Biomedical Engineering Program, University of Colorado Boulder, Boulder, CO, 80303, USA.
Department of Radiology, Cancer Center Animal Imaging Shared Resource, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
Sci Rep. 2024 Jul 24;14(1):17036. doi: 10.1038/s41598-024-67916-8.
Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood-brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation.
微泡（MBs）联合聚焦超声（FUS）已成为一种有前途的非侵入性技术，可使血脑屏障（BBB）通透性增强，将药物递送到大脑。然而，BBB 开放（BBBO）的安全性和生物学后果仍不完全清楚。本研究旨在研究介导 BBBO 的两个参数的影响：微泡体积剂量（MVD）和机械指数（MI）。在小鼠脑中采用高分辨率 MRI 引导的 FUS，通过操纵这两个参数来评估 BBBO。之后，在 FUS 治疗后 6 小时研究了无菌性炎症反应（SIR）。结果表明，MVD 和 MI 都显著影响 BBBO 的程度，较高的 MVD 和 MI 导致通透性增加。此外，RNA 测序显示 BBBO 后主要炎症途径和免疫细胞浸润上调，表明存在和程度的 SIR。基因集富集分析确定了 12 个与炎症反应相关的基因集，在较高的 MVD 或 MI 下显著上调。在治疗相关的 BBBO 和 SIR 发作之间建立了治疗窗口，提供了操作方案，以避免通过 TNFα 信号传导刺激 NFκB 途径引起的损伤，从而导致细胞凋亡。这些结果有助于优化和标准化 BBB 开放参数，以安全有效地将药物递送到大脑，并进一步阐明驱动无菌性炎症的潜在分子机制。
