Development of a flexible microfluidic system

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Development of a flexible microfluidic system integrating magnetic micro-actuators for trapping biological species

This content has been downloaded from IOPscience. Please scroll down to see the full text. 2009 J. Micromech. Microeng. 19 105019 (http://iopscience.iop.org/0960-1317/19/10/105019) View the table of contents for this issue, or go to the journal homepage for more

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IOP PUBLISHING

JOURNAL OF MICROMECHANICS AND MICROENGINEERING

doi:10.1088/0960-1317/19/10/105019

J. Micromech. Microeng. 19 (2009) 105019 (11pp)

Development of a flexible microfluidic system integrating magnetic micro-actuators for trapping biological species R Fulcrand1,2 , D Jugieu1 , C Escriba1,2 , A Bancaud1 , D Bourrier1 , A Boukabache1,2 and A M Gu´e1 1 2

CNRS; LAAS; 7 avenue du colonel Roche, F-31077 Toulouse, France Universit´e de Toulouse; UPS, INSA, INP, ISAE; LAAS; F-31077 Toulouse, France

E-mail: [email protected]

Received 22 April 2009, in final form 30 July 2009 Published 22 September 2009 Online at stacks.iop.org/JMM/19/105019 Abstract A flexible microfluidic system embedding microelectromagnets has been designed, modeled and fabricated by using a photosensitive resin as structural material. The fabrication process involves the integration of micro-coils in a multilayer SU-8 microfluidic system by combining standard electroplating and dry films lamination. This technique offers numerous advantages in terms of integration, biocompatibility and chemical resistance. Various designs of micro-coils, including spiral, square or serpentine wires, have been simulated and experimentally tested. It has been established that thermal dissipation in micro-coils depends strongly on the number of turns and current density but remains compatible with biological applications. Real-time experimentations show that these micro-actuators are efficient in trapping magnetic micro-beads without any external field source or a permanent magnet and highlight that the size of microfluidic channels has been adequately designed for optimal trapping. Moreover, we trap magnetic beads in less than 2 s and release them instantaneously into the micro-channel. The actuation solely relies on electric fields, which are easier to control than standard magneto-fluidic modules. (Some figures in this article are in colour only in the electronic version)

generally comprise some, possibly a few tens of, turns and enable the reaching of magnetic fields with maximum amplitudes ranging from a few mT to tens of mT (Ramadan et al 2006a). In order to increase this field, a magnetic core may be added to the device thus enabling to reach fields approximately ten times greater (Ramadan et al 2006b). On the basis of these technologies, it is possible to integrate elementary trapping functions in these lab-on-chips (Bilenberg et al 2004), as well as sorting (Rong et al 2006, Suzuki et al 2004) and separation functions (Inglis et al 2006), etc. Although the technique benefits from numerous advantages, it suffers however from high cost of fabrication and low flexibility in comparison to the design of the microfluidic circuit.

1. Introduction Since the introduction of the concept of micro total analysis systems, or μTAS, in 1990, magnetic actuation in miniaturized systems has rapidly become a strategic tool to perform microfluidic functions based on the manipulation of functionalized micro-beads (Gijs 2004). Magnetic actuation requires generating and controlling magnetic fields at the micrometer length scale by using micro-fabricated electromagnets. The typical way for microelectromagnets fabrication consists in designing planar spiral coils. Conventional fabrication schemes use PCB, silicon or glass/silicon as supporting material (Beyzavi and Nguyen 2008, Massin et al 2003). The structures released 0960-1317/09/105019+11$30.00

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© 2009 IOP Publishing Ltd Printed in the UK

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J. Micromech. Microeng. 19 (2009) 105019

