Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244

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Robotics and Computer-Integrated Manufacturing

0736-58

doi:10.1

n Corr

E-m

journal homepage: www.elsevier.com/locate/rcim

New design for the separation of microorganisms using microfluidicdeterministic lateral displacement

Mohamed Al-Fandi a,n, Mohammad Al-Rousan b, Mohammad A.K. Jaradat a, Lina Al-Ebbini b

a Department of Mechanical Engineering, Nano Technology Systems Lab., Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordanb Department of Computer Engineering, Nano Technology Systems Lab., Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan

a r t i c l e i n f o

Keywords:

Microfluidics

Deterministic lateral displacement

Airfoil posts

Trypanosome

45/$ - see front matter & 2010 Elsevier Ltd. A

016/j.rcim.2010.06.003

esponding author. Tel.: +962777791260.

ail address: mohamed_alfandi@just.edu.jo (M

a b s t r a c t

This paper presents a new design of microfluidic device for the separation of soft microorganisms using

the deterministic lateral displacement principle. The novelty of the proposed design is based on

creating new post shape that should address the challenges posed using the conventional circular post

arrays. Based on experimental observations of trypanosome particles, circular posts have negative

effects on the separation process of deformable and non-spherical cells. These effects reside in either

shifting soft cells toward random streamlines further down the array or clogging the device. Airfoil and

diamond post shapes have been proposed and compared against the circular posts. The flow around

these posts has been simulated and analyzed numerically based on computational fluid dynamic (CFD).

The results show that airfoil post shape has the potential to overcome complications when working

with soft biological samples, namely the cells that are not rigid and not spherical. Microfluidic systems

based on airfoil obstacles could easily be manufactured for clinical laboratory and biomedical

applications providing a good promise in nano/micro-separation field.

& 2010 Elsevier Ltd. All rights reserved.

1. Introduction

The separation of cells is an important technology in medicine.Every day millions of separations are conducted in hospitals allover the world using the conventional cell separation methods.Today, the development of disposable microfabricated post arrayor lab-on-a-chip technology represents a promise in clinicaldiagnosis and plays a very important role in academic research. Infact, the use of microfluidic cell separation devices has a numberof well-known advantages [1–4] compared to the traditionalseparation methods: (i) smaller sample volume consumption,(ii) ease of portability, (iii) relatively low fabrication costs,(iv) improved sterility, (v) faster analysis and (vi) easier for inte-gration with downstream analytical components.

Microfabricated post arrays have recently been used tocontinuously separate a stream of different particles size rangingfrom micro- to nano-scale in fluid using a principle known asdeterministic lateral displacement (DLD) [5,6]. The basic principleof the nano/micro-separation method is to make use of thelaminar flow of fluid lanes through a regular array of obstacleswhere each row is displaced a small distance compared tothe preceding row. For instance, in Fig. 1, each row is shifted by

ll rights reserved.

. Al-Fandi).

one-third of the distance between two adjacent posts (l) forminga slope e relative to the fluid flow direction of about 0.333 rad. Inthis case, the fluid flow through each gap can be split into threeequivalent lanes, which alternatively permute from column tocolumn. The lanes are divided by stagnation streamlines whichbegin and terminate at the posts. Particles greater than the widthof the closest lane to each post, b, are displaced laterally by Dlinto a neighboring lane at each subsequent row and follow adeterministic path through the array in the so-called ‘‘bumping’’mode, while smaller particles (i.e. particle’s radius less than b)travel along streamline paths in a zigzag transport mode. Thus,hard sphere particles ideally travel along one of the two types ofpath within a microfabricated array of posts depending on theirsize, as shown in Fig. 1. However, this is not true for soft particles;there are some complications when working with soft biologicalcells within a microfluidic DLD device. First, they are not rigid andare able to deform due to the forces the cells experience in thearray. Thus their apparent size seems to change with differentstream velocities within the array, where large force might makethem to stick to the surface. Second, some cells are not spherical,thus the orientation of a cell will affect its path through the deviceto either shift toward different streamlines further down the arrayor clog the device as explained in many previous studies [2,7] andin our experimental observations. In particular, these difficultiescould be related to the design itself of the conventional circularposts, where most of the existing models of microfabricated

Fig. 1. Schematic illustrating the two modes of travel for small and large particles

through a microfluidic deterministic lateral displacement device.

