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Sheathless focusing and separation of microparticles using tilted angle travelling surface acoustic waves Husnain Ahmed, Ghulam Destgeer, Jinsoo Park, Muhammad Afzal, and Hyung Jin Sung Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b01593 • Publication Date (Web): 18 Jun 2018 Downloaded from http://pubs.acs.org on June 19, 2018

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Sheathless focusing and separation of microparticles using tilted angle travelling surface acoustic waves Husnain Ahmed, Ghulam Destgeer, Jinsoo Park, Muhammad Afzal and Hyung Jin Sung* Department of Mechanical Engineering, KAIST, Daejeon 34141, Korea. E-mail: [email protected] ABSTRACT: The sheathless focusing and separation of microparticles is an important pre-processing step in various biochemical assays in which enriched sample isolation is critical. Most previous microfluidic particle separation techniques have used a sheath flow to achieve efficient sample focusing. The sheath flow diluted the analyte, and required additional microchannels and accurate flow control. We demonstrated a tilted angle travelling surface acoustic wave (taTSAW)-based sheathless focusing and separation of particles in a continuous flow. The proposed device consisted of a piezoelectric substrate with a pair of interdigitated transducers (IDTs) deposited at two different angles relative to the flow direction. A Y-shaped polydimethylsiloxane (PDMS) microchannel having one inlet and two outlet ports was positioned on top of the IDTs such that the acoustic energy coupling into the fluid was maximized and wave attenuation by the PDMS walls was minimized. The two IDTs independently produced high-frequency taTSAWs, which propagated at ±30° with respect to the flow direction and imparted a direct acoustic radiation force onto the target particles. A sample mixture containing 4.8 and 3.2 µm particles was focused and then separated by the actuation of the IDTs at 194 and 136 MHz frequencies, respectively, without using an additional sheath flow. The proposed taTSAW-based particle separation device offered a high purity > 99% at the both outlets over a wide range of flow speeds (up to 83.3 mm/s).

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recent decades, microfluidic particle separation has emerged as a promising tool for industrial, biological, chemical and biomedical applications, including cell biology, disease diagnostics and therapeutics.1–3 For instance, the isolation of circulating tumor cells from human peripheral blood is essential to cancer diagnosis, prognosis and therapy.4,5 Cures for malaria rely on the separation of malaria-infected red blood cells from healthy cells.6–8 The separation of different types of stem cells, such as embryonic stem cells,9,10 tissue-specific stem cells,11 mesenchymal stem cells12 and induced pluripotent stem cells,13,14 is essential for the analysis of various diseases and organ-on-a-chip technologes15 for the development of new therapies and drugs. Size-based particle separation is particularly important for multichannel particle sensors, in which different sized particles are guided into separate channels to achieve the desired sensitivity and high-throughput dynamic range detection.16 A variety of active and passive microfluidic methods for manipulating particles17 have been reported, including hydrophoretic filtration,18,19 inertial microfluidics,20,21 dielectrophoresis22,23 and optofluidics.24,25 Acoustophoresis or acoustofluidic-based particle separation involving coupling acoustic waves into the fluid inside a microfluidic channel has recently received attention.26–28 Acoustic radiation force (ARF)-driven particle separation techniques are ideal for labon-chip devices due to their biocompatible and non-invasive nature, low power consumption, ease of fabrication and ability to separate a vast number of particles. Most acoustofluidic devices used to separate particles,29–31 cells,32–34 biomolecules35 or droplets36–38 have required additional sheath flows to align different sized micro-objects prior to separation in a microchannel. The use of sheath flows faces several drawbacks, such as analyte dilution, the need for additional microchannels for the sheath flow and the accurate con-

trol over the sheath flow and sample flow ratio for realizing efficient separation. Sheathless focusing is indispensable for biological assays in which sample enrichment is critical to separating micro-objects. Previous studies that demonstrated sheathless focusing and patterning of micro-objects using acoustic waves lacked separation capabilities.39–41 Guldiken et al. used two pairs of interdigitated transducers (IDTs) placed outside of a polydimethylsiloxane (PDMS) channel to generate an standing surface acoustic wave (SSAW)-based single pressure node that focused microparticles in a first stage, after which two pressure nodes separated microparticles in a second stage.42 A similar SSAW-based mechanism was used to achieve density-based particle separation.43 TSAWs have not yet been tested for the simultaneous focusing and separation of microparticles in a single-layered microfluidic channel because microchannel anechoic corner effects hinder the complete deflection of particles during the focusing stage.44–46 Moreover, the IDTs placed outside of a microchannel transfer only a portion of the acoustic energy into the sample because the PDMS walls partially dampen acoustic waves prior to coupling with the fluid.47–49 Recently, these limitations have been circumvented by positioning the IDTs directly beneath the microchannel.50–52 Collins et al. used a single IDT to produce standing waves within a microchannel to separate hydrodynamically pre-focused particles.50 We demonstrated the separation of vertically focused particles using a single sheath flow and an IDT placed at the bottom of a microchannel.51 A similar design was used to concentrate particles adjacent to the IDT by capturing target particles in a dilute sample.52 In the present study, a unique device design was proposed to overcome the limitations of the microchannel anechoic corner effect,45 which can prevent deflection of some of the particles positioned in corner regions. This device also precluded

