Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Lab Chip. 2023 Jul 25;23(15):3453-3466. doi: 10.1039/d3lc00514c.
Lipid shell-stabilized nanoparticles with a perfluorocarbon gas-core, or nanobubbles, have recently attracted attention as a new contrast agent for molecular ultrasound imaging and image-guided therapy. Due to their small size (∼275 nm diameter) and flexible shell, nanobubbles have been shown to extravasate through hyperpermeable vasculature (, in tumors). However, little is known about the dynamics and depth of extravasation of intact, acoustically active nanobubbles. Accordingly, in this work, we developed a microfluidic chip with a lumen and extracellular matrix (ECM) and imaging method that allows real-time imaging and characterization of the extravasation process with high-frequency ultrasound. The microfluidic device has a lumen and is surrounded by an extracellular matrix with tunable porosity. The combination of ultrasound imaging and the microfluidic chip advantageously produces real-time images of the entire length and depth of the matrix. This captures the matrix heterogeneity, offering advantages over other imaging techniques with smaller fields of view. Results from this study show that nanobubbles diffuse through a 1.3 μm pore size (2 mg mL) collagen I matrix 25× faster with a penetration depth that was 0.19 mm deeper than a 3.7 μm (4 mg mL) matrix. In the 3.7 μm pore size matrix, nanobubbles diffused 92× faster than large nanobubbles (∼875 nm diameter). Decorrelation time analysis was successfully used to differentiate flowing and extra-luminally diffusing nanobubbles. In this work, we show for the first time that combination of an ultrasound-capable microfluidic chip and real-time imaging provided valuable insight into spatiotemporal nanoparticle movement through a heterogeneous extracellular matrix. This work could help accurately predict parameters (, injection dosage) that improve translation of nanoparticles from to environments.
脂质壳稳定的全氟碳气体核纳米颗粒，即纳米气泡，最近作为一种新的分子超声成像和影像引导治疗的对比剂引起了人们的关注。由于其小尺寸（275nm 直径）和灵活的外壳，纳米气泡已被证明可以通过高通透性血管（肿瘤中的血管）渗漏。然而，对于完整的、声活性纳米气泡的渗漏动力学和深度知之甚少。因此，在这项工作中，我们开发了一种带有腔室和细胞外基质（ECM）的微流控芯片和成像方法，该方法允许使用高频超声实时成像和表征渗漏过程。微流控装置具有一个腔室，并且被具有可调孔隙率的细胞外基质所包围。超声成像和微流控芯片的结合有利地产生了基质整个长度和深度的实时图像。这捕获了基质的异质性，相对于其他具有较小视场的成像技术具有优势。本研究的结果表明，纳米气泡通过 1.3μm 孔径（2mg/mL）的胶原蛋白 I 基质的扩散速度比通过 3.7μm 孔径（4mg/mL）的基质快 25 倍，渗透深度深 0.19mm。在 3.7μm 孔径的基质中，纳米气泡的扩散速度比大纳米气泡（875nm 直径）快 92 倍。相关时间分析成功地用于区分流动和腔外扩散的纳米气泡。在这项工作中，我们首次表明，超声微流控芯片与实时成像的结合为通过异质细胞外基质的纳米颗粒的时空运动提供了有价值的见解。这项工作可以帮助准确预测参数（例如，注射剂量），从而改善纳米颗粒从实验室环境到临床环境的转化。