An interesting alternative approach consists in integrating the magnetic source into a polymer microfluidic system. Plastic substrates are particularly attractive for emerging applications because they enable the manufacturing of devices that can be rolled up, folded and that can be stretchable if necessary. Due to their ease of manufacturing (requiring low temperature conditions for example), low-cost, wide availability and high compatibility with most chemical and biochemical species (Joshi et al 2007), they tend to replace traditional substrate materials, such as Si, in a growing number of cases. Alongside the demands for flexible electronics, flexible displays, flexible radio frequency identification (RFID) tags, flexible and conformal sensors sheet and flexible batteries, polymeric microfluidic components are the first step toward high added-value lab-on-chips which will ultimately associate one or more of these functional elements and which could be integrated in a large variety of non-flat structures such as catheters, medical tubes or implanted devices (Li et al 2008). In that framework, we have already shown that full polymeric devices with multilevel micro-channels networks can be achieved using the SU-8 negative photoresist as structural material through the combination of photolithography and lamination technologies (Abgrall et al 2008). This approach offers numerous advantages: chemical resistance, transparency to UV, good mechanical properties, high design flexibility, compatibility with high voltage (Sikanen et al 2007) and compatibility with large surface area processes. In this paper, we demonstrate that this approach is compatible with the integration of a magnetic actuation. A technological process for the direct fabrication of microinductances on a polymer substrate has been developed. Realtime experiments show that the integrated micro-coils enable efficient and reliable trapping of micro-beads. We also demonstrate that the trapping performances strongly rely on the dimensions and shapes of the microfluidic channels and micro-coils, as well as on their location in the microsystem. Moreover, in order to design and evaluate the magnetic performance of these structures, we develop a finite element model and show its quantitative agreement with experimental results.

carrying substrate and (d) easy release of the structure to form flexible totally SU-8 microfluidic structures. This approach is also fully compatible with standard metallization processes such as evaporation, sputtering and electrodeposition and therefore enables integration of active elements. We propose here a generic process for integrating electroplated microstructures, i.e. micro-coils which have been used as microelectromagnets for magnetic beads manipulation. Our approach combines standard electroplating techniques (Park et al 2008) and lamination technologies (Abgrall et al 2006) in order to achieve flexible and transparent full polymer systems with the precision and reliability of ‘state-of-the-art’ microsystems. 2.1. Realization of the integrated planar inductor The sequence flow is reported in figure 1: • As a first step, a 50 μm thick adhesive was laminated (manual laminator Shipley 350HR, Rohm and Haas Electronic Materials, France) on top of a 525 μm 4 silicon wafer. Then a stack PET/adhesive/PET R -8796 from Adhesives (50/25/75 μm thick ARClear Research) was laminated on top of the adhesive sheet (figure 1(a)). The bottom side of the PET layer has a lower adhesion, making the release step easier. This PET protective layer was chosen for the following properties: (i) poor adhesion, (ii) transparency and (iii) flexibility. It has also been shown that the PET layer promoted stress reduction in the SU-8 layer (Abgrall et al 2008). This stress is mainly due to the large difference between the coefficients of thermal expansion (CTE) of silicon (2.5 ppm K−1 ) and SU-8 (52 ppm K−1 ). The CTE of PET is in the range 20–80 ppm K−1 . The insertion of a PET film is shown to reduce the stress (Abgrall et al 2008). • Then, 2 μm thickness SU-8 3005 was spin-coated (figure 1(b)): deposition of the resist (4 ml), resist spinup (5000 rpm s−1 ), spinning off at constant spinning speed (5000 rpm) and spinning time (30 s). The softexposure bake was then performed at 95 ◦ C for 1 min to evaporate the solvent from the resist. The resist was subsequently exposed to UV light in order to induce SU-8 cross-linking. The exposure was performed with a nearUV broadband semi-automatic mask aligner (Karl S¨uss MA-150) in the range of 350–405 nm. We determined that the optimal incidence dose for a 2 μm thick SU8 layer was 40 mJ cm−2 . The post-exposure bake was performed on a hotplate at 95 ◦ C for 1 min in order to complete the polymerization process and to obtain a hard material. Finally, the layer was developed in a bath of propylene glycol methyl ether acetate (PGMEA) for 2 min and rinsed in isopropanol (IPA). • Next, conductive tracks were obtained by sputtering and patterning a Ti/Au layer of 0.1 μm and 0.8 μm, respectively (figure 1(c)). Then, a second layer of SU8 3005 was spin-coated in order to realize an insulating layer separating the conductive tracks from the coils, and to create electrical vias (figure 1(d)). A seed layer (Ti/Cu: 0.05 μm/0.05 μm) was homogeneously sputtered.

