Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety.
Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety.
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DOI：
10.7150/thno.76199
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发表时间：
2023
期刊：
影响因子：
12.4
通讯作者：
Konofagou EE
中科院分区：
文献类型：
--
作者：
Batts AJ;Ji R;Noel RL;Kline-Schoder AR;Bae S;Kwon N;Konofagou EE
背景：聚焦超声(FUS)介导的血脑屏障(BBB)开放是一种无创、安全、可逆的靶向给药技术。大多数临床前系统都是由一个独立的几何聚焦换能器和被动空化探测器(PCD)或成像阵列组成。这项研究建立在我们团队之前的工作基础上，开发了一种用于同时打开和监测BBB的单一成像相控阵配置，称为无创超声(Theranostic超声)，利用超短脉冲长度(USPLs)和一种新的快速交替转向角(RASTA)脉冲序列设计，用于同时进行目标特定USPL的双侧超声检查。使用RASTA序列进一步评估USPL对BBB开放体积、能量空化成像(PCI)像素强度、BBB关闭时间线、药物输送效率和安全性的影响。方法：使用Verasonics Vantage超声系统驱动的P4-1相控阵换能器，使用自定义脚本运行RASTA序列，该序列由交错引导、聚焦传输和被动成像组成。对比剂增强磁共振成像(MRI)在血脑屏障开放后72小时内通过纵向成像确认血脑屏障的初始开放体积和闭合。在药物传递实验中，系统地给小鼠注射70 kDa荧光葡聚糖或腺相关病毒血清9型(AAV9)，用于荧光显微镜或酶联免疫吸附试验(ELISA)，以评估其介导的分子治疗传递。其他脑切片也进行H&E染色以评估组织学损伤，以及IBA1和GFAP染色以阐明由此介导的BBB开放对刺激参与神经免疫反应的关键细胞类型、小胶质细胞和星形胶质细胞的影响。结果：在同一小鼠中，这样的RASTA序列同时诱导了不同的BBB开放，其中体积、PCI像素强度、葡聚糖递送水平和AAV报告基因的转基因表达与大脑半球特异性USPL相关，与1.5、5和10周期USPL组之间的统计学差异一致。BBB关闭后，因此需要2-48小时，取决于USPL。急性损伤和神经免疫激活的可能性随着USPL的增加而增加，但这种可见的损伤在USPL后96小时几乎被逆转。结论：这是一种多用途的单阵列技术，显示了在脑内研究各种非侵入性治疗应用的潜力。
Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL. The RASTA sequence was further employed to evaluate the impact of USPL on BBB opening volume, power cavitation imaging (PCI) pixel intensity, BBB closing timeline, drug delivery efficiency, and safety. Methods: A P4-1 phased array transducer driven by a Verasonics Vantage ultrasound system was operated using a custom script to run the RASTA sequence which consisted of interleaved steered, focused transmits and passive imaging. Contrast-enhanced magnetic resonance imaging (MRI) confirmed initial opening volume and closure of the BBB by longitudinal imaging through 72 hours post-BBB opening. For drug delivery experiments, mice were systemically administered a 70 kDa fluorescent dextran or adeno-associated virus serotype 9 (AAV9) for fluorescence microscopy or enzyme-linked immunosorbent assay (ELISA) to evaluate ThUS-mediated molecular therapeutic delivery. Additional brain sections were also H&E-stained to evaluate histological damage, and IBA1- and GFAP-stained to elucidate the effects of ThUS-mediated BBB opening on stimulation of key cell types involved in the neuro-immune response, microglia and astrocytes. Results: The ThUS RASTA sequence induced distinct BBB openings simultaneously in the same mouse where volume, PCI pixel intensity, level of dextran delivery, and AAV reporter transgene expression were correlated with brain hemisphere-specific USPL, consistent with statistically significant differences between 1.5, 5, and 10-cycle USPL groups. BBB closure after ThUS required 2-48 hours depending on USPL. The potential for acute damage and neuro-immune activation increased with USPL, but such observable damage was nearly reversed 96 hours post-ThUS. Conclusion: ThUS is a versatile single-array technique which exhibits the potential for investigating a variety of non-invasive therapeutic delivery applications in the brain.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
DOI：
10.1109/tbme.2009.2034533
发表时间：
2010-01
期刊：
IEEE transactions on bio-medical engineering
影响因子：
--
作者：
Choi JJ;Feshitan JA;Baseri B;Wang S;Tung YS;Borden MA;Konofagou EE
通讯作者：
Konofagou EE
DOI：
10.1073/pnas.1105116108
发表时间：
2011-10-04
影响因子：
11.1
作者：
Choi, James J.;Selert, Kirsten;Konofagou, Elisa E.
通讯作者：
Konofagou, Elisa E.
DOI：
10.1109/tuffc.2009.1132
发表时间：
2009-05
期刊：
IEEE transactions on ultrasonics, ferroelectrics, and frequency control
影响因子：
--
作者：
Fabiilli ML;Haworth KJ;Fakhri NH;Kripfgans OD;Carson PL;Fowlkes JB
通讯作者：
Fowlkes JB
影响因子：
3.7
作者：
Downs ME;Buch A;Sierra C;Karakatsani ME;Teichert T;Chen S;Konofagou EE;Ferrera VP
通讯作者：
Ferrera VP