Fig. 2. The observed dynamic behavior of trypanosome motion through circular

post array. (a) Trajectory of trypanosome particle displaced after N¼8.

(b) Trajectory of trypanosome particle displaced after N¼15. Pictures were

generated by overlaying of multiple video frames.

M. Al-Fandi et al. / Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244238

arrays confined to this common circular post shape in theirchannel. More recently, Kevin Loutherback et al. [8] employedtriangular posts in an array where the trajectory of particles in acertain size range is not reversible when the pressure gradient isreversed at a low Reynolds number.

In fact, the fluid flow exerts forces that are mainly normal tothe surface of circular posts, resulting in high degree of celldeformation, as it runs into a post. As the flow velocity isincreased, stronger hydrodynamic forces on the soft particlealigns the cell’s long axis with fluid flow. Also, large fluid forcesnear a post could make a soft cell to stick to the surface or changeits orientation. The change in orientation would allow the particleto fit into the width of the first streamline, and no longerdisplaced within the device. However, these facts have beenverified experimentally and investigated numerically as explainedin the next sections.

In this paper, we hypothesized that new post design should beconsidered to limit such problems and to achieve particleseparation with a reasonable degree of accuracy and reliability.However, most of the researches focused on the separation ofblood cells based on their size [9–11]. In [9], it was pointed outthat the behavior of deformable, non-spherical particles in a DLDarray resulted in complex motion, because of this effect the termhydrodynamic size is used to refer to particle size as measured bya DLD device. While in [10] and [11], the authors did not addressthe fact of morphological change of blood cells. In this paper, weconsidered the separation of trypanosomes that were conveyed tohumans by the bites of infected tsetse flies [12]. Many patientswho suffer from this disease live in underdeveloped countrieswhere there are no means for the doctors to make the rightdiagnosis [13]. Furthermore, the developing world does not haveaccess to many of the best medical diagnostic technologies thatwere designed for air-conditioned laboratories, refrigeratedstorage of chemicals, a constant supply of calibrators andreagents, stable electrical power, highly trained personnel andrapid transportation of samples [14]. Thus, in order to improvediagnosis and survival rate, new systems need to be developed.These systems must be inexpensive, but also accurate, reliableand well suited to the medical and social contexts of thedeveloping world. Ultimately, recall that the DLD process ismainly based on particles size during the separation process, so itis worth mentioning that the DLD process separates largeparticles even at low concentrations. Thus, DLD is a reliable andconfident method since usually the amount of infected cells/microorganisms for being displaced are as low as few cells permillilitre of blood.

The rest of the paper is organized as follows. Section 2 presentsa discussion of the conducted methodology, which is divided into

two subsections: firstly, we examined the observation oftrypanosome behavior in circular post array. Secondly, numericalsimulation of the proposed post designs were conducted and flowanalysis is presented. Section 3 explains the results and discussionof the new findings. Finally, in Section 4 some conclusions arepresented.

2. Methodology

2.1. Observation of trypanosome motion in circular post array

Here, we are aware of observing the dynamic behavior and themorphological changes of trypanosome microorganisms througha microfabricated circular post array. The design parameters ofthe studied array are as follows: the gap between two adjacentposts G¼10 mm, post size¼20 mm, periodicity of the array N¼20,a tilt angle e of about 2.861 (0.05 rad) and theoretical criticaldiameter (Eq. (1); [5]) for a particle to be displaced Dc is around2.7 mm.

Dc ¼ 2aGe ð1Þ

where a is a correction factor to accommodate for non-uniformflow through the gap.

