Rollable Microfluidic Systems with Microscale Bending Radius and

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Rollable Microfluidic Systems with Micrometer-Scale Bending Radius and Tuning of Device Function with Reconfigurable 3D Channel Geometry Jihye Kim, Jae Bem You, Sung Min Nam, Sumin Seo, Sung Gap Im, and Wonhee Lee ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b00741 • Publication Date (Web): 07 Mar 2017 Downloaded from http://pubs.acs.org on March 8, 2017

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ACS Applied Materials & Interfaces

Rollable Microfluidic Systems with MicrometerScale Bending Radius and Tuning of Device Function with Reconfigurable 3D Channel Geometry Jihye Kim,†,# Jae Bem You,‡,# Sung Min Nam,† Sumin Seo, † Sung Gap Im,*, ‡ ,§ and Wonhee Lee*,†, §

†

Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and

Technology (KAIST), Daejeon 34141, Republic of Korea ‡

Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of

Science and Technology (KAIST), Daejeon 34141, Republic of Korea §

KAIST Institute for NanoCentury, Korea Advanced Institute of Science and Technology

(KAIST), Daejeon 34141, Republic of Korea

KEYWORDS: Flexible microfluidics, Inertial microfluidics, Initiated Chemical Vapor Deposition, Parylene microfluidics, Rollable microfluidics

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ABSTRACT

Flexible microfluidic system is an essential component of wearable biosensors to handle body fluids. Parylene-based, thin-film microfluidic system is developed to achieve flexible microfluidics with microscale bending radius. A new molding and bonding technique is developed for parylene microchannel fabrication. Bonding with nano-adhesive layers deposited by initiated chemical vapor deposition (iCVD) enables the construction of microfluidic channels with short fabrication time and high bonding strength. High mechanical strength of parylene allows less channel deformation from internal pressure for thin-film parylene channel than bulk PDMS channel. At the same time, negligible channel sagging or collapse is observed during channel bending down to a few hundreds of micrometers due to stress relaxation by pre-stretch structure. The flexible parylene channels are also developed into a rollable microfluidic system. In a rollable microfluidics format, 2D parylene channels can be rolled around a capillary tubing working as an inlet to minimize device footprint. In addition, we show that creating reconfigurable 3D channel geometry with microscale bending radius can lead to tunable device function: tunable Dean-flow mixer is demonstrated using reconfigurable microscale 3D curved channel. Flexible parylene microfluidics with microscale bending radius is expected to provide important breakthrough for many fields including wearable biosensors and tunable 3D microfluidics.


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1. INTRODUCTION While current wearable sensor technologies are mostly focused on physical sensing1 such as temperature2, electrocardiogram (ECG)3-4, blood pressure5, acceleration6, and change of strain7-8, demands for biochemical sensors are continuously increasing because body fluids and their components can provide valuable data that is normally collected in clinical trials. Flexible microfluidics is not only important as an essential component of wearable biosensor but also as new methods to allow tunable microfluidic functions by reconfiguring 3D channel geometry. Microfluidic channel design, including channel cross section and channel curvature, can be used to control fluid flows and particles within a microchannel, as seen in chaotic mixers9, deterministic lateral displacement (DLD) devices10, hydrophoresis devices11, and inertial microfluidics12-19. For example, fluid flows and particle motions within a curved channel heavily depend on the channel geometry at finite-Reynolds number flows15-19. For such systems, the channel structures can be used to control the functionality of the device by mechanically reconfiguring the channel structure if an appropriate flexible microfluidic system is provided. Widely used poly(dimethylsiloxane) (PDMS) microfluidic systems have been used for applications such as flexible microfluidics4,

20-21

and supporting substrates of flexible

electronics22-23. However, ironically, the major problem of PDMS for flexible microfluidic material comes from its high deformability. Since highly elastic PDMS channels can easily collapse or inflate by external stress and internal pressure, the channel deformations lead to large alterations in channel geometry that affect fluidic resistance and flow rate and even results in channel failure, which causes difficulty in controlling fluid and particle motions24. In addition, PDMS has several well-known drawbacks including swelling in organic solvents25, sample evaporation and absorption of small molecules due to high gas permeability26. On the other hand, thin-film microfluidics using rigid polymeric materials is 3 ACS Paragon Plus Environment