2. Concept and realization The proposed method is based on low-cost, collective processes. SU-8 is an epoxy photoresist which allows fabrication of high-aspect-ratio microstructures, typically from 1 μm up to 1.5 mm, with a single coating (Lin et al 2002). It presents excellent chemical resistance, high transparency and is biocompatible (Kotzar et al 2002). Moreover, by successively stacking and patterning uncrosslinked SU-8 dry films, it is possible to create complete polymer 3D microfluidic networks. The key features of the technique include (a) lamination of a SU-8 film through a flexible carrying substrate avoiding reported problems due to surface inhomogeneities, (b) patterning of the layer after bonding that allows an excellent level-by-level alignment, (c) easy peeling of the flexible 2

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(e)

(d) (c) (b)

(a)

Figure 1. Main steps for the integration of planar micro-coil into a flexible substrate. (a) Adhesive PET lamination; (b) first SU-8 layer; (b) conductive tracks patterning; (c) second SU-8 layer (planarization and electrical vias); (d) micro-coil electroplating.

The Ti layer was deposited to improve the adhesion, and a positive photoresist (AZ 4562, spin-coating: 5000 rpm s−1 , 1500 rpm, 30 s; pre-bake: 105 ◦ C, 60 s hotplate; exposure: 405 nm at 20 mW cm−2 for 22 s; post-bake: 115 ◦ C, 50 s hotplate) was subsequently patterned in order to create the electroplating mould (thickness ≈ 5.5 μm). Finally, copper coils, 5 μm in thickness, were electroplated into the resist mould. Then the photoresist mould was removed and the seed layer was chemically etched (figure 1(e)).

each soft and pre-bake. The resist was then exposed to UV light (90 mJ cm−2 ), and post-baked for 1 min at 65 ◦ C and 3 min at 95 ◦ C to cross-link the photoresist. Finally, the resist was developed in PGMEA for 3 min. This SU-8 layer served as a bottom part for micro-channels and as an insulator for micro-coils (figure 3(a)). Following floor fabrication, 8 ml of SU-8 3050 was then spin-coated at 1500 rpm with an acceleration of 3200 rpm s−1 for 30 s, resulting in a 50 μm thick film in order to realize micro-channel walls. The resist was then soft-baked (1 min at 65 ◦ C, 27 min at 95 ◦ C), polymerized under UV light (217 mJ cm−2 ), postbaked (1 min at 65 ◦ C and 3 min at 95 ◦ C) and developed in PGMEA (9 min) (figure 3(b)). A photosensitive SU-8 dry film was then laminated to close the structures. The fabrication of dry films starts by laminating adhesive and PET/adhesive/PET sheets on top of another silicon wafer as already described in section 2.1. Dry films were then obtained by spin coating 4 ml of SU-8 3005 at 900 rpm with an acceleration of 500 rpm s−1 for 30 s, resulting in a 10 μm thick film. After spin coating, a soft bake is performed. The duration of this soft bake was voluntarily increased compared to ‘standard process’ in order to evaporate most solvent and harden the layer. The SU-8/PET stack was then peeled from the substrate. Prior to the lamination of the resulting SU-8 layer, an oxygen plasma treatment was first performed on the structure embedding planar micro-coils to improve adhesion between SU-8 layers. A lamination pressure of 2 bar and a temperature of 65 ◦ C were chosen. The resist was then exposed to UV light through the appropriate mask in order to pattern microfluidic vias. Post-exposure bake was then performed on a hotplate (1 min at 65 ◦ C, 3 min at 95 ◦ C), release liner was peeled and uncrosslinked SU8 was developed in PGMEA (3 min) (figure 3(c)). Finally, the complete microstructure could be simply peeled off the substrate at the end of the process or could be directly used if a rigid substrate is required.

As can be seen in figure 2, the structures obtained following this process are of high quality: the design of coils is well defined without any residual seed layer between the copper coils (figure 2(a)) and contact between coil and tracks features presents excellent adhesion properties (figure 2(b)). A general view of a ten turns micro-coil realized on top of a SU8 layer is given in figure 2(c). 2.2. Fabrication of microfluidic channels The microfluidic channels are then fabricated directly on top of the structure by using the lamination technique and SU-8 patterning. So as to proceed with the manufacturing method, it is however indispensable to go back to the perfectly planar surface. The first step required is hence a step of planarization. Fortunately, SU-8 is a material particularly well adapted to this step, which naturally ensures compatibility with the global method. Thus, the first step consists in depositing a low viscosity SU-8 layer: SU-8 3005 has been selected in this perspective. A 10 μm thick film is obtained by spin coating 4 ml of SU-8 3005 at 900 rpm with a 900 rpm s−1 acceleration for 30 s. The resist was then soft baked for 1 min at 65 ◦ C, ramped at a rate of 10 ◦ C min−1 up to 95 ◦ C, held at 95 ◦ C for 7 min and finally cooled down to room temperature at 5 ◦ C min−1 . The same temperature ramps were used for 3

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J. Micromech. Microeng. 19 (2009) 105019

µ

µ

µ

(a)

(b)

(c)

Figure 2. SEM images of the micro-coils fabrication. (a) Detail of a square micro-coil with five turns, separated by 10 μm; (b) electrical contact between the conductive track and coil; (c) a general view of a square micro-coil with ten turns.

