Microfluidic manufacturing of uniform nano and microbubbles for ultrasound based imaging and therapeutics**applications

这项NSERC战略项目资助了一种基于微流体的制造技术的开发，该技术可以实现直径在50纳米- 10微米范围内的纳米和微泡的均匀尺寸和高通量生产。（我们简单地把这些气泡称为微气泡。）我们采用的策略实现了高度均匀的微泡，克服了现有商用微泡的大尺寸分布限制，这些微泡被用作临床超声造影剂，也越来越多地用作治疗递送剂。具体来说，尽管微泡在超声成像和治疗中具有重要的潜在效用，但市售微泡尺寸分布较大，导致成像条件和治疗效果不理想。我们先进的制造方法克服了这些问题，使用户能够精确控制微泡的大小。我们的技术的一个关键的新颖之处是在微流体产生气泡后，应用真空收缩的微气泡。我们在这个项目中的目标是：1)模拟并实现50 nm - 10µm气泡尺寸的精确控制；2)通过将边缘乳化微流体微气泡生成方案集成到我们的制造技术中，将微气泡的生产规模扩大到临床相关水平；3)通过超声检查嵌入微气泡的在线质量控制。****我们正在制造的微泡是安全的：在许多国家，包括加拿大和美国，市售的微泡已经被批准用于临床使用。微泡超声造影剂的全球市场也在不断增长，从2016年的44.6亿美元增长到2021年的54.4亿美元，复合年增长率（CAGR）为4.1%。因此，我们预计我们的技术的发展将帮助加拿大的微型和纳米技术制造业进入这个潜在的高利润市场，并改善加拿大在制造技术部门的就业。****

This NSERC Strategic Projects grant is funding the development of a microfluidics-based manufacturing technology that achieves uniform size and high-throughput production of nano and microbubbles in the diameter range of 50 nm - 10 µm. (We simply refer to these bubbles as microbubbles.) The strategy we employ achieves highly uniform microbubbles that overcome the large size distribution limitations of existing commercially available microbubbles that are used as clinical ultrasound contrast agents and also increasingly as therapeutic delivery agents. Specifically, despite the significant potential utility of microbubbles in ultrasound imaging and therapeutics, commercially available microbubbles have a large distribution of sizes, which result in sub-optimal imaging conditions and therapeutic effects. Our advanced manufacturing approach overcomes these issues by enabling precise user-control of microbubble sizes. One key novelty of our technique is the application of vacuum-shrinkage of microbubbles after the bubbles are generated microfluidically. Our goals in this Project are to 1) model and achieve precise control of bubble sizes from 50 nm - 10 µm, 2) scale-up the production of the microbubbles to clinically relevant levels by integrating an edge emulsification microfluidic microbubble generation scheme to our manufacturing technology, and 3) embed in-line quality control of the microbubbles by ultrasound inspection. ****The microbubbles we are making are safe: commercially available microbubbles have been approved for clinical use in many countries, including in Canada and the United States. The microbubble ultrasound contrast agents also have a growing global market, from $4.46B USD in 2016 to a projected $5.44B USD in 2021 at a compounded annual growth rate (CAGR) of 4.1%. Thus, we anticipate that the development of our technology will help the Canadian micro and nanotechnology manufacturing industry gain access into this potentially highly lucrative market, and improve Canada's employment in the manufacturing technology sector.****