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an alternative to fabricating flexible microfluidics27-29. Thin-film, rigid polymer microfluidics are typically fabricated by molding30-31 or stacking multiple channel layers27, 32-33. However, thin-film microfluidic channels built by these methods usually have rather limited flexibility; minimum bending radii are larger than a few millimeters (mostly tens of millimeters) and they are not widely adapted for flexible microfluidic applications. The limits in the minimum bending radius are influenced by a number of factors including film thickness, bonding strength of layers, brittleness, and modulus of the material. Therefore, it is necessary to develop a proper fabrication technique for a rigid material with superior mechanical properties such as high toughness. Poly(p-xylylene) (parylene) is vapor-deposited polymer which can provide uniform, conformal coating as thin as a few hundred nanometers and it is a good candidate for flexible microfluidic material. Parylene microfluidic systems are conventionally fabricated using a sacrificial photoresist (PR) layer34-37. Removing of the sacrificial PR from parylene channel takes a long time (as long as several days for ~1 cm long channel) because the dissolution of the PR is diffusion-limited process. In addition, parylene-to-parylene bonding strength still remains problematic38 because parylene is chemically inert and has low surface energy Alternatively, thermal bonding method using high temperature (~ 200°C) could be used to bond parylene layers via interfacial diffusion39. However, high temperature process above the glass transition temperature (Tg) of parylene (i.e. parylene C: Tg ~ 90 °C) can cause channel deformation. In addition, the release of the bonded parylene channels from the mold becomes difficult and choice of mold material is also not trivial. Moreover, parylene C undergoes thermal oxidative degradation, which makes the parylene fragile and less flexible40-41. We developed a low temperature molding and bonding technique for flexible parylene microfluidics using double cross-linked nano-adhesive (DCNA) layers deposited by initiated chemical vapor deposition (iCVD)28. The fabricated thin-film microfluidics has a microscale 4 ACS Paragon Plus Environment

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bending radius without leakage and significant cross-sectional deformation. With this highly flexible thin-film microfluidics, we fabricated rollable microfluidic systems by rolling the parylene channels around inlet capillary tubing. The rollable microfluidic systems, as a result of microscale bending capability, can provide high compactness and tunable functionality, which was demonstrated by tunable microfluidics mixer using asymmetric Dean flow arising from microscale 3D curvature.

2. RESULTS AND DISCUSSION 2.1 Fabrication of Thin-Film Parylene Microchannel We developed a new molding and bonding technique for parylene microfluidic channel fabrication (Figure 1a). Two thin-film parylene layers (~1-10 µm thickness) were bonded to form flexible parylene microfluidics using DCNA layers deposited by iCVD process28. Parylene layers were prepared on both microchannel patterned mold and bare Si wafer. The Si mold was fabricated by photolithography and deep reactive-ion-etch (RIE) process. The substrates were cleaned using piranha solution (95.0 % H2SO4: 35.5% H2O2 = 2:1) at 130 °C to remove organic residues. Tridecafluoro-1,1,2,2-tetrahydrooctyltrichlorosilane (FOTS, Gelest) was treated on the substrates for easy release of the parylene microfluidics from the substrates (for more information, see experimental section and supporting information). FOTS silanized Si wafer showed very low surface energy (hydrophobic) with water contact angle of ~ 120° (N=3) (Figure S1b, Supporting Information), which is known maximum value reported for smooth CF3-terminated surfaces42. After surface modification of the substrates, the parylene layers were deposited by chemical vapor deposition (SCS Labcoater 2, Specialty coating system, USA) at room temperature to produce uniform and conformal films with controllable thickness. In this study, ~ 5 µm thickness parylene layers were used to fabricate parylene microfluidics. 5 ACS Paragon Plus Environment


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To bond the parylene layers deposited on the substrates, a DCNA layer was applied on the parylene layers (Figure 1a and S1a). DCNA layer provides chemical bonding between epoxy and amine groups at interface of parylene layers and results in high bonding strength. Epoxy containing polymer, poly(glycidyl methacrylate) (PGMA), was deposited (~ 400 nm) via iCVD on O2 plasma activated parylene layers (O2 2.5 sccm, 60 W, 60 s). The PGMAcoated parylene layer on the flat substrate was reacted with vaporized ethylenediamine (EDA) in a glass petri dish for 3 minutes on a 70 °C hot plate. Then, the parylene coated substrates were aligned and held together using a custom-built compressor. The aligned sample was placed in 80 °C vacuum oven for 8 hours to achieve complete reaction between epoxy and amine groups. The use of vacuum oven improves bonding by preventing air trap between parylene layers. After bonding, the unreacted epoxy groups connected chemically with parylene film can be retained and used for further functionalization. The epoxide can react with various functional groups such as hydroxyl, amine and thiol via addition reaction without producing byproduct. Therefore, desired channel surface properties such as biocompatibility, cell adhesion or antifouling properties can be introduced by linking unreacted epoxides with amine-, hydroxyl-, or thiol-terminated moieties. With the use of such functionalized surfaces, the microfluidic device can be applied for various purposes such as long-term cell culture systems43 or biomolecular detection systems44. After bonding, inlets and outlets were constructed and the parylene microfluidic channel was completely released from the Si substrates (Figure 1a). First, the flat Si wafer was detached from the bonded parylene channel. Next, a piece of polyethylene terephthalate (PET) film (100 µm thickness) as a supporting layer was attached to the inlet and outlet parts of the parylene channel using UV glue. After cutting the parylene channel in desired shape, the parylene channel and PET supporting were peeled off from the Si mold substrate. The 6 ACS Paragon Plus Environment

