Magnetically Actuated Droplet Manipulation and Its Potential

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Magnetically Actuated Droplet Manipulation and Its Potential Biomedical Applications Guoyou Huang, Moxiao Li, Qingzhen Yang, Yuhui Li, Hao Liu, Hui Yang, and Feng Xu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b09017 • Publication Date (Web): 19 Dec 2016 Downloaded from http://pubs.acs.org on December 20, 2016

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ACS Applied Materials & Interfaces

Magnetically Actuated Droplet Manipulation and Its Potential Biomedical Applications Guoyou Huang,†,§ Moxiao Li,‡,§ Qingzhen Yang,†,§ Yuhui Li,†,§ Hao Liu,†,§ Hui Yang,∥ Feng Xu,*,†,§ †MOE

Key Laboratory of Biomedical Information Engineering, School of Life

Science and Technology, ‡State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Aerospace, and§Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University, Xi’an 710049, P.R. China ∥School

of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, P.R.

China

KEYWORDS:

droplet manipulation, magnetic nanoparticles, liquid marble,

ferrofluid, biomedicine

ABSTRACT Droplet manipulation has found broad applications in various engineering and biomedical fields, such as biochemistry, microfluidic systems, drug delivery and tissue engineering. Many methods have been developed to enhance the ability for manipulating droplet, among which magnetically actuated droplet manipulation has attracted widespread interests due to its remote, non-invasive manipulation ability and biocompatibility. This review summarizes the approaches and their principles that

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enable actuating the droplet magnetically. The potential biomedical applications of such a technique in bioassay, cell assembly and tissue engineering are given. 1. Introduction Droplet is a small liquid compartment partly or completely bounded by free interfaces. Due to the advantages of flexibility and independence, droplets have found widespread applications in multiple fields, including industry,1-2 agriculture,3-4 chemical engineering,5-6 and more recently biomedical engineering.7-10 In biomedicine area, droplet can provide separate compartments that work as miniaturized bioreactors for diagnostics and drug screening. Along with the development of microfluidic technologies, droplet-based systems (e.g., digital droplet systems) are emerging as integrated multiplex systems that can fulfill the requirement of performing experiment on a single system with a small volume. For such applications, it is crucial to manipulate droplets as demanded, which may include multiple steps such as droplet generation,11-15 moving,16-18 coalescence,19-21 and separation.22-26

To date, various approaches have been developed for manipulating droplets, including electrowetting,27-28 dielectrophoresis,29-31 acoustic wave32-33 and optical force.34-35 Electrowetting is based on modifying the surface tension of droplet by applying an electric field and moving the droplets through the surface tension effect. Although this method provides advantages of mechanical simplicity and low energy consumption, it needs an extra digital microfluidic device with integrated electrode array. Dielectrophoresis exploits a contrast in electrical permittivity and/or conductivity 2 ACS Paragon Plus Environment

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between the objects and bulk liquid by imposing an external voltage (usually an alternating voltage), but it also requires a complex electrical system. Moving the droplets by acoustic waves allows individual drop to be directed along microchannel paths in a non-invasive mean and can be effective for lab-on-a-chip devices, but it demands specifically designed microchannels with satisfactory acoustic reflection properties. The method based on optical force is associated with comparatively low throughput and the laser used in the system may cause the issue of biocompatibility. With recent advances in biotechnology, droplet manipulation based on magnetic force, i.e., magnetically actuated droplet manipulation, has attracted increasing attention.36-40 Its principle is based on the magnetic response property of the droplets, which can be achieved by introducing magnetic response element (e.g., magnetic nanoparticles (MNPs), paramagnetic molecules) into or on the surface of the droplets. This strategy offers several advantages, including but not restricted to remote controllability, switchable manner, non-invasive feature, as well as biocompatibility, holding promises for biomedical applications.

We herein summarize the latest state-of-the-art research advances of magnetically actuated droplet manipulation. We first introduce the approaches and the corresponding principles that make the droplets magnetic responsive. The potential applications of magnetically actuated droplet manipulation in biomedicine area, including bioassay, cell assembly and tissue engineering, are then discussed. Finally, current challenges and future perspectives on the development of magnetically actuated droplet manipulation are given. 3 ACS Paragon Plus Environment


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2. Magnetic-responsive droplets Most of the droplets are non-inherently magnetic responsive and thus magnetic elements need to be introduced. Based on the form and spatial distribution of magnetic elements in droplets, the methods that make droplets magnetic responsive can be mainly classified into three types, i.e., MNP-laden droplet, magnetic liquid marble and ferrofluid droplet.