(b)

(a)

(c)

Figure 3. Main steps for the realization of the final device. (a) Third SU-8 level (floor); (b) fourth SU-8 levels (walls); (c) lamination and patterning of the photosensitive SU-8 dry film level. Table 1. Summary of processing parameters for different SU-8 negative photoresist series. SU-8 series

Viscosity (cSt)

Thickness (μm)

Soft bake at 65 ◦ C (min)

Soft bake at 95 ◦ C (min)

Exposure dose (mJ cm−2 )

Post-exposure bake at 65 ◦ C (min)

Post-exposure bake at 95 ◦ C (min)

Development in PGMEA (min)

3005 3025 3050

65 4 400 12 000

2–10 25 50–100

0–1 1 1–1

1–7 15 27–44

40–95 170 217–365

0–1 1 1–1

1–3 3 3–3

2–5 9 12–15

• the electric field can be ignored and • the magnetic field is constant with respect to time. ∇ × H = J

We report in table 1 typical values of processing parameters obtained and optimized for different series of SU-8. Figure 4(a) shows the successful integration of a circular micro-coil embedded in a channel. As it can be seen in figure 4(b), the complete microfluidic system is flexible and optically transparent. These properties give our device original qualities, in particular those linked to easy handling and optical observations or measurements.

(1)

∇ × B = 0  = χ H + M r M

(2)

 = μ0 · μr · H + μ0 · M r B = μ0 · (H + M)

(4)

(3)

where H is the magnetic field strength, B is the magnetic flux density, J is the conduction current density, M is the magnetization, χ is the magnetic susceptibility, Mr is the remanent magnetization, μ0 = 4 ∗ π ∗ 10−7 H m−1 : the permeability of vacuum and μr is relative permeability. Solving these equations allowed us to evaluate the magnetic force exerted on a micro-bead and also to select the most efficient microelectromagnet design. Various shapes of the magnetic actuator have been modeled and their performances compared.

3. Design and modeling of a trapping microfluidic module In order to evaluate the relevance of this new technology for lab-on-chip applications, we have designed and realized a trapping module. In this view, we have simulated the static magnetic field induced by different micro-coil configurations by using a finite element method (FEM). The magnetostatic field induced by a dc current flowing in an electric conductor was deduced from Maxwell’s equations. It has been assumed that

3.1. Magnetic field created by various micro-coils Five micro-coil designs have been studied as reported in table 2. The simulation was performed with MAXWELL3D

• electrostatic effects can be neglected, 4

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(a)

(b)

Figure 4. Photographs of the final flexible microsystem. (a) Magnetic micro-actuator embedded into the micro-channel. (b) Handling of the flexible microsystem when it was peeled off the silicon substrate.

existing methods, including the use of fewer computational resources, the excellent numerical stability, which does not require gauges and the significant reduction of cancellation errors. The magnetostatic solver handles both 3D linear and nonlinear problems. The magnetostatic solver computes the magnetic field produced by a combination of known dc current density vector distributions. Figure 5 shows an example of simulation results for the magnetic flux density generated by a five-turn square micro-coil. By convention, the x-axis is taken in the direction of the channel (and hence of the fluid flow) and the z-axis perpendicular to the axis of the channel. In the following, the current intensity flowing in micro-inductors was set to 100 mA and the material on top of the device was assumed to be air. The conductive copper lines are 5 μm wide and 5 μm thick separated by 5 μm. The magnitudes of the x- and z-components of the magnetic field were evaluated at different heights above the micro-coil (figures 6 and 7). Serpentine micro-coils generate a periodic magnetic field, particularly abrupt just above the surface as shown in figure 6. This behavior is due to the alternating directions of the current flowing through the coil. The maximal values of BZ and BX reach respectively BX max = 2.45 mT and BZ max = 2.22 mT for z = 5 μm, i.e. at the bottom of the channel, but decrease drastically for higher values of z. Figure 7 shows the magnetic field behavior (BX and BZ ) produced by a square micro-coil with five turns. In this case, the magnetic field BZ is maximal at the center of the coil, with a value of BZ max = 6.5 mT and, moreover, BX max = ± 4.7 mT. These values are respectively 4 and 2.5 times higher than those obtained with serpentine structures. Furthermore, the level of magnetic field increases with the number of turns due to the positive superposition of the magnetic field generated by each segment of the coil (table 3). Thus, doubling the number of turns enables the component BZ of the field to be increased by 40%. These values are in good agreement with the results published in the literature (Rostaing et al 2007, Rida et al 2003). As the magnetic field created by circular coils is quite similar to that obtained with square coils, we simply give the maximal values of the components BX and BZ in table 3. It is important to note that on the one hand the values of the field decrease very rapidly with z, in particular for a serpentine micro-coil, and that on the other hand the magnetic field is located above the coil very clearly.