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parylene channel could be easily peeled off by the FOTS treated surface (Figure S1c). The Si substrates can be reused repeatedly after piranha cleaning. For planarization of the parylene channels, a PET film with inlet/outlet holes (~2 mm diameter) was aligned and bonded to the other side of the PET supporting film attached part. To construct the inlet and outlet, parylene was dry-etched by oxygen plasma etching. Finally, tubing was connected to the detached flexible parylene microfluidics with custom-made connectors (Figure 1c, inlet part). Alternatively, PDMS block can be used as inlet/outlet connections: PDMS block was plasmabonded to a coverslip with holes and bonded to the PET supporting layer (Figure 1c, outlet part). Figure 1b shows SEM images of parylene channel from each fabrication step (~ 5 µm thickness parylene). Figure 1b (i) shows a mold substrate that was fabricated by patterning microchannels on a Si wafer. Deep RIE was used to achieve relatively smooth etched surfaces and vertical side walls of the microchannels. Figure 1b (ii) shows the mold substrate that is conformally coated with uniform parylene layer (~ 5 µm thick). Figure 1b (iii) shows the detached parylene channel from the mold and the figure 1b (iv) is the higher magnification image showing the cross section of channel. The thickness of the channel walls are ~ 5 µm thick as observed in previous steps. Most area of flexible parylene device is flat region with two parylene layers combined. This region is observed as twice thick as the channel wall. The upper channel wall is deformed downward slightly and the edges of the section are not smooth because of the cutting process with a razor blade (Figure 1b (iv). The completely released parylene channel precisely reproduces the shape of the Si mold and there are no sign of thermal damage or deformation of parylene layers due to low temperature process. Figure 1d and 1e show the final flexible parylene channels. Figure 1d shows highly flexible parylene channel that is filled with yellow and blue dye solutions forming laminar 7 ACS Paragon Plus Environment


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flows. The parylene channel is extremely flexible and robust so that it can even be folded without any apparent leakage in channels (Figure 1e and S3). SU-8 has a similar Young’s modulus (2.0 GPa) to parylene C (2.8 GPa, SCS parylene properties), but the thin-film SU-8 channels are brittle and prone to crack and break easily under a small amounts of stress32. The elongation-to-break value of parylene is 200% which is significantly higher than that of SU-8 (~ 4.8%)45 or polyimide (~10-80%)46. More detailed analysis on flexibility of the fabricated channel can be found in the following section. The molding and bonding method using DCNA layer via iCVD has several advantages compared to conventional parylene microfluidics fabrication: i) short process time ii) low temperature process and iii) high bonding strength. The conventional parylene channel fabrication process, which uses sacrificial PR layer, requires extremely long time to remove PR for long channel because the etching time (i.e., diffusion time, td) increases proportionally to the square of channel length (td ~ L2). On the other hand, the time taken in molding and bonding process is not influenced by the channel length. In addition, the channel mold can be reused, which means that this process is available for industrial mass production. Parylene deposition on channel molds and flat substrates can be performed simultaneously in a parylene coating chamber, and both substrates can be coated via iCVD at once to deposit the DCNA layer. During the entire bonding process, the temperature of substrate is maintained below Tg of parylene C, which ensures no deformation and easy detachment of the parylene channel from the mold. One of the advantages of DCNA bonding is extremely high bonding strength (~25 bar)28. We confirmed that the DCNA layer can provide similar bonding strength for parylene bonding. Pneumatic pressure was applied to a dead-end channel having circular chamber with 400 µm diameter to measure the burst pressure. First, the channel was filled with dye solution and the outlet was sealed with epoxy glue. No-leakage of dye solution or channel delamination was observed up to 6 bar. Beyond 6 bar, the tubing connection and the glued inlet part started to 8 ACS Paragon Plus Environment

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fall apart. This burst pressure at 400 µm diameter chamber corresponds to ~12 bar at typical microchannels with 100 µm width.