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acoustic wave damping by the PDMS walls53 as the IDTs were positioned directly beneath the microchannel and nearly spanned the microchannel width. We designed a two-stage acoustofluidic device that utilized tilted-angle travelling surface acoustic waves (taTSAWs) to focus and separate microparticles based on their sizes in a Y-shaped PDMS microchannel. The proposed device differed from tilted-angle standing surface acoustic wave (taSSAW)-based devices reported earlier because the two IDTs operated independently in the taTSAW device whereas both IDTs worked together in the taSSAW device to form the standing waves.28,54 The IDTs were deposited onto the piezoelectric substrate at specific an-

gles with respect to the flow direction in the microchannel. A sample fluid containing microparticles of different sizes was pumped through the inlet as the taTSAW produced from the first IDT (IDT1) deflected the particles toward the opposite sidewall of the microchannel via the direct ARF (FARF) effect while the Stokes’ drag force (Fd) moved the particles forward. The taTSAW produced from the second IDT (IDT2) selectively deflected the larger particles from the focused streamlines toward the opposite wall of the microchannel such that particle separation provided > 90% homogeneity in size at both outlets without the need for additional sheath flows.

Figure 1. Schematic diagram showing the taTSAW-based sheathless particle focusing and integrated particle separation. IDT1 aligned a mixture of red and green particles alongside the lower microchannel wall via direct ARF (FARF) and the drag force (Fd) on the particles, and IDT2 selectively deflected the larger green particles from their focused streams to induce separation.

EXPERIMENTAL SECTION Device fabrication: A taTSAW-based particle separation device was prepared using a single-layered PDMS microfluidic channel attached to a piezoelectric substrate (lithium niobate, LiNbO3, 128 Y–X cut, MTI Korea, Korea). A pair of IDTs was patterned (using E-beam evaporation and liftoff processes, IAMD, Korea) at angles of 180 + 30° and 180 – 30° relative to the principal axis of the LiNbO3 wafer.55 A thin layer of SiO2 (2000 Å) was deposited to enhance the PDMS–substrate bond strength and to avoid incurring mechanical damage to the IDTs. The set of IDTs comprised 20 electrode finger pairs and had a total aperture of 500 µm. The wavelengths produced by IDT1 and IDT2 were 19 µm and 26 µm, respectively. A soft lithography process was used to fabricate the PDMS microchannel bonded to the LiNbO3 substrate using oxygen plasma bonding (Covance, Femto Science, Korea). The height and width of the microchannel were 20 µm and 500 µm, respectively. Experimental setup: A pair of fluorescent polystyrene particles of different sizes (4.8 µm green, 3.2 µm red, Thermo Scientific, U.S.A.) having the same density (1.05 g/cm3) were suspended in a solution (49% of each DI water and D2O, and 2% surfactant) to prepare the sample.52 A syringe pump (neMESYS, Cetoni GmbH, Germany) was used to inject the sample solution into the microchannel through a single inlet port (Harris Uni-Core). The experiments were conducted on a fluorescent microscope (BX53, Olympus, Japan). The acoustic waves were generated by applying radio frequency signals of

194 and 136 MHz to IDT1 and IDT2, respectively. Two separate signal generators (N5181A, Agilent Technologies, U.S.A; N5171B, Keysight Technologies, U.S.A.) and amplifiers (LZT-22+, Mini-Circuits, U.S.A; ZHL-100W-GAN+, MiniCircuits, U.S.A.) were used to run the IDTs. The microscopy images were captured using a charge-coupled device camera (DP72, Olympus, Japan) and were post-processed using ImageJ (http://imagej.nih.gov/ij/) to enhance visualization.