2.1 MNP-laden droplet The simplest way to make droplet magnetic responsive is to directly introduce MNPs (tens to hundreds of nanometer diameter) into the droplet (i.e., MNP-laden droplet),41 Figure 1. When no magnetic ﬁeld is applied, the MNPs in the droplet will simply sediment to the bottom of the droplet. While in the presence of magnetic field, the MNPs will aggregate into clusters and climb along one side of the droplet surface due to the magnetic force. Usually a magnet is placed in a proper position and would generate a magnetic force upon the MNPs in the horizontal direction. Once MNP clusters reach a speciﬁc orientation and position, the clusters pull the droplet surface and strongly distort the droplet shape.42 The droplet will move as driven by the MNP clusters when the magnet is moving. From the view of force balance,42 there are three forces on the droplet, i.e., the magnetic force ( ), the capillary force ( ), and the retention force between the droplet and the substrate ( ), Figure 1. The total magnetic force experienced by MNPs in the droplet can be obtained by:43 4 ACS Paragon Plus Environment

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=

∆ (∇)

(1)

where [kg] is the total mass of MNPs, [kg·m-3] is the density of MNPs, [H·m-1] is the magnetic permeability, ∆ [1] is the difference in magnetic susceptibility between the MNPs and the liquid, [T] and ∇ [T·m-1] are magnetic flux density and magnetic field gradient, respectively. When subjected to a magnetic force, the MNPs will press against the boundary of the droplet, further inducing droplet deformation. Such a deformation can cause capillary force, which can be written as:42 = /( − )

(2)

where [N·m-1] is the surface tension of the liquid-air interface, D [m] is the diameter of the cluster, [1] is the angle between the magnetic force and the vertical direction, and [1] is the angle between capillary force and the vertical direction. Driven by the magnetic force, the droplet starts to move on the solid substrate and suffers a retention force. The retention force is caused by deformation of the droplet and can be expressed as: = 2 −

× ( − " ) 2

(3)

where [1] is the advancing contact angle, " [1] is the receding contact angle, #

and − $

[m] is the radius of the contact area. Usually, droplets are

transported at a low speed. The total force balance in the horizontal and vertical direction can be shown as in Eqs. 4-5, respectively: 5 ACS Paragon Plus Environment


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%& − %& − = 0

(4)

− = 0

(5)

The above governing equation is applicable for droplet moves in air (or other gases) with a small velocity. However, if the droplet moves in fluid medium, the dynamic friction between the droplet and the fluid should be added to the retention force. This friction is proportional to the radius of the contact area and the velocity of the droplet,44 ( = )( * +

(6)

where )( [1] is the friction constant, * [m] is the radius of the droplet, [Pa·s] is the viscosity of the liquid, and + [m·s-1] is the velocity of the droplet. Usually, MNP-laden droplet can be transported by moving the magnet at a low speed. The capillary force tends to hold the particles back when they try to flee away. However, there is a maximum value for the capillary force, which can be written as:42 , =

(7)

If the magnetic force is smaller than this value, the MNPs will keep in the droplet. However, if the magnetic force is too large, the MNPs may break the droplet into two and can be even extracted from the droplet.45 Thus, the moving speed of magnet may act as a flexible switch.45 In addition, MNP-laden droplet with size down to microscale level may evaporate dramatically during manipulation. This can be


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addressed by coating the droplet with a protect layer (e.g., oil layer around water droplet).

2.2 Magnetic liquid marble Liquid marble is a small amount of liquid covered by particles, usually prepared by rolling liquid droplet on a layer of particle powders (Figure 2a).46 Different particles, including both hydrophobic and hydrophilic particles, can be used to coat droplet to form liquid marbles. The particles change the contact mode of the droplet-substrate from liquid-soild contact to solid-solid contact. The self-organization of particles on the liquid-air interface of droplets makes a perfect non-wetting system whose contact angle can achieve nearly 180°° by using hydrophobic particles.47 Ever since the first report in literature,48 different particles have been utilized to coat droplet to form liquid

marble,

including

latex,49

polyethylene,50

ionic

liquid,51

methylsilsesquioxane,52 silica,48 graphite,53 and carbon black.54 Among them, latex powders have been designed to switch from hydrophobic to hydrophilic when pH value changes from high (i.e., alkaline) to low.55 By using two different kinds of liquid or powders, the concept of liquid marble has been extended into two-phase emulsion and Janus particles. It has been shown that by varying the hydrophobicity of the coating particles from hydrophilic to hydrophobic, the particle-stabilized emulsions can switch from oil-in-water to water-in-oil phase.56 Moreover, Janus particles made from liquid marbles, with one half of the surface hydrophilic and the other hydrophobic, have also been created.57-58 Recently, MNPs have also been used as coating materials to fabricate magnetic liquid marbles, which can be easily actuated 7 ACS Paragon Plus Environment


