Trans‐blood‐brain barrier delivery of compounds at pharmacologically relevant molecular weights in the hippocampus of mice using Focused Ultrasound

2008 ◽  
Vol 123 (5) ◽  
pp. 3217-3217
Author(s):  
James Choi ◽  
Shougang Wang ◽  
Yao‐Sheng Tung ◽  
Barclay Morrison ◽  
Elisa Konofagou
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Molecular Weights ◽  
Blood Brain

scholarly journals The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

2014 ◽  
Vol 34 (7) ◽  
pp. 1197-1204 ◽  
Author(s):  
Hong Chen ◽  
Elisa E Konofagou
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Acoustic Pressure ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Hydrodynamic Diameter ◽  
Molecular Weights ◽  
Blood Brain ◽  
Cavitation Detection ◽  
Bbb Opening

Focused ultrasound (FUS) in combination with microbubbles (MBs) has been successfully used in the delivery of various-size therapeutic agents across the blood–brain barrier (BBB). This study revealed that FUS-induced BBB opening size, defined by the size of the largest molecule that can permeate through the BBB, can be controlled by the acoustic pressure as dictated by cavitational mechanisms. Focused ultrasound was applied onto the mouse hippocampus in the presence of systemically administered MBs for trans-BBB delivery of fluorescently labeled dextrans with molecular weights 3 to 2,000 kDa (hydrodynamic diameter: 2.3 to 54.4 nm). The dextran delivery outcomes were evaluated using ex vivo fluorescence imaging. Cavitation detection was employed to monitor the MB cavitation activity associated with the delivery of these agents. It was found that the BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa). These findings indicate that the BBB opening size can be controlled by the acoustic pressure and predicted using cavitation detection.

scholarly journals Cavitation dose painting for focused ultrasound-induced blood-brain barrier disruption

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yaoheng Yang ◽  
Xiaohui Zhang ◽  
Dezhuang Ye ◽  
Richard Laforest ◽  
Jeffrey Williamson ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Dose Painting ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

scholarly journals DDEL-13. FOCUSED ULTRASOUND MEDIATED BLOOD BRAIN BARRIER DISRUPTION IN A MURINE MODEL OF PONTINE GLIOMA: A SAFETY AND FEASIBILITY STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii286-iii286
Author(s):  
Zachary Englander ◽  
Hong-Jian Wei ◽  
Antonios Pouliopoulos ◽  
Pavan Upadhyayula ◽  
Chia-Ing Jan ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Center Frequency ◽  
Single Element ◽  
Pontine Glioma ◽  
Orthotopic Model ◽  
Function Generator ◽  
Blood Brain ◽  
Glioma Model

Abstract BACKGROUND Drug delivery remains a major obstacle in DIPG, as the blood brain barrier (BBB) limits the penetration of systemic therapies to the brainstem. Focused ultrasound (FUS) is an exciting new technology that, when combined with microbubbles, can open the BBB permitting the entry of drugs across the cerebrovasculature. Given that the utility of FUS in brainstem tumors remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. METHODS A syngeneic orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells (10,000/1ul) into the pons of B6 albino mice. A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier (acoustic pressure=0.7MPa) was used with concurrent intravenous microbubble injection (FUS+MB) to sonicate the tumor on post-injection day 14. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen (KIS) testing was completed to measure motor function. Mice were either immediately sacrificed for histopathological assessment or serially monitored for survival. RESULTS In mice treated with FUS (n=11), there was no measured deficit in KIS testing. Additionally, the degree of intra-tumoral hemorrhage and inflammation on H&E in control (n=5) and treated mice (n=5) was similar. Lastly, there was no difference in survival between the groups (control, n=6, median=26 days; FUS, n=6, median=25 days, p>0.05). CONCLUSION FUS+MB is a safe and feasible technique to open the BBB in a preclinical pontine glioma model.

scholarly journals Contrast-Enhanced Ultrasound Imaging for the Detection of Focused Ultrasound-Induced Blood-Brain Barrier Opening

Theranostics ◽  
2014 ◽  
Vol 4 (10) ◽  
pp. 1014-1025 ◽  
Author(s):  
Ching-Hsiang Fan ◽  
Wun-Hao Lin ◽  
Chien-Yu Ting ◽  
Wen-Yen Chai ◽  
Tzu-Chen Yen ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ultrasound Imaging ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Contrast Enhanced Ultrasound ◽  
Blood Brain ◽  
Contrast Enhanced ◽  
Barrier Opening ◽  
Blood Brain Barrier Opening

scholarly journals Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Antonios N. Pouliopoulos ◽  
Nancy Kwon ◽  
Greg Jensen ◽  
Anna Meaney ◽  
Yusuke Niimi ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Safety Profile ◽  
Focused Ultrasound ◽  
Multiple Case Study ◽  
Brain Barrier ◽  
Non Invasive ◽  
Blood Brain ◽  
Multiple Case ◽  
Bbb Opening

AbstractAn emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.

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