Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications.
Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications.
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DOI：
10.1039/c3lc51016f
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发表时间：
2013-12-21
期刊：
影响因子：
6.1
通讯作者：
Lee AP
中科院分区：
文献类型：
--
作者：
Shih R;Bardin D;Martz TD;Sheeran PS;Dayton PA;Lee AP
超声成像通常需要注射造影剂，微米大小的气泡在血液中强烈回声，有助于区分血管组织。通过增加表面受体和治疗有效载荷，这种微泡也被扩大用于靶向药物输送和基因治疗。不幸的是，传统的生产方法产生的是一个多分散的种群，其不均匀的共振和载药量并不理想。另一种技术，微流控流聚焦，能够产生高度单分散的微泡，具有稳定的脂膜和携带药物的油层。然而，与传统方法相比，已公布的这些均匀药物气泡的1 kHz产生率非常低，必须在临床应用之前进行改进。在这项研究中，流动聚焦产生的油层脂质微泡被测试高达300 kHz，合并被高的脂质浓度或在脂溶液中加入Pluronic F68表面活性剂抑制。分析了几何控制和滴灌生产模式之间的转换，发现生产规模是连续的，其指数~5/12的趋势与文献相似。然而，与以前对这一趋势的研究不同，这里的比例曲线被发现是与压力相关的，特别是在较低的压力-流量平衡时(例如<；15磅/平方英寸)。观察到调整油流率具有类似的效果，类似于压力变化1-3磅/平方英寸。这种对高速双层气泡产生的分析和表征将实现更具预测性的生产控制，其速度适用于体内或临床使用。
Ultrasound imaging often calls for the injection of contrast agents, micron-sized bubbles which echo strongly in blood and help distinguish vascularized tissue. Such microbubbles are also being augmented for targeted drug delivery and gene therapy, by the addition of surface receptors and therapeutic payloads. Unfortunately, conventional production methods yield a polydisperse population, whose nonuniform resonance and drug-loading are less than ideal. An alternative technique, microfluidic flow-focusing, is able to produce highly monodisperse microbubbles with stabilizing lipid membranes and drug-carrying oil layers. However, the published 1 kHz production rate for these uniform drug bubbles is very low compared to conventional methods, and must be improved before clinical use can be practical. In this study, flow-focusing production of oil-layered lipid microbubbles was tested up to 300 kHz, with coalescence suppressed by high lipid concentrations or inclusion of Pluronic F68 surfactant in the lipid solution. The transition between geometry-controlled and dripping production regimes was analysed, and production scaling was found to be continuous, with a power trend of exponent ~5/12 similar to literature. Unlike prior studies with this trend, however, scaling curves here were found to be pressure-dependent, particularly at lower pressure-flow equilibria (e.g. <15 psi). Adjustments in oil flow rate were observed to have a similar effect, akin to a pressure change of 1–3 psi. This analysis and characterization of high-speed dual-layer bubble generation will enable more-predictive production control, at rates practical for in vivo or clinical use.
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