Table 2. Schematic representation of the various micro-coils designs.

1 level of metallization

3 levels of metallization

3D representation

Description • Spiral micro-coils with 5 to 20 turns.

• Square micro-coils with 5 to 20 turns.

• Double spiral microcoils with 10 to 20 turns. • A double square micro-coil with 10 turns.

• A serpentine microcoil with 9 turns

(Ansoft software), a finite element method simulator. It was used to evaluate the influence of design and experimental parameters on the magnetic fields and magnetic forces produced by each configuration of micro-coil. MAXWELL3D magnetostatic solver defines the magnetic field H with the following components: H = H p + ∇ · ϕ + H c

(5)

with ϕ the magnetic scalar potential, Hp the particular solution constructed by assigning values to all the edges in the mesh (in such a way that Ampere’s law holds on all contours of all tetrahedral faces in the mesh) and Hc the contribution of permanent magnets. Thus, the degrees of freedom (DOFs) are the nodal values of the magnetic scalar potential with ten values per tetrahedron at each of the four vertices and all six mid edge nodes, ensuring a quadratic approximation inside each finite element. This formulation offers several advantages over 5

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(a)

(b)

Figure 5. 3D representation of the magnetic field. (a) (x, z) plane and (b) (x, y) plane, produced by a five-turn square micro-coil. 3.0

3.0 5µm 10µm 25µm

50µm

BZ (mT)

BX (mT)

1.5 0.0

5µm 1.5 10µm 25µm

0.0 50µm -1.5

-1.5 -1000

-500

-1000

1000

500

0 X (µm)

-500

(a)

0 X (µm)

500

1000

(b)

Figure 6. Modeling results for magnetic field generated by a serpentine micro-coil with nine turns and I = 100 mA, at different heights into the micro-channel (5, 10, 25 and 50 μm).

10µm BX (mT)

2.5

5µm

6

25µm

4 BZ (mT)

5.0

50µm 0.0

5µm 10µm 25µm

2

50µm

0

-2.5

-2 -5.0

-1500

-750

0 X (µm)

750

-1500

1500

(a)

-750

0 X (µm) (b)

750

1500

Figure 7. Modeling results for the magnetic field generated by a square micro-coil with five turns and I = 100 mA, at different heights into the micro-channel (5, 10, 25 and 50 μm).

As the magnetic field depends on the current density in the micro-coil, it is important to assess the influence of the excitation current. Figure 8 shows the variations of the components, BX and BZ , of the magnetic field for several values of the current intensity in a ten-turn circular micro-coil, with 5 μm × 5 μm square conductor section. The components of the magnetic field are given for 10 μm height in the channel. As can be seen in figure 8, the behavior of the magnetic field highly depends on the current injected into the microcoil. Indeed, the magnetic field BZ (BZ = 11 mT) at 150 mA is three times greater than that generated for 50 mA intensity (BZ = 3.68 mT). The component BX also grows when the current intensity increases. Over this current range, we can

Table 3. Maximum magnetic field level (BZ and BX ) 5 μm into the microfluidic channel for each design. Designs

Turn number

Square Spiral Serpentine Double square

5 5 9 5

10 10 19 10

BZ max (mT) 6.5 5.5 2.2 1.1

9.2 8 2.5 2

BX max (mT) 4.7 4.5 2.4 1.2

5.7 5 2.7 2

The design of the channels will take into consideration these properties when conceiving the system for integrating concrete functions. 6

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12 9

100mA

3

BZ (mT)

BX (mT)

150mA

150mA

6

50mA

0 -3

100mA

6

50mA

3 0

-6

-3

-9 -2000

-1000

0 1000 X (µm)

-2000

2000

-1000

(a)

0 1000 X (µm) (b)

2000

2

5µm

1

10µm 25µm

0

1.0

50µm

-1

10µm 0.0 25µm

50µm

-0.5

-2 -1500

5µm

0.5 FZ (pN)

FZ (pN)

Figure 8. Modeling results for the magnetic field generated by a circular micro-coil with ten turns, at a height of 10 μm into the microfluidic channel and for three current intensities: 50, 100 and 150 mA.