WORKING MECHANISM The Y-shaped microchannel, which had a single inlet port and two outlet ports, was mounted on top of the taTSAW device such that the IDTs spanned ∼75% of the microchannel width (see Figure 1). The tilted angles of the IDTs allowed the two forces, FARF and Fd, to determine the positions of the particles inside the microchannel. The motion of a particle under taTSAW was characterized by the Helmholtz number ( / ), which depended on the particle diameter (d) and the taTSAW frequency (f), where cf is the speed of sound in the fluid.56,57 A mixture of particles having two different sizes (green and red) pumped through the inlet port without the acoustic field would collect at both the outlet ports without separation. Upon application of the acoustic field, the particles with a κ-value greater than one experienced FARF, whereas the particles with κ < 1 were minimally affected by FARF and were dragged along the flow.46 The taTSAW frequencies and the combination of particle sizes were selected such


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that κ > 1 for green particles against both IDTs. The red particles experienced a κ > 1 for IDT1 and < 1 for IDT2. The taTSAWs from IDT1 applied FARF to both the green and red particles, as κ > 1. The particles were deflected and focused through the ∼25% vacant space close to the microchannel wall where FARF was zero, whereas Fd continuously pushed the particles along the flow direction.

IDT2 pushed the larger green particles (κ > 1) from the focused streamlines toward the opposite wall of the microchannel without deflecting the smaller red particles with κ < 1. The deflected green particles and unaffected red particles were collected through outlets 1 and outlet 2, respectively. Sheathless particle separation was achieved using a two-step taTSAW-based acoustofluidic platform.

Figure 2. Experimental images collected during the sheathless focusing and separation of particles within the microchannel. (a) Focusing zone: the particle mixture (green and red) was dispersed across the microchannel width or aligned along the microchannel wall when IDT1 was off or on, respectively. (b) Separation zone: the green and red particles remained focused along the microchannel wall when IDT2 was off. With IDT2 turned on, the green particles were deflected from their streamlines and migrated toward the opposite side of the microchannel, resulting in separation. Scale bar: 250 µm.

RESULTS AND DISCUSSION The experimental images show particle focusing and separation under an applied FARF (see Figure 2). A sample mixture of 4.8 µm green and 3.2 µm red particles was pumped through the microchannel with an average velocity of 5.56 mm/s. In the focusing and separation zones, the distributions of the 4.8 µm and 3.2 µm particle streams across the microchannel width were investigated to confirm the separation process. When the SAW was turned off, the larger (green) and smaller (red) particles were randomly distributed across the microchannel, as shown in Figure 2(a). The acoustic wave frequencies of IDT1 and IDT2 were 194 (MHz) and 136 MHz, respectively. The κvalues of the suspended 4.8 µm (green) and 3.2 µm (red) particles under IDT1 were calculated to be 1.97 and 1.32, respectively. These values ensured that both the green and red particles experienced a significant FARF and were deflected by IDT1. The κ-values for the green and red particles under IDT2 were calculated to be 1.39 and 0.92, respectively, which ensured that the green particles experienced a significant FARF, whereas there a negligible FARF was experienced by the red

particles. Once the green and red particles were deflected by IDT1 (κ > 1), Fd continued to drag the sparsely aligned particles along the sidewall of the microchannel (see Figure 2(a)). These aligned particles were ultimately collected through outlet 2 when IDT2 was off (see Figure 2(b)). Once IDT2 was actuated, the green particles were deflected from their streamlines due to FARF (κ > 1), aligned along the opposite side of the microchannel and collected at outlet 1. The red particles continued to flow along their previously focused streamlines without deflection (κ < 1) and were collected at outlet 2. A quantitative measure of the focusing and separation of particles without a sheath flow is shown in Figure 3. The particle separation was quantitatively analyzed by examining the fluorescent signals of the two populations at different locations (white dotted windows) inside the microchannel (see Figure 3(a)). The dispersed particles were focused by IDT1 and then separated by IDT2 (see Figure 3(b–d)). The particle motions within the microchannel after the separation zone were tracked using the ImageJ software, as illustrated in Figure 3(e).




Figure 3. Separation of the microparticles. (a) A dispersed mixture of 4.8 µm (green) and 3.2 µm (red) polystyrene particles was first focused, then the particles were separated into distinct streamlines. The signals within the white dotted windows were analyzed to quantify the separation. Normalized mean intensity distributions across the microchannel width (y) were averaged over the dotted windows’ widths (x) and were plotted for the randomly dispersed (b), focused (c) and separated (d) particles. (e) Green and red particle tracking within the microchannel after the separation zone. A splitter (horizontal dashed line in (b–e)) was assumed at y = 0 µm to quantify the purity at each outlet. (f) The purities at outlets 1 and 2. The cross-sectional flow velocity was 5.56 mm/s and the peak–peak voltages were 0.7 Vpp and 1.0 Vpp at IDT1 and IDT2, respectively. Scale bar: 250 µm.