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by external magnetic field (Figure 2).37,

59-62

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The magnetic liquid marbles were

fabricated by encapsulating water droplets with novel silica-coated Fe/ O1 particles. Such remotely controllable liquid marbles hold great potential for applications in smart delivery of water-soluble agents to initiate chemical reactions on demand, sensors with visual indication capability and channel-free microfluidic systems.

Theoretically, the equilibrium state of liquid marbles can be described by the principle of minimum energy.63-64 Assuming that the particles are smooth and spherical with a radius [m], the total energy of the equilibrium system is: 2 = 34556" + (89 − 8: )3;?@

(8)

where [N·m-1] is the surface tension coefficient of upper free interface, 89 [N·m-1] is the surface tension coefficient of the solid-liquid interface, 8: [N·m-1] is the surface tension coefficient of the solid-air interface, 34556" [m2] is the area of upper surface, 3; [m·s-2] is the gravitational acceleration, ? [m3] is the volume of the spherical droplet, and @ [m] is the center mass height. For a small droplet, the gravity can be ignored and the droplet would take a spherical cap whose radius can be determined as, E

/ 3? =A D $ (1 − ) (2 + )

(9)

where V [m3] is the droplet volume, and [1] is the contact angle. However, if the droplet is large, the gravity will significantly affect the droplet morphology. As for 8 ACS Paragon Plus Environment

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that, some approximations (e.g., assuming the droplet is an elliptic cap) are needed to analytically resolve the droplet interface or numerical methods should be employed.

Based on equation (8), an improved model can be derived by taking particles into consideration.63 Assuming that the particles attaching on the liquid surface are in spherical shape, the solid-air interfacial area is 2π5$ (1 + 6 ), where 5 [m] is the radius of the particle and 6 [1] is the equilibrium contact angle. With the attachment of the particles, the liquid drop will lose liquid-air interfacial area of π5$ %&$ 6 , resulting in the net change in surface energy: G2 = 2π5$ (1 + 6 )(89 − 8: ) − π5$%&$ 6 9:

(10)

By using the Young’s law: 8: − 89 = 9: 6 , the net change in surface energy can be rewritten as: Δ2 = −9: π5$ (1 + 6 )$ . Since Δ2 is always negative, the particles will spontaneously attach to the liquid-air interface even if they are hydrophobic.

The original study on liquid marble used water as its core liquid, and later other liquids were also used, with the surface tension as low as 20.1 mN/m (the surface tension of water at room temperature is 72.2 mN/m).65 Commonly, liquid marbles can maintain a quasi-spherical shape (small size) as well as a puddle shape (large size) due to the competition between the surface tension and gravity.60,

64, 66

As for

movement, liquid marble has much more complicated dynamic properties than a common rigid rotating ball.67-68 It is reported that the dynamics of liquid marble is governed by three dimensionless number,48, 69 i.e., Reynolds number (I = +/ ) 9 ACS Paragon Plus Environment


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representing inertial force versus viscous force, the capillary number (JK = +/) representing viscous force versus surface tension, and the Weber number (LI = + $ / ) representing the fluid’s inertia compared to its surface tension. [kg·m-3] is the density, [Pa·s] is the dynamic viscosity of the liquid, + [m·s-1] is the characteristic velocity, [N·m-1] is the surface tension of the liquid. Considering magnetic actuation of liquid marbles, we can use simple force analysis to explain it. According to the Amonton’s friction law, the largest friction force can be obtained by: (M = >%&

(11)

where m [kg] is the mass of liquid marble, g [m·s-2] is the gravitational acceleration, and [1] is the sliding angle. Once magnetic field is applied, MNPs on the liquid marble will have the same magnetic moment pointing to the direction of maximum magnetic field gradient. According to the force analysis, we can get the motion of the liquid marble. The movement velocity of the magnetic liquid marble can reach as high as 25±3 cm/s for a droplet (20 µL marble under magnetic fields of 0.5 T).62

As compared to pure droplet without particle coating, the particles on the surface of liquid marbles can reduce liquid evaporation, e.g., by reducing diffusion-controlled evaporation rate of the encapsulated liquid.70 However, as compared to droplet with shell coating, liquid marbles can be only partially covered by particles and there are still some gaps between the particles, which leaves a nonnegligible evaporation problem. Many approaches have been tried to reduce evaporation of the droplet, 10 ACS Paragon Plus Environment

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including doping the water with glycerol or immersing the marbles in organic liquids.53, 71-72 However, such approaches involve potential issue of biocompatibility, limiting the applications in biomedical engineering.