-750

0

750

1500

X (µm) (a)

-1000

-500

0 X (µm) (b)

500

1000

Figure 9. Simulated forces exerted on a magnetic micro-bead by (a) circular micro-coil and (b) serpentine micro-coil, at different heights into the micro-channel (5, 10, 25 and 50 μm).

A square turn cross-section also seems optimal as much as it enables to obtain the most compact turn structure, wherein the minimal turn dimension is limited by the technological method properly speaking. The amplitude of the magnetic field may be increased with the number of turns or the current density. The latter point will be however limited by the heating effects which may take place at high current level. It will hence be significant to assess these effects so as not to generate undesirable effects in the chemical or biological protocols. Figure 10. Microfluidic experimental setup for the validation of our magnetic bead handling.

3.2. Magnetic force exerted on a magnetic micro-bead In a microfluidic channel, a suspended particle in a liquid is subject to a particular drag force described by Stokes’ law:

verify that the magnetic field varies linearly with the current density injected as predicted by the Biot–Savart law.

F drag = 6 · π · η · Rbead (V fluid )

It turns out from this study that circular or square coils are roughly equivalent and much more efficient than serpentine designs. Even if serpentine coils are simpler to fabricate, involving a single metallization level against three for square or circular coils, they exhibit insufficient performances for the large scale trapping of magnetic particles. As can be seen in figure 6, the maximum value of BZ is 2.2 mT at 5 μm from the coil against 6.5 mT for the spiral coil, and it rapidly decreases to ∼0 mT at 25 μm against 3.5 mT for the spiral coil, clearly demonstrating that the magnetic field generated by serpentine coils fades away in the bulk of micro-channels.

(6)

with R being the radius of the bead (in m), Vfluid the speed of the fluid (m s−1 ) and η its viscosity (ηwater = 0.896 × 10−6 Pa s−1 at T = 25 ◦ C). In the (x, y) plane (see magnetic field calculations), the hydrodynamic drag balances the magnetic force acting on the bead. When considering an average linear velocity of the fluid of 20 μm s−1 corresponding to a flow rate of 0.03 μl min−1 in a channel of 500 μm in width by 50 μm in height, the mean force exerted on a micro-bead of 2.8 μm diameter can be determined according to (6): Fdrag = 0.47 pN. So as to predict the trapping efficiency of the microcoils, the magnetic force generated by the designs described 7

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J. Micromech. Microeng. 19 (2009) 105019

µ

(a)

(b)

R Figure 11. (a) SEM photograph of Dynabeads M270. (b) Optical picture of flow micro-beads in the micro-channel.

(a)

(b)

(c)

Figure 12. Magnetic particles trapping for a square micro-coil (ten turns; conductor square section: 5 × 5 μm2 and space between coils: 5 μm); for the following conditions: I = 100 mA; flow rate = 0.03 μl min−1 ; concentration of beads = 2 × 106 beads ml−1 .

previously has been calculated using Maxwell 3D and compared to the drag force. Figure 9 shows the force exerted on a magnetic micro-bead of 2.8 μm diameter by the circular and serpentine micro-coils. R The magnetic particles used in the study are Dynabeads micro-beads and have a magnetic susceptibility of 0.165 and a density of 1.6 g cm−3 . Calculations were performed with conductors of 5 μm width by 5 μm thickness separated by 5 μm, with 5 turns and supplied with 100 mA current intensity. The curves represent the force at different heights above the micro-coil along the x-axis. As can be seen in figure 9(a), the force exerted on a magnetic particle is, in such a case, four times greater than the mean drag force generated by the fluid flow (at 5 μm in the channel); it is also equivalent to the drag force at 25 μm and practically zero at 50 μm. This first result enables us to conclude that trapping with a circular or square micro-coil will be effective under such conditions and gives a flow limit beyond which trapping will lose efficiency. Conversely, in the case of a serpentine coil (figure 9(b)), it becomes very difficult to trap magnetic beads efficiently. For the geometries described above, we can see that the behavior of the force is similar to the BZ magnetic field, i.e. its value decreases very quickly with the z-axis. The design of the microfluidic channel, in width as well as in height, shall take this peculiarity into consideration.

