Ultrasound-Induced Blood-Brain Barrier Opening

Abstract

Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.

Synthesis and Characterization of Transiently Stable Albumin-Coated Microbubbles via a Flow-Focusing Microfluidic Device

“…Larger microbubbles provide increased contrast (Streeter et al, 2010; Kaya et al, 2010), but as microbubbles exceed 10 μ m, they quickly get filtered by the lungs and can pose an emboli risk (Butler and Hills, 1979; Klibanov, 2002). Microbubble size has also been shown to affect drug delivery (Konofagou et al, 2012; Burke et al, 2012). Fan et al (2012) recently demonstrated that cell membrane pore size following sonoporation increases with microbubble size and that different acoustic pressures can be used to selectively porate cells in contact with different sized microbubbles.…”

Promising Approaches to Circumvent the Blood–Brain Barrier: Progress, Pitfalls and Clinical Prospects in Brain Cancer

“…A local and noninvasive strategy for BBB disruption is the use of focused ultrasound (FUS) in conjunction with ultrasound contrast agents (i.e., stabilized microbubbles approved by the US FDA for contrast-enhanced diagnostic ultrasound) [2,12]. When driven to oscillate nonlinearly, circulating ultrasound contrast agents generate mechanical forces that can temporarily increase BBB permeability to small (e.g., chemotherapeutic agents) and large (e.g., proteins) biomolecules [2].…”

“…When driven to oscillate nonlinearly, circulating ultrasound contrast agents generate mechanical forces that can temporarily increase BBB permeability to small (e.g., chemotherapeutic agents) and large (e.g., proteins) biomolecules [2]. The use of focused ultrasound allows for opening the BBB with a great deal of spatial selectivity and delivering anticancer agents specifically to targeted brain tumors [2,12]. The results from animal studies have been very encouraging and are paving the way for clinical trials.…”

Optical imaging to map blood-brain barrier leakage

“…It separates circulating blood from cerebrospinal fluid in the central nervous system (CNS)2. Certain drugs (e.g., nicotine and cotinine3), hypertonic agents (e.g., mannitol solution4), and cell-penetrating peptides5, as well as physical factors (e.g., high-intensity focused ultrasound6, electrical stimulation, or high-impact pressure waves78) can cause openings in the BBB. Disruption of the BBB is a serious condition that occurs in many pathological conditions, such as brain tumors9, brain injuries10, CNS infections11, neurological diseases1213, and epilepsy14.…”