Broadband microwave flow cytometry: comprehensive nanoparticle sensing and characterization

纳米颗粒无处不在，对每个人日常生活的许多方面都有很大的影响。 其中，细胞外囊泡、病毒和朊病毒蛋白是天然的纳米颗粒，在生物学、疾病和医学中发挥着重要作用。 例如，细胞外囊泡是细胞通讯、生长和发育的关键，并且可以有效地介导药物递送。 病毒引起严重的疾病，如流行性感冒和艾滋病毒/艾滋病。 朊病毒蛋白与阿尔茨海默氏症有关。 另一方面，已经合成了许多人工纳米颗粒用于许多重要的应用，包括磁共振成像（MRI）、癌症热疗、药物和基因递送、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，超过1000种商业产品是用纳米颗粒开发的。 因此，普遍且迫切需要方便且准确地测量颗粒尺寸、尺寸分布、密度（颗粒/mL）和表面电荷。 这些参数对于任何进一步的纳米粒子探索都是必不可少的，例如胶体稳定性，生物行为和毒性。 然而，测量这些基本参数是非常困难的，由于小的颗粒尺寸（直径小于100 nm），显着的尺寸变化，和不同的颗粒来源。 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电阻脉冲传感、先进流式细胞术、纳米粒子跟踪、动态光散射和透射电子显微镜所无法实现的。 本计画提出一种新的宽频微波流式细胞术方法来解决这个问题。 预计所提出的方法将显著促进纳米粒子的努力，如上述的那些，并强烈影响纳米材料，生物学，医学，介观物理，化学和纳米粒子产品的发展和进步。 该项目还为纳米粒子仪器科学和技术新兴领域的研究生和博士后学者提供支持和培训。 它使一个女教师从一个主要的本科院校参与尖端的纳米科学研究。 此外，它提供了一个令人兴奋的主题，以吸引高中，本科生，和代表性不足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展示宽带微波流式细胞术技术，用于检测和全面测量纳米粒子在一个无标记和非侵入性的方式。 将开发自动可调干涉仪以及纳米传感结构和纳米流体通道，以在多个微波频率下测量单个纳米颗粒。 目标粒径为直径20 nm至200 nm。 最小可检测颗粒体积比可调谐电阻脉冲传感小约10倍，可调谐电阻脉冲传感是一种被认为是最有前途的纳米颗粒表征方法之一的现有技术。 少数纳米粒子的物理和电学模型将被建立用于数据解释和参数提取。 将开发算法以获得纳米颗粒的尺寸、尺寸分布、密度（颗粒/mL）、表面电荷（即zeta电位）和频率依赖性介电性质。 这种介电特性目前还不能用任何其他技术获得。 对于综合多参数测量，目标通量为1个粒子/秒，对于简单检测，目标通量为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）和共聚物胶束将被用来测试所提出的技术，并通过比较光散射测量结果的性能进行评估。

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.