4. Experimental setup and results According to simulation results, the experimental study has focused on square and circular micro-coils. Characterization has been performed in static (no flow) and dynamic modes. As the current intensity circulating in micro-coils is an important parameter, we have evaluated heating side effects by performing infrared (IR) thermal characterization. 4.1. Characterization of trapping properties The experimental setup is shown in figure 10. The instrumental bench includes a CCD camera for recording bead trapping, a syringe pump for dispensing the liquid sample and a DC power supply. In this study, characterizations have been performed R M270 with paramagnetic micro-beads from Dynabeads Carboxylic Acid with a diameter of 2.8 μm, as shown in figure 11. Prior to the experiment, the solution of beads was diluted in deionized water with 1% Tween-20, which allows the suspension to be stabilized. The observations were carried out with five and ten turns of circular and square micro-coils. The conductor section was 5 × 5 μm2 , turns were five in number and the distance between turns was 5 μm. This study has been performed with a working current ranging from 50 mA to 100 mA, a concentration of micro-beads varying in the range of 2 × 105 to 2 × 107 beads ml−1 and a flow rate fixed at 8

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(a) Before trapping (t = 0s), I=0mA.

(b) During trapping (t = 2s), I=100mA.

Figure 13. Magnetic particles trapping according to the shape of micro-coil. (a) Before magnetic actuation and (b) during trapping.

0.03 μl min−1 . The width and height of the channel were respectively 500 μm and 50 μm corresponding to a fluid velocity of 20 μm s−1 . It was observed that the trapping ratio of the magnetic beads was less than 50% when a driven current of 50 mA was applied to the micro-coil. On the other hand, for current exceeding 70 mA, it became easy to trap magnetic beads with an excellent efficiency of 100%. Figure 12 shows a trapping sequence before and after micro-coil actuation when I = 100 mA. As expected, beads accumulated within approximately 2 s at the center of micro-coils (figure 12(b)). In addition, micro-beads could be instantaneously released in the microfluidic channel by stopping the power supply (figure 12(c)). According to the results obtained in section 3, the trapping efficiency has been demonstrated for the different types of circular and square coils (20, 10 and 5 turns). Under such conditions, the magnetic force generated by the micro-coil is vastly greater than the fluid-generated drag force. Also, it should be noted that trapping micro-beads is efficient above the electromagnet. On both sides of the latter, it may be observed that beads are not stopped. This result is in agreement with our simulation results showing high localization of the magnetic field above the micro-coil. In the dilution range of beads used, no significant difference in behavior has been observed. The trapping efficiency has also been studied according to the fluid flow rate. It has been demonstrated that under the previous conditions (square and circular coils, 5, 10, 20 turns, I = 100 mA), trapping is total up to 0.225 μl min−1 (corresponding to a fluid velocity of 150 μm s−1 ) and becomes partial above that. Indeed, at this value the drag force may be

assessed as 3.4 pN and proves greater than the magnetic force according to the simulation results. Moreover, the accumulation pattern of micro-particles depends strongly on micro-coil geometry as depicted in figure 13. We can see that for square coils, the microbeads were distributed along a cross geometry, whereas for circular coils the distribution remained circular. In conclusion, we demonstrated the successful manipulation of magnetic particles with our devices. 4.2. Thermal characterization The micro-inductors thermal behavior was evaluated by using infrared thermography. Intensity profiles were measured at the surface of the micro-coil for a set of actuation currents ranging from 0 to 50 mA (figures 14(a)–(d)). In order to avoid thermal damage, the driving current was limited to 50 mA. It is unfortunately impossible to perform thermal characterization in flow conditions and the results presented herein have been obtained in air. As a consequence, the temperature elevation shown below is presumably overestimated compared to working conditions in microfluidic experiments, but gives interesting information on the respective thermal behavior of the various designs. Thermal simulations are now being performed to deduce temperature elevation in flowing media. As can be seen, the temperature rise may be considerable in particular when the number of turns is significant (figure 14(a)). For many biological or chemical analyses, the temperature should remain in the 25–40 ◦ C range and it will hence be necessary to limit the number of turns to 10 (figure 14(d)). 9