Figure 4. Effect of the change in voltage (VIDT2) of the separator on the purity measured at the outlets. (a) taTSAW off: the particle mixture flowed through the lower outlet streamlines beside the microchannel wall, yielding no particle separation. (b–c) Changing VIDT2 from 0.6 Vpp to 1.0 Vpp translated the green particles to the upper outlet streamlines under FARF, resulting in efficient separation. (d–g) Changing VIDT2 from 1.4 Vpp to 3.4 Vpp shifted most of the red particle streamlines from outlet 2 to outlet 1 due to the formation of SSAWs via internal wave reflection, decreasing the purity at outlet 1. Scale bar: 250µm. (h) Purities at outlets 1 (green circles) and 2 (red circles) as VIDT2 was manipulated over the range 0–3.4 Vpp.

The purities at the outlets were quantified by assuming a splitter at the bifurcation (y = 0 µm), and the numbers of tracked particles (NTPs) in the green and red streams were calculated (black dashed lines). The purities of the green (G) and red (R) particles were defined as PG = 100NTP (G,y+)/NTP (G,t) and PR =

100NTP (R,y-)/NTP (R,t), where y+ represents the region for y > 0, y– represents the region for y 1. The change in the purity at the outlets due to the change in VIDT2 is plotted in Figure 4(h). The behaviors of the different sized particles were further explored in Figure 5, as VIDT2 was increased to 4.0 Vpp. At this voltage, FARF was dominant over Fd, which acted on the 4.8 µm (green) particles and led to their accumulation ahead of IDT2 (see Figure 5(a)). On the other hand, the 3.2 µm red particles were deflected from the lower outlet streamlines due to the formation of SSAWs within the channel. In this manner, the proposed system acted as a hybrid platform to simultaneously generate TSAWs and SSAWs for the manipulation of different sized microspheres.

Figure 5. Behaviors of the different sized particles within the microchannel at a high separator voltage (VIDT2 = 4.0 Vpp). (a) Separation zone: The majority of the 4.8 µm green particles were deflected from their focused streamlines and concentrated due to the dominant effects of the taTSAW-based FARF, whereas the 3.2 µm red particles were deflected from their focused streamlines and followed the pressure nodes of the SSAWs generated close to IDT2. The red particles were then collected at the upper outlet (b). Scale bar: 250 µm.

In addition to characterizing the input voltage at IDT2, we tested the performance of our device at high flow velocities for the separation of 4.8 µm and 3.2 µm particles (see Figure 6). Input voltages were manipulated across both IDTs (focuser and separator) at the different flow velocities such that the focuser aligned almost all of the green and red particles toward the lower outlet streamlines and the separator deflected only the green particles, without affecting the red particles, from their focused streams to achieve efficient separation. We confirmed that no green particles were present in the lower focused stream after the separation zone, thereby maintaining 100% purity at outlet 2, even at higher flow velocities within the range 5.56–83.3 mm/s. A few red particles were deflected with the green particles due to the effect of FARF, which slightly decreased the purity at the outlet 1 from around ∼99% to ∼ 94%. This effect was attributed to the broad size distribution of the fluorescent polystyrene particles. The increase in the flow velocity from 5.56 mm/s to 83.3 mm/s required an increase in the input voltages applied to both IDTs to maintain the purities at both outlets; 100% at outlet 2 and > 93% at outlet 1.

Figure 6. Particle purities measured at the outlets at different flow velocities for the separation of 4.8 µm green and 3.2 µm red particles. The input voltages were manipulated across IDT1 and IDT2 at each flow velocity to achieve a high purity at the outlets.

Conclusions We reported a novel taTSAW-based acoustofluidic platform for the sheathless focusing and separation of particles having two different sizes (3.2 µm and 4.8 µm) within a singlelayered microfluidic channel. This method did not require additional sheath flows to focus and separate the particles




within the microchannel. The particles were continuously focused to one side of the microchannel wall and then separated by the taTSAWs. The IDTs were positioned directly beneath the microchannel to avoid creating microchannel anechoic corner effects that could hinder complete deflection of the particles. The present technique allows for the highly efficient (> 93% and 100% at outlet 1 and 2) separation of particles over a wide range of cross-sectional flow velocities. This device provides the first demonstration of taTSAW-based separation within a microchannel, thereby removing exterior sheath flows. This taTSAW-based particle separation device could be a useful addition to lab-on-a-chip systems, with applications to biological and biomedical assays.

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Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Video S1: sheathless focusing and separation of microparticles using taTSAWs.

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AUTHOR INFORMATION Corresponding Author *Email: [email protected]

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Author contributions

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H.A. and G.D. conceived the research. H.J.S. supervised the research. H.A., G.D. and J.P. designed the experiments. H.A., G.D. and M.A. performed the experiments. H.A. and G.D. analyzed the results. All authors contributed to the manuscript writing.

Notes The authors declare no competing financial interest.

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ACKNOWLEDGMENT

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This work was supported by the National Research Foundation of Korea (no. 2018-001483), the KOPRI project and the KUSTARKAIST Institute.

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