the most limiting factor to successful treatment of brain disease is the blood-brain barrier (BBB) which prevents access of ∼98% of current pharmaceutical agents to the brain when delivered intravenously. ■ THE BLOOD-BRAIN BARRIER (BBB)The BBB is a specialized structure between the cerebral capillaries and the brain parenchyma that is relatively impermeable except for a selection of very small (<400 Da), lipophilic compounds. 3 The BBB is different from the barriers between the peripheral vasculature and other organs in the body due mainly to the presence of tight junctions between adjacent endothelial cells.3 Cell adhesion molecules, most notably claudins and occludins, connect the endothelial cells together to create the tight junctions. The intracellular domains of the proteins are anchored to the cytoskeleton and the extracellular domains form homodimers with proteins on adjacent endothelial cells. These independent tight junctional proteins work in concert to make the endothelial cellular layer impermeable to fluid thereby limiting paracellular transport mechanisms.

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Therapeutic Ultrasound Triggered Silk Fibroin Scaffold Degradation

DeBari

Niu

Scott

et al. 2021

Adv Healthcare Materials

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A patient's capacity for tissue regeneration varies based on age, nutritional status, disease state, lifestyle, and gender. Because regeneration cannot be predicted prior to biomaterial implantation, there is a need for responsive biomaterials with adaptive, personalized degradation profiles to improve regenerative outcomes. This study reports a new approach to use therapeutic ultrasound as a means of altering the degradation profile of silk fibroin biomaterials noninvasively postimplantation. By evaluating changes in weight, porosity, surface morphology, compressive modulus, and chemical structure, it is concluded that therapeutic ultrasound can trigger enhanced degradation of silk fibroin scaffolds noninvasively. By removing microbubbles on the scaffold surface, it is found that acoustic cavitation is the mechanism responsible for changing the degradation profile. This method is proved to be safe for human cells with no negative effects on cell viability or metabolism. Sonication through human skin also effectively triggers scaffold degradation, increasing the clinical relevance of these results. These findings suggest that silk is an ultrasound-responsive biomaterial, where the degradation profile can be adjusted noninvasively to improve regenerative outcomes.

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Noninvasive and Localized Blood—Brain Barrier Disruption using Focused Ultrasound can be Achieved at Short Pulse Lengths and Low Pulse Repetition Frequencies

Cited by 133 publications

References 27 publications

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

Therapeutic Ultrasound Triggered Silk Fibroin Scaffold Degradation

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