Ten video clips that visualize the motion of the rod-shapetrypanosomes through microfabricated array of circular postswere investigated using manual tracking plugin of the ImageJsoftware (developed by National Institutes of Health). Actually, itwas a challenge to track the same particle along a number ofcontinuous frames without interruption. However, Fig. 2 showstwo pictures that were generated by overlaying multiple videoframes. During particle motion, it was noticed that the rod-shapetrypanosome, which is about 3.7–4.4 mm in effective diameter,stretches around the circular post. The deformation into aspherical shape was observed when the trypanosome particle

Fig. 4. Schematic of the geometrical configuration of the proposed airfoil design.

M. Al-Fandi et al. / Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244 239

approaches and leaves a circular post as the stagnation streamlinehits the post. Consequently, some particles might get stuck ontheir way. At this point, the average measured size oftrypanosome particle after such deformation is approximately4.7–5.8 mm in diameter. Thus, the size of both the deformed andnon-deformed cells is above the designed Dc. Hence, they shouldtravel according to the typical displacement mode of DLD, but weexperimentally observed that some of the trypanosome particlesbumped into posts down the stream as their shape gets deformed.Note that the fluid velocity at the center of each encounteredgap has no significant effect on the critical diameter, since the Dc

is a design issue. Furthermore, the separation process in thementioned experiment occurs in random paths regardless of thesupplied fluid flow rate of the designed array.

As shown in Fig. 2, the paths traced out by the trypanosomeparticle demonstrate that the particle shifts toward differentstreamlines further down the array. It is clearly seen in Fig. 2(a)that the particle changes its path after eight posts; while inFig. 2(b) it travels along fifteen posts then bumped to anotherpath. In this mostly impractical case, it is expected that theobserved change in the average apparent size of trypanosomecells within a DLD device is due to the hydrodynamic forces thecell experienced in the array. These forces have been quantified asexplained in later sections. In essence, as the cell interacts with apost, forces cause an increase in the effective diameter. Further,we believe that gradient in fluid velocity around a soft particleresult in tumbling and a change in the orientation of the cell; as aresult the cell might no longer correctly, laterally be displaced.Moreover, it was observed that there is a tendency for particles toget stuck to the post surface through some type of collision, whichhas the potential to harm the living microorganisms.

Therefore, based on the understanding of the observeddynamic behavior of trypanosome particles and the resultantdramatic change in their bumping mode, it is reasonable todevelop a new post array that would maximize the efficiency ofthe separation process and overcome the above mentionedproblems. Finally, it is worth mentioning that numerical simula-tion for the design of the above used array has been conducted asdepicted in Fig. 3, where there is a good agreement between thetheoretical critical diameter and the numerically found dividingline between zigzagging and bumping particles.

2.2. Numerical simulation of the proposed posts

Our objective was to find the best geometric configuration fora reliable post shape and analyze its efficiency along with its

Fig. 3. A simulated unit of the used bumper device (N¼20, post size¼20, G¼10 mm)

bumpers together with stagnation streamline indicates that Dc¼2.8 mm.

surrounding flow. In particular, diamond and airfoil post arrayshave been proposed and studied using commercial computersoftware package called COMSOL multiphysics 3.5a (Comsol Inc.Burlington, MA). A study of two-dimensional diamond and airfoilgeometries represent a reasonable starting point for exploration,where they are characterized by surfaces that are somehowtangential to the fluid flow direction. Diamond post with 20 mmdiameter length was used and a gap G between posts of 10 mm,resulting in a l of 30 mm and Dl of 10 mm. Similarly, an array ofairfoil posts was designed using the same design parameters.However, the geometry of airfoil shape is much more complexthan the diamond one, where there are other attributes thatshould be taken into account, such as airfoil camber percent andangle-of-attack (AOA). Our airfoil geometry is based on Joukowskiairfoil module [15]. Actually, based on the first approach of theproposed airfoil design, the results were not satisfactory as it ispointed out in a later section. Therefore, design optimization isdemanded. We have investigated the effects of airfoil’s length,camber percent and AOA. However, after several runs, we endedup with a reasonable airfoil design as depicted in Fig. 4, it ischaracterized by a chord length of 65 mm, a thickness equal to13 mm (i.e. one-fifth of the chord length), an effective AOA around51 and a lower camber that is about 30% of the thickness. Inparticular, the thickness of the airfoil plays a crucial role on theresults, where we found that lesser the airfoil thickness, the betterresults can be obtained. However, this is asserted in many studiesrelated to airfoil theory [16,17].