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Figure 14. Square micro-coils thermal behavior at different currents: (a) 20 turns, (b) 10 turns and (c) 5 turns. (d) The maximum temperature is plotted as a function of the number of turns for 50 mA current. Microsyst. Technol.-Micro-Nanosyst.-Inf. Storage Process. Syst. 14 1205–14 Abgrall P, Lattes C, Conedera V, Dollat X, Colin S and Gue A M 2006 A novel fabrication method of flexible and monolithic 3D microfluidic structures using lamination of SU-8 films J. Micromech. Microeng. 16 113–21 Beyzavi A and Nguyen N T 2008 Modeling and optimization of planar microcoils J. Micromech. Microeng. 18 095018 Bilenberg B, Nielsen T, Clausen B and Kristensen A 2004 PMMA to SU-8 bonding for polymer based lab-on-a-chip systems with integrated optics J. Micromech. Microeng. 14 814–8 Gijs M A M 2004 Magnetic bead handling on-chip: new opportunities for analytical applications Microfluidics Nanofluidics 1 22–40 Inglis D W, Riehn R, Sturm J C and Austin R H 2006 Microfluidic high gradient magnetic cell separation J. Appl. Phys. 99 08K101 Joshi M, Kale N, Lal R, Rao V R and Mukherji S 2007 A novel dry method for surface modification of SU-8 for immobilization of biomolecules in Bio-MEMS Biosens. Bioelectron. 22 2429–35 Kotzar G, Freas M, Abel P, Fleischman A, Roy S, Zorman C, Moran J M and Melzak J 2002 Evaluation of MEMS materials of construction for implantable medical devices Biomaterials 23 2737–50 Li C Y, Wu P M, Han J and Ahn C H 2008 A flexible polymer tube lab-chip integrated with microsensors for smart microcatheter Biomed. Microdevices 10 671–9 Lin C H, Lee G B, Chang B W and Chang G L 2002 A new fabrication process for ultra-thick microfluidic microstructures utilizing SU-8 photoresist J. Micromech. Microeng. 12 590–9 Massin C, Vincent F, Homsy A, Ehrmann K, Boero G, Besse P A, Daridon A, Verpoorte E, de Rooij N F and Popovic R S 2003 Planar microcoil-based microfluidic NMR probes J. Magn. Reson. 164 242–55 Park B N, Sohn Y S and Choi S Y 2008 Effects of a magnetic field on the copper metallization using the electroplating process Microelectron. Eng. 85 308–14 Ramadan Q, Samper V, Poenar D P and Yu C 2006a An integrated microfluidic platform for magnetic microbeads separation and confinement Biosensors Bioelectron. 21 1693–702

5. Conclusion The fabrication of a polymer microfluidic network which integrates magnetic micro-actuators for the manipulation of micro-beads has been demonstrated. The final microsystem is flexible, transparent and compatible with a wide range of use. Micro electromagnets have been designed as micro-coils with the help of a finite element solver. As can be seen, the magnetic behavior of a micro-coil is highly dependent on its geometry, number of turns and the electrical intensity injected in the actuator. The most appropriate micro-coils are square or circular and implement three metallization levels. These predictions were subsequently tested in standard lab-on-chip conditions, and real-time trapping–release of magnetic particles under continuous flows was demonstrated. The approach hence appears perfectly relevant in a labon-chip objective. However, it is important to adapt the design of the microfluidic channels so as to optimize the trapping efficiency of the micro-coils. Indeed, we have been able to demonstrate, using our simulation results and microfluidic characterizations, the relationship between the sizing of the magnetic actuator and that of the channel. This technology represents a significant advancement in microfluidic integration technologies because it provides the unique potentialities of multilevel fluidic devices embedding active functions. Therefore, it opens a way to numerous and original applications in terms of particle or cell sorting, magnetophoresis, magnetotactic bacteria control, etc.

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Rostaing H, Chetouani H, Gheorghe M and Galvin P 2007 A micromagnetic actuator for biomolecule manipulation Sensors Actuators A 135 776–81 Sikanen T, Tuomikoski S, Ketola R A, Kostiainen R, Franssila S and Kotiaho T 2007 Fully microfabricated and integrated SU-8-based capillary electrophoresis-electrospray ionization microchips for mass spectrometry Anal. Chem. 79 9135–44 Suzuki H, Ho C M and Kasagi N 2004 A chaotic mixer for magnetic bead-based micro cell sorter J. Microelectromech. Syst. 13 779–90

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