2.2 Properties of Flexible Parylene Microfluidics 2.2.1 Cross-Sectional Deformation from Internal Pressure Flexible microfluidic channels may suffer from large cross-sectional deformation by internal pressure, which changes channel cross-sectional area and will lead to difficulty in flow control from unpredictable fluidic resistance changes. Larger cross-sectional deformation also leads to larger fluidic capacitance and longer flow stabilization time. In addition, the deformation of the channel shape can reduce the device efficiency and limit the operational flow rate range in many microfluidic devices such as chaotic mixer, DLD, hydrophoresis, microfluidic filters, and inertial microfluidic devices where the channel crosssectional geometry is an important design parameter. We observed that the parylene microfluidics provides remarkably low cross-sectional deformation from internal pressure without sacrificing the flexibility of the system. To quantify the cross-sectional deformation of thin-film parylene channel in response to internal pressure, 4.5 µm thickness parylene microchannels with 50, 100, 150, and 200 µm widths were prepared (Figure 2). The exact film thickness was measured with an alpha-step stylus profiler. The deflection of channel wall was observed under non-contact optical profilometer (Nanofocus AG) at varying internal pressures. To accurately measure the deflection of channel wall, parylene channels were not completely released from the mold and only the flat substrate was removed. Thin gold layer (~3 nm) was sputtered on the parylene channel in order to facilitate the reflection of measurement beam47. Au layer with 3 nm thickness does not affect the deflection of parylene channel because Au layer is discontinuous. Figure 2a shows the measurement scheme and optical profilometer images of 9 ACS Paragon Plus Environment


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membranes with various widths at an applied pressure of 2.00 bar. The deflection profiles of 100 µm width channel with a pressure range of 0.25-2.00 bar are shown in Figure 2b. Even at 2.00 bar, maximum displacement of membrane of 100 µm width was only ~ 1.6 µm considerably smaller than previously reported bulk PDMS channel deformation under similar internal pressure24. A simple FEM simulation was conducted for deflection of a parylene channel with 100 µm width and 4.5 µm thickness and the results showed that maximum displacement of the wall was ~1.4 µm at 2.00 bar, which is close to the experimental result. The maximum displacement value of parylene channels and bulk PDMS-PDMS channels (Sylgard 184 in a 10:1 ratio) were also measured and compared (Figure 2c). Deformation of bulk PDMS-PDMS channels was observed from side-view (Figure S2). The PDMS-PDMS channels showed maximum displacements of 10.3 µm and 15.3 µm with channel widths of 100 µm and 150 µm at applied pressure of 2.00 bar, respectively. Compared to the bulk PDMS channels, the parylene channels showed ~ 6 and ~3 fold smaller channel deformation at channel widths of 100 µm and 150 µm, respectively. Bulk PDMS channels (typical > 5 mm thickness), though flexible, have limited bending radius due to their bulkiness. Thin-film PDMS channels may be built to achieve small bending radius. In this case, the channel deformation, especially the cross-sectional deformation from internal pressure, will be too large to be used in practical flexible microfluidic channel applications. The deformation of PDMS membrane structure has been studied and used for applications such as on-chip valves48 and tunable microfluidic lenses47, which are benefited by high deformability of PDMS. However, such high deformability can be problematic for a general flexible microfluidic channel that requires firm cross-sectional shape. Although the modulus of PDMS can be modified with the ratio of curing agent in PDMS mixture (Sylgard 184)24 and become even more rigid as the h-PDMS49 and bottlebrush crosslinked PDMS50, the loss of flexibility prevents the use of rigid PDMS in developing flexible microfluidics. 10 ACS Paragon Plus Environment