2.3 Ferrofluid droplet Ferrofluids are colloidal solutions made of MNPs (with diameters of ~10 nanometers or less) suspended in a carrier fluid (e.g., organic solvent or water). Compared to MNP-laden droplet, the MNPs in ferrofluid are small enough to be suspended by Brownian motion and thermally dispersed evenly in the carrier fluid. Moreover, the MNPs are usually coated with surfactant, which can produce sufficient electrostatic repulsive force to prevent magnetic agglomeration.73 Therefore, ferrofluid can response to magnetic field as a whole without phase separation. Generally, MNPs can be produced by grinding magnetite with agent like oleic acid or long chain hydrocarbon, which are then coated with Fe3+ or Fe2+ by mixing with Fe2+ and Fe3+ salts and dispersed in carrier liquid by either an electric double layer or a polymer coating to prevent agglomeration.

Ferrofulid is a unique material that can act like both a magnetic solid and a liquid. When there is no magnetic stimulation, MNPs in ferrofluids act like normal metal particles in suspension. When a magnetic field is applied, MNPs are temporarily magnetized and spatially aligned with the magnetic field, generating a net magnetization in the ferrofluid. This enables the fluid’s motion to be controlled by the application of external magnetic field. 11 ACS Paragon Plus Environment


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Considering isothermal incompressible ferrofluids and assuming MNPs to be rigid, spherical, monodisperse and have a spatially uniform distribution, the manipulation of ferrofluid droplet can be divided into two parts, i.e., the flow of ferrofluids and the deformation. According to Rosensweig’s theory,74 the flow of ferrofluid is mainly governed by the combination of constitutive, static Maxwell, and Navier-Stokes (N-S) equations:

O∙+ =0

(12)

O ∙ = 0, O × @ = 0

(13)

+ = −OR + > + S ∙ O@ + 2T(O × U) + (V + W − T)O(O ∙ +) + (W + T)O $ + Q

(14)

where [T] is the magnetic flux density, S [A·m-1] is the magnetization of the suspension, @ [A·m-1] represents the magnetic field, + [m·s-1] is the velocity, [kg·m-3] is the density, R [Pa] is the pressure, > [m·s-2] is the gravitational acceleration, [H·m-1] is the permeability of free space, V [Pa·s] is the bulk viscosity, W [Pa·s] is the shear viscosity, and T [Pa·s] is the vortex viscosity. Equation 12 represents the continuity equation of incompressible flow. Equation 13, i.e., the Maxwell’s equation, shows what the magnetic field should obey under a low frequency magnetic field. The motion of the ferrofluid is described by the continuity equation and momentum (N-S) equations (Equation 14) but without considering hydrodynamic or magnetic interaction.


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Recently, it was found that the spin viscosity is important in describing ferrofluid flow.75-77 To study such a complex situation, more variables should be considered. For instance, when the magnetic density changes with the external magnetic field, an extra magnetization relaxation is required to get the rotation of particles.

In the absence of fluid motion, the shape of the ferrofluid droplets is governed by the balance between surface tension and magnetic force of the ferrofluid droplets, as depicted by the magnetic Bond number, = @$ /X , representing the ratio of magnetic force to interfacial tension force, where X [m-1] is the curvature of undeformed droplets. For a ferrofluid droplet on a super hydrophobic surface, the droplet will gradually deform into a spiked cone with increasing magnetic field strength and finally cleavage into two smaller droplets at the critical field strength (Figure 3).78 The deformation of a ferrofluid droplet under magnetic field has been studied theoretically.79 The results indicate that the ellipsoid shape of the droplets is due to a competition between magnetic energy, which favors elongated droplets in the field direction, and surface energy, which favors a spherical shape. However, the equilibrium shape of ferrofluid droplets under a magnetic field is not easy to describe analytically and approximations have to be made to solve the problem.80-83 For large deformation, as a kind of nonlinearity, different approximate theories are deviated from each other. The equilibrium shape of the droplet and finally the dynamics of the interior flow are likely to be turbulent while the levitated mass is of the order of a few grams. Extensive researches have been used to obtain the deformation of both freely sessile droplets and suspended droplets within a uniform magnetic field.84-86 For 13 ACS Paragon Plus Environment


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example, field finite element method (FEM) was used to implement the nonlinearly magnetized ferrofluid droplets84, 87.