In particular, both of the proposed arrays consist of lattice ofeither diamond or airfoil posts that are rotated at angle e withrespect to the average fluid flow direction. For simplicity, theresults of this paper are presented using arrays with a tilt angle eof 18.431 (0.333 rad) as shown in Fig. 5. In both designs, constant

during the experimental observation of trypanosome motion. A close-up of some

Fig. 5. Geometric design of (a) diamond post array and (b) airfoil post array.

M. Al-Fandi et al. / Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244240

flow velocity was assumed at the inlet of the array, the outlet wallwas fixed at atmospheric pressure and no-slip condition wasapplied at the other boundaries. The numerical simulations werecarried out at different Reynolds numbers, where the appliedconstants are: fluid viscosity (Z)¼0.001 Pa s and fluid density(r)¼1000 kg/m3. Reynolds number is a dimensionless quantityrepresenting a measure of the ratio of inertial forces to the viscousforces, probably the most important dimensionless parameter inour simulations.

Indeed, the novelty of this work resides in developing a newpost shape that should exert lower normal forces on the cells andhence, less deformation. In other words, higher tangential forcesto the post surface should be generated that would increaseslipping motion of the cells and accordingly decrease theiropportunity of getting stuck or getting clogged. Most importantly,the proposed designs have been numerically evaluated bycomparing them against circular posts that were designed underthe same conditions. The next section explains different impor-tant issues that were considered in this study, including: criticalparticle size, distribution of the velocity field and normal andtangential forces at post surface.

3. Results and discussion

Whenever a solution is obtained by means of numericalcomputation, applicability and validity of the desired model mustbe assessed. This section aims at addressing some basic issuesrelated to the validity of the desired model and the extent towhich it represents the best physical system.

3.1. Critical particle size

Firstly, numerical simulation of the flow stagnation stream-lines was performed. Visualization of the stagnation streamlinesenables us to predict the flow pathway of different particles size,as well as to optimize the configuration of the array. For bothcircular and diamond posts, there is top–bottom symmetry ofposts, where b is exactly alike on either side of the post.Quantitatively, b¼3.6 mm on both sides for circular and diamondposts. Thus, the resulted Dc for a particle to be displaced equals

7.2 mm, where Dc¼2b as explained in many research [5,18].For airfoil posts, the bump array relies on different asymmetricbifurcation of fluid streams due to unsymmetrical geometryof airfoil post. The velocity of flow is higher at the uppersurface of the airfoil and hence the stream lanes are the smallestthere. Qualitatively, the lane width above the upper surface isnarrower than that of the lane below the lower cambered surfaceof the post. The calculated Dc at the upper surface wasabout 5.6 mm, while at the lower surface it was near 8.0 mm. Atthis point, we can conclude that the Dc at the lower camberedsurface is 30% greater than that at the upper surface, whichrepresents enough percent to allow large particles to be displacedsomehow in a different manner compared to the regular postshapes.

As a proof of concept, spherical particle motion has beeninvestigated through a simulation of particles implemented inmicrochannels of circular, diamond and airfoil posts. During thesimulation, it was assumed that the released particles are hardand have no influence on the flow. However, the results can beseen as a series of several iterations with a single particle, giving aqualitative picture of the ability of the given geometry to separate.The particle’s path in each design was simulated using a MATLABscript that utilizes the velocity data from COMSOL Multiphysicsand a predefined time step. A critical part of the simulation wasthe time step in the travelled path, where a too large time stepgives inaccurate results, while small time step causes in somecase wasted calculation times. A determination of an optimal timestep has been performed, where we found that the optimal timestep equals 0.001 s. Lower than this value produces the sameresults with too much of time consuming, while greater than itcauses rough and inaccurate results. The simulation for smallparticle (e.g. particle diameter¼5.0 mm) is shown in Fig. 6(a), (c)and (e). The figures show the center position of the particle; it isobvious that the particle in each design follows the zigzag mode.For larger particles, such as particle diameter¼8 mm in arrays ofcircular and diamond posts and particle diameter¼9 mm in thecase of airfoil posts, the paths of the particle’s center areillustrated in Fig. 6(b), (d) and (f). Obviously, the particle isbeing bumped by the circular, diamond and airfoil posts,respectively. On the other hand, we observed that if the largeparticle travels through the closest lane of the lower camber