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2.2.2 Minimum Bending Radius Minimum bending radius and cross-section deformation of bent channels were analyzed to quantify the flexibility of thin-film channel. Straight parylene channels with a height of 50 µm and various widths (20 µm to 200 µm) were fabricated. The thickness of parylene layers was fixed at ~ 5 µm. Fabricated parylene channels were wrapped around standardized gauge needles to control bending radii, R3D (Figure 3). Needles of 30G with 155 µm radius, 25G with 255 µm radius, 20G with 455 µm radius, and 16G with 825 µm radius were used. Figure 3a shows the SEM images of parylene channels wrapped around 30G and 16G needles as representative examples of channel bending with small and large radii. To fix the deformed shape of the channels for SEM imaging, UV glue (NOA 71, Norland) was filled into the parylene channels and cured after channel deformation. For high aspect ratio channels (20 µm and 30 µm width), the observed channel cross-sectional deformation was negligible regardless of the bending radius. For low aspect ratio channels (150 µm and 200 µm width), however, significant channel collapse was observed. Especially for small bending radii (30G needle), the channels were completely collapsed. It could be deduced that the reduction of the bending radius increases the stress exerted on the outer channel wall, leading to larger deformation and channel collapse. No deformation was observed on the high aspect ratio channels because the side walls could support the structure, while the middle part of the top channel wall could not be fully supported by side walls in low aspect ratio channels. In case of extremely small bending radii, i.e. complete folding, deformation of the side walls also could be found (Figure S3a and S3b). In case of channels with high aspect ratio, we found interesting pattern formation on the channel surface. The channel cross-sectional shape was maintained, but scratch-like patterns, identified as permanent plastic deformation of the parylene film, appeared on the top surface 11 ACS Paragon Plus Environment


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(white arrows) as shown in Figure 3a and 3d. At large bending radii (or small stress), elongation of the top channel wall was reversible (in elastic deformation regime). However, when the stress in the channel wall exceeded its yield strength (~ 55 MPa), the parylene layer underwent irreversible plastic deformation and formed a stretch mark. Surprisingly, the bent channels with stretch marks were still intact and showed no signs of leakage (Figure 3b and 3d). The stretch marks did not develop further with repeated channel bending after the first bending. Since the plastic deformation area is more easily deformed than other areas, the stretch marks function as a stress relief function. We utilized stretch marks formed on the parylene channels to prevent channel sagging and to further reduce the minimum bending radius. We intentionally bend the channel beyond elastic deformation regime (Figure 3c and 3d) to induce the stretch marks. Liquid paraffin (melting point 44-46 °C) at 65 °C water bath was filled into the parylene channel. After cooling and solidification of paraffin, we wrapped the parylene channel around a 30G needle. Filling with paraffin helped maintain a rectangular cross-section of the channel and create relatively uniform stretch marks (Figure 3d). The paraffin was later melted in warm water bath and then removed with IPA after the stretch mark formation. SEM image in Figure 3d shows that the parylene channel with the stretch marks is intact without leakages. Figure 3e shows normal channel without stretch marks and pre-stretched channels bent around a 25G needle. The pre-stretched parylene channels exhibits significant improvement in maintaining channel cross-sectional shape during bending compared to normal channels. With the aid of pre-stretching, flexible parylene channels can have a bending radius of a few hundreds of micrometers, regardless of aspect ratio.


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2.3 Rollable Microfluidic System We developed a rollable microfluidics system from the flexible thin-film microfluidics with microscale bending radii and high bonding strengths. In a rollable microfluidics format, parylene channels can be rolled and packed into a small size. More importantly, the flexibility allows tunability of the device function: tunable Dean-flow mixer is demonstrated using reconfigurable microscale 3D geometry.

2.3.1 Compact 3D-Packing of 2D Thin-Film Microfluidics Rollable 3D microfluidic channel was fabricated by connecting parylene channels to a tubing working as an inlet, by which the size of device can be dramatically decreased (Figure 4). To demonstrate the compactness of rollable microfluidics, we built two large size microfluidic devices as examples: a long channel and a gradient generator. Fabricated parylene channels with 5 µm thickness parylene layers were connected with a PEEK tubing (Revodix®, 775 µm radius). Inlets of parylene channel were aligned with pre-patterned holes in the tubing and bonded with UV-glue (Figure 4a). Double-sided tape can also be used as an adhesive layer between parylene channel and tubing if high pressure operation is not required. Tape-bonded inlets can withstand pressure up to ~ 1.5 bar.. Figure 4b shows a simple microchannel having 0.5 m length (150 µm width and 30 µm height). The channel designed to cover a 52 mm × 10 mm area in 2D can be tightly packed into a cylinder of ~ 1.2 mm radius and 10 mm height. Since the parylene channel wall is only 5 µm thickness, the rolling does not add much volume. The volume of the 3D cylinder is mostly the size of the inlet tubing. Microfluidic gradient generators typically take up a fairly large area. A microfluidic gradient generator was designed to have ~ 80 mm × 10 mm area and tightly packed into a cylinder with ~ 1.3 mm radius and 10 mm height (Figure 4c). An outlet was constructed with 13 ACS Paragon Plus Environment


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PET supporting film as described above. A chemical gradient was generated in the wide channel under the PET supporting and can be observed with a microscope. Two inlets are constructed through single tubing by blocking the middle as shown in Figure 4a. This two inlets configuration may be used as inlet and outlet with proper modification of design. If multiple inlets/outlets are needed, bundle of capillary tubing can be a quick solution. Currently we are developing a simpler and stronger method to connect the parylene channel inlets/outlets to the tubing.

