Broadband microwave flow cytometry: comprehensive nanoparticle sensing and characterization

纳米粒子无处不在，对每个人日常生活的许多方面都有很大的影响。其中，胞外囊泡、病毒和病毒蛋白是天然的纳米粒子，在生物学、疾病和医学中发挥着重要的作用。例如，胞外囊泡是细胞通讯、生长和发育的关键，可以有效地介导药物的传递。病毒会导致严重的疾病，如流感疫情和艾滋病毒/艾滋病。另一方面，大量的人工纳米粒子被合成用于许多重要的应用，包括磁共振成像(MRI)、癌症热疗、药物和基因输送、柔性电子制造、太阳能电池开发和表面等离子体共振传感。此外，1000多种商业产品都是用纳米颗粒开发的。因此，对颗粒大小、粒度分布、密度(颗粒/毫升)和表面电荷的方便而准确的测量有着广泛而迫切的需求。这些参数对于任何进一步的纳米颗粒探索都是必不可少的，例如胶体稳定性、生物学行为和毒性。然而，由于颗粒尺寸小(直径小于100 nm)、尺寸变化大以及颗粒来源多样，测量这些基本参数非常困难。它们需要单粒子、多参数、高灵敏度和高通量测量，这是现有技术如可调谐电阻脉冲传感、先进的流式细胞仪、纳米粒子跟踪、动态光散射和透射电子显微镜所不具备的。本项目提出了一种新的宽带微波流式细胞仪方法来解决这一问题。所提出的方法有望极大地促进纳米粒子的努力，并对纳米材料、生物、医学、介观物理、化学和纳米粒子产品的发展和进步产生强烈的影响。该项目还为新兴纳米颗粒仪器科学和技术领域的研究生和博士后学者提供支持和培训。它使一名来自以本科生为主的机构的女性教职员工能够参与尖端纳米科学研究。此外，它还提供了一个令人兴奋的主题，以吸引高中生、本科生和未被充分代表的学生体验和学习先进的科学、技术、工程和数学。该项目的目标是开发和演示宽带微波流式细胞术技术，以无标记和非侵入性的方式检测和综合测量纳米颗粒。自动可调谐干涉仪将与纳米传感结构和纳米流体通道一起开发，以测量多个微波频率下的单个纳米颗粒。靶向粒径为20 nm~200 nm。最小可检测颗粒体积比可调谐电阻脉冲传感技术小约10倍，后者被认为是最有前途的纳米颗粒表征方法之一。将建立几个纳米粒子的物理和电学模型，用于数据解释和参数提取。将开发算法来获得纳米颗粒的尺寸、尺寸分布、密度(颗粒/毫升)、表面电荷(即Zeta电位)和与频率相关的介电特性。这种介电特性目前在任何其他技术中都不可用。综合多参数测量的目标吞吐量为1个粒子/秒，简单检测的目标吞吐量为10个粒子/秒。在未来的发展中，吞吐量可以进一步提高。常用的纳米粒子(聚苯乙烯和磁性氧化铁)和共聚胶束将被用来测试所提出的技术，并将通过与光散射测量结果的比较来评估其性能。

Nanoparticles are ubiquitous and have large impacts on many aspects of everyone's daily life. Among many others, extracellular vesicles, viruses, and prion proteins are natural nanoparticles and play essential roles in biology, disease, and medicine. For instance, extracellular vesicles are key in cell communication, growth and development, and can effectively mediate drug delivery. Viruses cause severe diseases like influenza epidemic and HIV/AIDS. Prion proteins are linked to Alzheimer's. On the other hand, numerous artificial nanoparticles have been synthesized for many important applications including magnetic resonance imaging (MRI), cancer hyperthermia therapy, drug and gene delivery, flexible electronics manufacturing, solar cell development, and surface plasmon resonance sensing. Additionally, more than 1000 commercial products are developed with nanoparticles. Thus, there is a widespread and urgent need for convenient and accurate measurement of particle size, size distribution, density (particles/mL), and surface charge. These parameters are essential for any further nanoparticle exploration, such as colloidal stability, biological behavior, and toxicity. Nevertheless, measuring these basic parameters is very difficult due to small particle size (less than 100 nm in diameter), significant size variation, and diverse particle origin. They require single-particle, multi-parameter, high sensitivity and high throughput measurement, which is not available from existing techniques such as tunable resistive pulse sensing, advanced flow cytometry, nanoparticle tracking, dynamic light scattering, and transmission electron microscopy. This project proposes a novel broadband microwave flow cytometry method to address the problem. The proposed method is expected to significantly facilitate nanoparticle efforts, such as those mentioned above, and strongly impact the development and advancement of nanomaterials, biology, medicine, mesoscopic physics, chemistry, and nanoparticle products. The project also provides support and training to graduate students as well as postdoctoral scholars in the emerging area of nanoparticle instrumentation science and technology. It enables a female faculty member from a predominantly undergraduate institution to participate in cutting-edge nanoscale science research. Additionally, it offers an exciting topic to attract high school, undergraduate, and underrepresented students to experience and study advanced science, technology, engineering, and mathematics.The objective of this project is to develop and demonstrate broadband microwave flow cytometry techniques for the detection and comprehensive measurement of nanoparticles in a label-free and non-invasive manner. Automated tunable interferometers together with nano-sensing structures and nanofluidic channels will be developed to measure single nanoparticles at multiple microwave frequencies. The targeted particle size is from 20 nm to 200 nm in diameter. The minimum detectable particle volume is about 10 times smaller than that of tunable resistive pulse sensing, an existing technique considered as one of the most promising nanoparticle characterization methods. Physical and electrical models of a few nanoparticles will be established for data interpretation and parameter extraction. Algorithms will be developed to obtain the size, size distribution, density (particles/mL), surface charge (i.e. zeta potential) and frequency dependent dielectric properties of nanoparticles. Such dielectric properties are currently not available with any other technique. The targeted throughput is 1 particle/second for a comprehensive multi-parameter measurement and 10 particles/second for simple detection. The throughputs can be further improved in future development. Commonly used nanoparticles (polystyrene and magnetic iron oxide) and copolymer micelles will be used to test the proposed techniques, and the performance will be evaluated by comparing with light scattering measurement results.