Similar to electrowetting-on-dielectric (EWOD), MNPs in droplet can have similar implications. The shape and contact angle of a magnetic droplet can be strongly dependent on the applied magnetic field strength (termed magnetowetting), which can be observed both in ferrofluid droplets and magnetic liquid marbles.79,

88

This

phenomenon has been confirmed by density functional theory.89 In uniform and nonuniform magnetic fields, the magnetic droplet behaves differently with increasing magnetic field strength.80,

89

Moreover, the water-based and oil-based magnetic

droplets may have contrary wetting behavior under the same magnetic field.90 To well-control droplet magnetowetting behavior in a high-throughput manner, microcoil arrays or magnetically controllable nanostructured surfaces can be used.91 Based on magnetowetting, particles with different shapes can be easily generated without using specific templates.92 Moreover, as a new subfield of micro-magnetofluidics, magnetowetting may provide an alternative strategy to manipulate droplet for digital microfluidics and lab-on-a-chip applications.93

3. Potential biomedical applications of magnetic droplet manipulation Droplet manipulation is becoming a common requirement in biomedical areas and various approaches based on optical, electric, magnetic or acoustic forces have been developed to expand the capabilities and generality of droplet manipulation. Among all of them, magnetically actuated droplet manipulation holds several advantages such 14 ACS Paragon Plus Environment

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as remote and switchable controllability, non-invasive ability and biocompatibility. It has thus attracted increasing interests in biomedical applications, especially in bioassay, cell assembly and tissue engineering.

3.1 Bioassay With magnetic force, droplet operations including transport, dispensing, fusion and even opening have been achieved. This makes it especially useful for bioassay in which multi-step processes including sample extraction, purification, dilution, mixing and detection in small volume (e.g., in small droplet) are often involved.

Bio-microelectromechanical system (Bio-MEMS), with miniaturized reactors and analytical systems, is particularly useful in bioassay. However, bio-MEMS has been mainly realized by continuous flow microfluidic systems, which involves complicated components such as microvalves, micropumps and interface connections, limiting their operability and applicability.94-98 Recently, the development of droplet manipulation has led to the emerging of digital microfluidics, i.e., the micromanipulation of discrete droplets in MEMS.99 Magnetic force can be easily controlled by patterning magnetic arrays or magnetic matrix onto MEMS to provide a flexible and easy way to manipulate the target droplet without the need of any peripheral accessories.100-101 Moreover, magnetic force can be combined with other forces (e.g., dielectrophoresis force102) on a single chip to expand the capabilities and generality of droplet manipulation and thus holds great potentials in bio-MEMS applications.103-105 15 ACS Paragon Plus Environment


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A typical example of magnetically actuated droplet manipulation in bioassay is for polymerase chain reaction (PCR).106-107 To detect nucleic acids or identify pathogen based on gene analysis, several steps, including extraction, purification, amplification and analysis, are usually included (Figure 4a). Lehmann et al.108 reported a MNP-laden droplet manipulation system to achieve DNA purification, where MNPs worked not only as force mediators but also mobile substrates (Figure 4b). Simple coils were used instead of external moving magnets to actuate droplets with high operational flexibility.109 Different types of genomic material were successfully extracted and purified with good reproducibility. A possible drawback of this method is that several washing processes are needed to remove undesired cell debris. In another example, Shikida et al.110 designed a rotary-drive bio-MEMS with multi-layered flat coils to agitate magnetic beads in droplet during extraction and purification processes (Figure 4c). This improved the yield and purity since agitation enables more biomolecules to bind on magnetic beads in extraction and the biomolecule-bound magnetic bead to get washed more thoroughly in purification. A so called “immiscible filtration assisted by surface tension” method was further developed to replace the washing process.111 The whole processing time was greatly reduced without comprising purity, yield and scalability.