2.3.2 Tunable Dean-Flow Mixer with Reconfigurable 3D Structure At finite-Reynolds number flows, curvature of microchannel can result in Dean-flows caused by the difference between fluid acceleration at channel center and walls. The magnitude and qualitative features of the Dean flow is characterized by Dean number (De = Re(DH/2R)0.5, where Re, R, and DH are Reynold’s number, radius of channel curvature, and hydraulic diameter, respectively)14. Decreasing the radius of curvature (R) increases the magnitude of Dean flow. Dean-flow in microfluidics has been used in many applications including control of the interface of two fluids19, hydrodynamic focusing of particles15, 17-18 and fluid mixing16. Here we demonstrated re-configurability of the rollable microfluidics for a tunable Dean-flow mixer with controllable radius of curvature of thin-film microfluidics. As the rollable microfluidic systems have microscale radius of curvature (R), the mixing of fluids can be tuned effectively by simply changing the rolling diameter. We designed the tunable mixers to have symmetric serpentine channels with various radii of curvature (R2D) as shown in Figure 5a. In a Dean-flow mixer, the formation of Dean vortices improves the mixing of fluids because the boundary between the fluids flowing in parallel becomes elongated. Unlike spiral channels, the symmetry in serpentine channels reverses the direction of Dean-flow, so that repetitions of the 2D curvature dose not 14 ACS Paragon Plus Environment

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efficiently improve the mixing of fluids. On the other hand, rolling of the 2D serpentine channels in third axis will create a 3D curvature that enhances the mixing of fluids by breaking the symmetry in Dean-flow. The serpentine channels had 30 µm height and 100 µm width. The thickness of parylene channel walls was 5 µm and 3D curvatures were formed by rolling channels around 23G needles with 320 µm radius. Figure 5b shows the fluorescent microscopy images of the flat channels and the 3D channels. Here the 3D geometry of channels was fixed with UV glue and needles were removed for imaging. As seen in SEM images (Figure 5c), no cross-section deformations were found for the 3D channels. The serpentine channel geometry helped release the bending stress and the pre-stretching was unnecessary for the 3D Dean-flow mixer. We confirmed that the channel was rolled tightly from confocal microscope image (Figure 5d). The expected total thickness of one cycle coiling system is 760 µm and the confocal image shows a maximum difference of 780 µm depth. The 20 µm difference is expected to be a gap between rolled parylene channels. The mixing efficiency was analyzed by measuring florescence intensity on the channel while flowing DI water together with FITC solution (1 mg/mL in DPBS) from the two inlets. Figure 6a shows the fluorescent images of the flat and the 3D channel with R2D = 450 µm and R3D = 320 µm. Mixing of two liquids became noticeable in the 3D channel with increasing flow rates. The intensity profiles in Figure 6b show the results more clearly; while the flat channel shows insignificant changes, the 3D channel shows clear enhancement in mixing. The intensity profiles were normalized with maximum intensity in each measurement. Figure 6c shows the degree of mixing from each channel with different R2D as a function of flow rate (Figure S4 and S5 show corresponding florescent images and normalized intensity profiles). We defined the degree of mixing as the ratio of average fluorescent intensity (A/B) at the region A and B (Figure 6b). The degree of mixing is higher in the 3D channels and enhancement of mixing was more effective at higher flow rates. At the low flow rate (low 15 ACS Paragon Plus Environment


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Reynold number), the value of degree of mixing between the flat and 3D system is similar because the induced Dean-flow is not significantly strong and the mixing occurs mostly due to the diffusion of FITC molecules. However, as the flow rate is increased, the degree of mixing in 3D system increases more rapidly than the mixing in flat system. Numerical simulations of the flow fields were conducted for the flat and 3D channel. Figure 6d and 6e show the Dean vortices at the cross-sections with opposite channel curvature. As expected, Dean vortices form symmetrically in the flat channel (Figure 6d), consecutive left and right curvature will reverse the mixing effect. However, the upward curvature of the 3D channel can create Dean-flows in diagonal directions, which can efficiently elongate boundary of the parallel flows (Figure 6e). The alteration of Dean vortex shape was possible because the channel curvature in the third axis was comparable to the channel curvature in flat configuration, which is only possible with microscale bending radius of flexible, rollable microfluidics. The results demonstrate the tunability of the device function by rolling the channel and changing channel geometry at microscale. Note, the mixing efficiency of the mixer was not optimized and it can be further increased by adjusting the channel geometry, such as R2D, channel height and width, which is beyond the scope of this paper.

