UC Santa Cruz

Cancer is the second leading cause of death worldwide, with as many as 13 million deaths estimated by 2030. [31]. Of these 13 million, approximately 3.9 million of these deaths would be preventable if patients are diagnosed and treated before the occurrence of cancer metastases, which are believed to cause 90% of cancer-related deaths [20]. Cancer metastases arise after the dissemination of circulating tumor cells (CTCs) into the peripheral bloodstream from primary or secondary tumor sites [28, 62]. CTCs belong to a class of cells known as ultra- rare, with an occurrence frequency of around 1 in 107 leukocytes in the peripheral blood of cancer patients [52]. In the past 10 years, the use of CTCs as a real-time liquid biopsy has received much attention, and further analysis of these cells may greatly advance our understanding of the metastatic cascade, tumor evolution, heterogeneity and resistance to therapy. However, because CTCs are ultra rare, they must be isolated from the peripheral streams in order to be effectively studied. Hence, there is great incentive for a robust cell separation technique that allows fast and efficient isolation of CTCs for downstream analysis.

Over the past decade, the introduction of surface acoustic waves (SAW) has revolution- ized the field of microfluidics, opening up a sub-field commonly known as acoustofluidics, which has become indispensable in manipulation of microparticles in a simple, compact, non-invasive and biocompatible manner. Acoustofluidic devices have prevalently been used in separating [23], patterning [66], and transporting microparticles [7], to name only a few of their many ap- plications. Many state-of-the-art acoustofluidic devices utilize active devices called interdigital

transducers (IDTs) to generate and pattern the required acoustic fields. Typically, these IDTs are arranged in matched pairs to form a standing SAW (SSAW). Recently, many groups have demonstrated that SSAWs can be used to isolate CTCs from biological samples [16, 32, 68, 3].

In this work, we present a summary on the design, fabrication, and optimization of SSAW based microfluidic devices for high throughput, label-free rare cell separation. Using existing designs in the literature as a reference, we have fabricated a novel design separation of sub-micrometer sized microparticles. This design has successfully facilitated separation of 4.0 μm diameter from those with 2.0 μm diameter. In addition to the development of fabrication and design processes, we developed both two-dimensional and three-dimensional finite-element method simulations of IDT-based SSAW generation on lithium niobate substrates. A particle tracing code was also developed in MATLAB to simulate trajectories of microparticles under the influence of specified SSAW field and drag forces due to fluid flow. We hope that the simulation techniques and the devices presented here can have a significant impact on the field of rare-cell isolation and detection.