As one of the pioneer work on magnetically actuated droplet manipulation for full-process control and real-time PCR, Pipper and co-authors developed a platform for detecting highly pathogenic avian influenza virus H5N1 directly from a throat swab sample.112 The viral RNA was sequentially isolated, purified and 16 ACS Paragon Plus Environment

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preconcentrated by manipulating droplet with silica coated MNPs. The sample was then subjected to ultrafast real-time PCR, showing equal sensitive, 440% faster and 2000-5000% cheaper compare to commercially available test. Instead of using silica coated superparamagnetic particles, in a later work anti-CD15-coated particles were used to catch THP-1 cells from whole blood.113 Four temperature zones were prepared on the biochip, in which temperature zone 1 with 95°C was used to get the purified THP-1 cells thermally lysed; the droplet containing DNA and PCR mixture was then moved clockwise to pass zone 1-4 in order to accomplish PCR process (Figure 4d).

Surface energy traps have been incorporated with magnetic force to dispense droplet when it was moved on open surface. Serial dilutions for antibiotic susceptibility tests were prepared. Moreover, versatile droplet operations including droplet transport, fusion, dispensing and particle extraction were achieved.114 With this method, DNA was extracted from human whole blood, dispensed onto surface energy traps, mixed with gene-specific PCR reagents, and subjected to thermal cycling for PCR, which was monitored with a customized fluorescence detection system. The identification of different genes (TP53, HER2, and RSF1) was achieved, demonstrating its ability for multiplexed biomarker detection.

To prevent evaporation, MNP-laden droplets need to be immersed in oil, which involves potential issue of unwanted liquid-liquid extraction,115 the inability of using oil-miscible liquid and the inconvenience of integrating some on-chip analysis techniques.116-117 In contrast, magnetic liquid marbles are able to partially, although 17 ACS Paragon Plus Environment


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not completely, prevent the evaporation of water with the use of hydrophobic shell.118-122 Zhao et al.59 generated magnetic liquid marbles that can be opened and closed reversibly by controlling magnetic field (Figure 5a). By combining fluorinated decyl polyhedral oligomeric silsesquioxane and MNPs, stable magnetic liquid marbles were fabricated with solvents whose surface tension can be as low as 20.1 mN/m.123 The fabricated liquid marbles, which may contain different solvents in single marble, can move on water or hexadecane surfaces (Figure 5b). With a reflection-mode probe, the optical property of the inside liquid can be detected when the liquid marble is open.61 Recently, they presented a novel “on-line” detection system by taking advantage of the open-close property of the magnetic liquid marbles (Figure 5c).124 Optical absorbance of the liquid in marble was obtained and dopamine was quantitatively detected with a miniaturized three-electrode probe. It was also demonstrated that low melting point material (e.g., wax) could be incorporated into magnetic particle shell to facilitate the storage of non-volatile ingredients.

Magnetically actuated droplet manipulation has also been applied for immunoassay. For example, Malaquin’s group103 developed a programmable “magnetic tweezer” for multiple trapping-release of MNPs in droplet with reduced volume. The operations in droplet including purification, extraction, enzymatic reaction and detection were achieved. Immunoassays were performed for detecting neonatal congenital hypothyroidism and analyzing umbilical-cord plasma sample.


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The measurements of cell bioassay usually rely on ensemble average of heterogeneous cell populations. This may lead to hasty conclusions and overlook individual contributions considering cell-to-cell variations. In this case, cell sorting is needed to separate target cells from heterogeneous populations. Many techniques including

conventional

flow

cytometry,

hydrodynamic

techniques,

and

electric-field-based techniques have been developed for sorting cells. However, these techniques need specific equipment to implement. Chen et al.125 developed a method that integrates a mobile magnetic trap array with microfluidic chip for magnetic separation and compartmentalization of cells in droplets. 75% separation efficiency was achieved for breast cancer cell lines. Preliminary assay on cell viability was performed and the potential of this method for single-cell analysis was demonstrated.

3.2 Cell assembly and tissue engineering Cells contain a large amount of water (usually >70%) and have partially free interfaces that allow them to transform and move. We thus regard cells as special droplets in this review. In vivo, cells usually work as building blocks and self assemble into organized and heterogeneous tissue constructs for performing special functions. Due to their important role in tissue engineering and regenerative medicine, various methods have been developed to assemble cells in vitro.126-129 Among them, magnetically actuated cell assembly has attracted increasing interest. To magnetically assemble cells, cells must be magnetic responsive, which is usually achieved by labeling the cells with MNPs on membranes, making the cells uptake MNPs or label-free negative magnetophoresis.130 Benefiting from the use of biocompatible 19 ACS Paragon Plus Environment