3. Conclusion In summary, we developed the flexible thin-film microfluidics with microscale bending radius. New molding and bonding process with DCNA layer deposited by iCVD provided fast and low-temperature fabrication method for parylene microfluidics that could endure high pressure for practically all microfluidic applications. Because the low temperature process allowed less thermal damage, the released channel had high structural integrity of the channel mold. The flexible parylene microfluidics showed smaller cross-sectional 16 ACS Paragon Plus Environment

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deformation than a bulk PDMS channel with internal pressure while providing high flexibility with microscale bending radius. Channel sagging issue in low aspect channels was resolved by forming stretch marks using simple pre-stretching technique. Fabricated flexible thin-film microfluidics was developed as a rollable microfluidics platform. With its microscale bending radius, the compact rollable microfluidic system with capillary tubing worked as inlets and the reconfigurable 3D geometry of 2D microfluidic system are demonstrated. Rollable microfluidics can provide new method to minimize device size and to miniaturize lab-on-a-chip devices. Reconfigurable 3D curvature by rolling 2D structure allowed Dean-flow mixer with tunable mixing efficiency. We expect that the flexible thin-film microfluidics provides important components for advances in many fields including wearable biosensors and tunable 3D microfluidics.

4. Experimental Section FOTS treatment: The substrates, cleaned with piranha solution (95.0 % H2SO4 : 35.5% H2O2 = 2:1), were placed into a desiccator. Two vials with a drop of FOTS (Gelest) and DI water were put inside the desiccator to maintain a constant vapor partial pressure of each molecules51. Then, the cleaned substrates reacted with FOTS molecules inside the desiccator for 1 hour 30 minutes at 65 Torr. After reaction took place between vaporized FOTS molecules and hydroxyl groups on the Si substrates, the substrates were rinsed with isopropyl alcohol (IPA) to remove physically adsorbed FOTS molecules on the surface and the substrates were annealed at 120 °C oven for 1h to strengthen the adhesion between FOTS molecules and the substrate caused by dehydration condensation reaction. FOTS molecules can covalently bond to OH groups on Si wafer, however, the resulting Si-O-Si bond can be slowly hydrolyzed and decomposed over time. FOTS silanized wafers were stored in desiccator box between fabrication processes, and for better results, parylene channel was 17 ACS Paragon Plus Environment


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bonded within one week after the FOTS treatment. Although the Si channel mold can be reused, fresh FOTS treatment is required for each parylene channel bonding after the piranha cleaning. Deposition of DCNA layer using iCVD process: Epoxy containing polymer, poly(glycidyl methacrylate) (PGMA), was deposited via iCVD process using glycidyl methacrylate (GMA, 97%, Aldrich) and tert-butyl peroxide (TBPO, 98%, Aldrich) as monomer and initiator, respectively. The flow rates of GMA and TBPO were set to 4 and 1 standard cubic centimeters per minute (sccm). The temperature of substrate was kept at 30 °C using a circulator. The filament temperature and operating chamber pressure were set to 120 °C and 140 mTorr. After 75 minutes, a 400 nm of PGMA layer was conformally deposited on the substrates. The PGMA-coated parylene layer on flat substrate was then place in a glass petri dish and was exposed to ethylenediamine (EDA) vapor at 70 °C for 3 min. The EDA-treated substrate was placed face-to-face with PGMA-coated parylene layer on channel patterned substrate. The assembly was compressed using a custom-built compressor (Max. pressure 3 MPa) and stored in vacuum oven at 80 °C for 8 hours to achieve strong adhesion between the parylene films. Simulation of fluid velocity: All simulations were computed on a FEM simulator (COMSOL Multiphysics V5.2) and the laminar flow module was used to map the fluid flow dynamics inside the flat and 3D channels. Fluidic channel dimensions were set to resemble the actual channel as much as possible and the fluid normal velocity at the inlet was given at 0.5 m/s. The flow was first given 300 µm of straight channel for stabilization and a 180 ° curve of 250 µm in radius was placed after the straight part. Another 300 µm straight channel was placed after the first curvature before placing another curvature. A perpendicular cut to the channel walls at the middle of each curvature was used to visualize the secondary flows orthogonal to the base flow. 18 ACS Paragon Plus Environment

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Figure 1. Molding and bonding technique for fabrication of thin-film parylene channel. (a) Schematic of fabrication process. (b) SEM images showing the (i) channel mold, (ii) parylene coated mold and (iii), (iv) detached parylene channel consisting of ~ 5 µm thickness parylene layers. (c) Fabricated parylene microfluidics connected to inlet/outlet tubing using custommade O-ring connector and PDMS connector. The fabricated parylene channels can be (d) bent and (e) folded easily without resulting leakage.



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Figure 2. Cross-sectional deformation of thin-film parylene channel from internal pressure. (a) Measurement scheme and 3D optical profilometer images of 4.5 µm thickness parylene microchannels with 50 µm, 100 µm, 150 µm, and 200 µm widths at applied pressure of 2.00 bar. (b) The deflection profiles of 100 µm width channel with pressure range of 0.25-2.00 bar. (c) Maximum displacement value of parylene channels (N=5) and PDMS-PDMS channels (N=3) as a function of applied pressure.


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Figure 3. Bending parylene microfluidic channels with a hight of 50 µm and various widths. (a) SEM images of parylene microfluidic channels with 20 µm, 30 µm (high aspect ratio), 90 µm, 100 µm (medium aspect ratio), 150 µm, and 200 µm (low aspect ratio) width wrapped around 30G and 16G needles. (b) Optical image of wrapped parylene channel around a 30G needle without leakage. (c) Schematics of stretch mark formation using paraffin for channel reinforcement. (d) SEM and Optical microscope image of the pre-stretched channel with 100 µm width. No crack or fracture was found at the stretch marks in the SEM image. (e) Comparison of the normal channels without stretch marks and the pre-stretched channels wrapped around 25G needles. Pre-stretched channels maintain cross-sectional shape while normal channels are collapsed. 21 ACS Paragon Plus Environment


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Figure 4. Rollable parylene microfluidics for compact packed system. (a) Schematic of a rollable microfluidics having 2 inlets as shown in (c). Single tubing can support 2-inlets for microchannels by blocking in the middle. Inlets of the fabricated parylene channel were aligned with the holes in the PEEK tubing and bonded with UV-glue or double-sided tape. Rollable microfluidic systems of (b) 0.5 m length channel with single inlet and (c) microfluidic gradient generator with two inlets.


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Figure 5. Tunable 3D geometry of 2D channels. (a) Design of a serpentine channel with various 2D curvatures (R2D). (b) Fluorescent images of the flat and 3D channels. Using high flexibility of parylene channels, channels were rolled around two 23G needles to form 3D curvature for Dean-flow mixer (scale bar: 400 µm). (c) SEM and (d) confocal microscope images of the 3D channel.



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Figure 6. The mixing of fluids inside flat and 3D channels. (a) Fluorescent images and (b) normalized intensity profiles at the flat and 3D channel with R2D= 450 µm and R3D= 320 µm depending on change of flow rate. While the flat channel shows insignificant changes, the 3D channel shows clear enhancement in mixing. (c) The degree of mixing in the flat (F) and 3D (R) channels with different R2D as function of flow rate (N=4). The enhancement ratio is the ratio of the degree of fluids mixing between the flat and 3D channels (R3D/R2D). Results of numerical simulation for fluid flows within the (d) flat and (e) 3D channel. Fluid velocity


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profiles (color map) along with secondary flow field (black arrows) and Dean vortices (thick green arrows) are shown.

ASSOCIATED CONTENT Supporting Information Parylene bonding with DCNA layer deposited via iCVD and substrates treatment; Deformation of bulk PDMS-PDMS microchannels caused by internal pressure; Extreme deformation of fabricated parylene microfluidics; Fluorescent images at the flat channel and 3D channel having different R2D and R3D= 320 µm depending on change of flow rate; Fluorescent intensity profiles from Figure S4; “This material is available free of charge via the Internet at http://pubs.acs.org.”

AUTHOR INFORMATION Corresponding Author *

Corresponding authors

Wonhee Lee*: [email protected] Sung Gap Im*: [email protected]

Author Contributions #

These authors contributed equally.

ACKNOWLEDGMENT



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This work was supported by the Radiation Technology R&D program (NRF2015M2A2A4A02044826) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning and the Technology Innovation Program (10054488) funded by the Ministry of Trade, Industry and Energy (MI, Korea) and the Center for Advanced Soft-Electronics funded by the Ministry of Science, ICT and Future Planning as Global Frontier Project (CASE-2011-0031638). We thank Dr. Dong Ki Yoon for supporting confocal microscopy measurements.

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Rollable Microfluidic Systems with Microscale Bending Radius and

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