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MNPs, which can be easily obtained by coating the MNPs with biocompatible molecules such as lipid and chitosan, magnetically actuated cell assembly has the advantage of excellent biocompatibility. Moreover, magnetically labeled cells can be driven by low-intensity magnetic field (usually lower than 0.2 T) in a remote and non-contact manner, with reduced or neglectable harmful effect on cells.131-133

Ho and co-authors explored non-covalent binding between biotin and streptavidin to label cells with MNPs on cell membrane.134-137 Two-dimensional cell patterns and three-dimensional (3D) multicellular spheroids were fabricated by manipulating different labeled cells, including HeLa, TE671 and human monocytes.134,

136

The

created cellular spheroids can be further fused together to form larger tissue constructs directed by magnetic force (Figure 6a).135,

138

When combined with

hanging drop cell culture, magnetically actuated cell manipulation can promote the formation of cellular spheroids in hanging drops in a few seconds and overcome the difficult in changing medium.137 Souza et al.139 explored magnetic levitation for cell assembly and culture at the air-medium interface in the presence of magnetic iron oxide-containing hydrogels (Figure 6b). Human glioblastoma cells showed morphological and molecular similarity to those observed in human tumour xenografts. In addition, controlled cellular spheroid shape, and co-culture of human glioblastoma cells and normal astrocytes were achieved. Such magnetic cell levitation methods were also applied for engineering adipose140 and aortic valve141 tissue models. Moreover, cellular rings 20 ACS Paragon Plus Environment

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were fabricated by using magnetic cell levitation and time closure of the rings was monitored for analysis purpose.142 In a recent work from Park’s group, a magnetic pin-array system was developed to concentrate magnetic field for controlling the assembly process of cells during magnetic levitation.142 Cellular spheroids with controlled sizes and high reproducibility were fabricated. Versatile and accelerated formation of random mixed, core-shell and fused cellular spheroids was also demonstrated.

One of the facile methods to endow cells magnetic responsive is to make cells uptake biocompatible magnetite cationic liposomes.143-146 Ito and co-authors used this method to label different types of cells and magnetically manipulated cells to form engineered or functional cellular structures such as cell sheets and skeletal muscle tissues.135,

143, 146

Improved cell invasion efficiency was obtained by introducing

chitosan coated MNPs into cells and applying magnetic stimulation. Apart from the above approaches, Eben et al.147 developed a label-free negative magnetophoresis method to magnetically manipulate cells without directly applying MNPs to cells. Ordered cellular structures were obtained, showing promises in tissue engineering and regenerative medicine. Cells can also be embedded into magnetic responsive microgels, which can be then assembled into multiply structures for fabricating complex and controlled tissue constructs (Figure 6c).148-152



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4. Conclusions and future perspectives Benefiting from the advances in nanotechnology and bio-MEMS, magnetically actuated droplet manipulation has made great progress and attracted increasing interests. The advantages and disadvantages of different magnetic-responsive droplets are shown in Table 1. However, there are still several challenges to be addressed before its broad applications. A major challenge for such open-surface droplet platforms is reagent storage and transport. Although inorganic substances in droplet may be kept at room temperature without degradation, fragile organic components such as enzymes may lose efficacy when stored outside a freezer. Enzymatic processes are indispensable as they are involved in both the sample preparation stage as well as signal amplification and detection stages. In addition, the full range actuation capability of magnetically actuated droplet manipulation was only demonstrated until recently, its automatization and integration with other constituent systems should be further investigated. Despite the above challenges, the advantages of magnetically actuated droplet manipulation over other counterparts, including the ability

of

precise

droplet

manipulation,

switchable

remote

controllability,

non-invasive ability and biocompatibility, make it a promising candidate for enormous potential applications in biomedical area.

AUTHOR INFORMATION Corresponding Author 22 ACS Paragon Plus Environment

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*E-mail: [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was financially supported by the National Natural Science Foundation of China (11602191, 11372243, 11522219), the China Postdoctoral Science Foundation (2013M540742, 2015M570826), the Doctoral Program of Higher Education of China (20130201120071) and the Fundamental Research Funds for the Central Universities (8143051, xjj2016074), the Young Talent Fund of University Association for Science and Technology in Shaanxi, China (20150101). Q. Y. also acknowledges the partial support from National Engineering Laboratory for Highway Maintenance Equipment (Chang’an University) (310825161103) and the Foundation of Shaanxi Postdoctoral Science.

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Figure 1. Magnetically actuated droplet manipulation using MNP-laden droplets. (a) Small droplet containing fractions of MNPs can be manipulated by magnet smoothly on a super hydrophobic surface. (b) Real image of MNP-laden droplets and the MNPs aggregate into clusters under the magnet array. Reprinted with permission from ref

41

. Copyright 2007 Springer Science+Business Media, LLC. (c) Force

analysis of the MNP-laden droplet.



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(a)

Magnetic liquid (b) marble

Page 44 of 52

(c)

Substrate

(d)

(e) HCl

Figure 2. Magnetically actuated droplet manipulation using magnetic liquid marble. (a) Schematic diagram illustrating a liquid marble coated with MNPs. (b, c) Digital images showing the magnetic liquid marbles located on a glass slide (b) and water surface (c). (d) The movement of magnetic liquid marble under a permanent magnet. (e) Snapshots showing the rupture of the magnetic liquid marble placed on the water surface after addition of concentrated HCl. Reprinted with permission from ref 46. Copyright 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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(a)

(b)

(c)

(d)

Figure 3. Magnetically actuated droplet manipulation using ferrofluid droplet. (a) Schematics shows how ferrofluid droplets at different distances (locations indicated by the number of 1, 2, 3, 4, respectively) from a cylindrical permanent magnet deform under magnetic field (white lines). (b) Photographs of deformed ferrofluid droplets corresponding to those located at the positions in (a). (c) Frames show how a ferrofluid droplet divided into two daughter droplets and (d) the plot of the distance between the two daughter droplets as a function of time. Reprinted with permission from ref 78. Copyright 2013 American Association for the Advancement of Science.



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(a)

(b)

(c)

(d)

Figure 4. Applications of magnetically actuated droplet manipulation in PCR. (a) Schematic illustration of microfluidic chips primed with buffer droplets for cell lysis, DNA extraction, purification and amplification. Reprinted with permission from ref 106

. Copyright 2010 Royal Society of Chemistry. (b) Schematic representation of DNA

purification from a lysed cell sample solution. Reprinted with permission from ref 108. Copyright 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (c) Agitation performance by two flat coil arrangements. Reprinted with permission from ref

110

.

Copyright © 2008, IOP PUBLISHING, LTD. (d) Sample preparation and RT-PCR. Reprinted with permission from ref 113. Copyright 2008 WILEY-VCH Verlag GmbH 46 ACS Paragon Plus Environment

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& Co. KGaA, Weinheim.



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(a)

(b)

(c)

Figure 5. Applications of magnetically actuated droplet manipulation in Bio-MEMS. (a) The opening and closing of a liquid marble containing a blue-colored water droplet under magnetic force. Reprinted with permission from ref

59

. Copyright 2010 WILEY-VCH Verlag

GmbH & Co. KGaA, Weinheim. (b) The generation and application of liquid marbles made from different liquids and powder. Reprinted with permission from ref

123

. Copyright 2010

WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (c) Schematic illustration of “on-line” detection and sample or reagent encapsulation based on magnetic liquid marbles. Reprinted with permission from ref 124. Copyright 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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(a) Micromagnet

i

Cell pattern

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D0

D8

D11

D15

D28

ii Magnetic tip Cell aggregate

Magnetic line

(b)

(c)

2 mm

2 mm

Figure 6. Applications of magnetically actuated droplet manipulation in cell assembly and tissue engineering. (a) Magnetic assembly of mesenchymal stem cells, cellular spheroid formation and cartilage sheet production. Reprinted with permission from ref 138. Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (b) Human glioblastoma cellular spheroid levitated at the interface and the magnetic iron oxide-containing hydrogels. Reprinted with permission from ref

139

. Copyright 2010 Rights Managed by Nature Publishing Group. (c)

Magnetic assembly of cell-laden microgels. Reprinted with permission from ref

153

. Copyright

2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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Table 1: The advantages and disadvantages of different magnetic-responsive droplets Droplets MNP-laden droplet 41,42,100-105

Magnetic liquid marble 46, 59-62 Ferrofluid droplet 73,75-79,88

Advantages • • • • • • • •

Easy to fabricate MNPs can be extracted from the droplets Versatile liquid can be used Reduced liquid evaporation Low friction Accurately controllable Stable Enable the manipulation from tiny droplet to liquid flow

Disadvantages

•

Not effective for manipulating large droplet Liquid evaporation

•

Limited biocompatibility

•

MNPs can not be extracted from the droplets

•


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Table of Contents (TOC)


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Magnetically Actuated Droplet Manipulation and Its Potential

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