Fig. 6. Particle implementation for both zigzag and displacement modes with stagnation streamlines in post arrays of e¼1/3, (a,b) circular posts, (c,d) diamond posts and

(e,f) airfoil posts. Only the centers of the particles are shown.

M. Al-Fandi et al. / Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244 241

surface of an airfoil post, it will be forced by the next post to jumpover to follow a new bumping path. Accordingly, particlesclogging may decrease significantly in an array of airfoil posts.

Fig. 7 shows the ratio of the calculated critical diametersbetween circular and airfoil posts versus array tilt angle. Ate¼0.333 rad, we found that the critical particle size for circular

Fig. 7. Ratio of critical particle sizes between circular and airfoil posts versus array

tilt angle.

Fig. 8. Velocity profiles at different points along the flow between two

M. Al-Fandi et al. / Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244242

posts is about 12% larger than that at airfoil posts. As the array tiltangle decreases, the ratio of the two critical particle sizesincreases substantially. This allows a higher bump angle for agiven gap size and maximum allowable particle/gap ratio. At thispoint, we conclude that improvements in clogging by increasingthe periodicity of the array are greater in arrays with airfoil poststhan that either in diamond or circular posts. In other words, thepredicted Dc for airfoil posts is always below the predicted Dc forcircular posts, so we will end up with smaller N, and thus highertilt angle in an array with airfoil posts. Therefore, lower time isneeded to perform a given separation. As a next step, theproposed airfoil post array will be considered for fabrication, inorder to be tested experimentally using live samples of softmicroorganisms.

3.2. Velocity field

Analysis of the velocity profile across the gaps of the proposeddesigns is of great practical importance. Fig. 8 examines thevelocity field issue at different points along the flow field betweentwo adjacent posts of the proposed designs, as well as for

adjacent posts of (a) circular, (b) diamond and (c) airfoil designs.

M. Al-Fandi et al. / Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244 243

conventional circular posts. The performed analysis on thevelocity profiles was based on the notion that high variation invelocity gradient has significant effect on soft, non-circular cellsdeformation and orientation.

Actually, in circular and diamond post arrays the results showthat the flow field demonstrated relatively high velocity gradientat the gap compared to that resulted between two adjacent airfoilposts. In particular, the flow field through circular and diamondposts shows that the average change in velocity gradient from theinlet to a gap is around 35%, as it is obvious in Fig. 8(a) and (b).While using the airfoil post array, the change in velocity gradientis only about 17% as shown in Fig. 8(c). In fact, due to the designconfiguration of both circular and diamond posts, the flow profilebroaden at the inlet of two adjacent posts, next the flowapproaches a parabola across the gap and then returns back tobroaden gradually. Of course, this has a profound impact on softparticle motion, where there would be high tendency for suchparticles to be rotated, deformed and subsequently directed to befit within the average flow direction and hence no longer to bedisplaced. Contrarily, in the airfoil post array, the distancebetween the upper and lower surfaces of two adjacent posts isalmost similar along the gap, where the maximum change in

Fig. 9. Post boundaries that faced flow direction are examined under normal and

tangential forces.

Fig. 10. A ratio of the applied (a) normal forces and (b) tangential forces on circular,

distance would be at most around 2 mm. Accordingly, the flowfield is almost homogeneous through the gap due to the designitself of the prescribed airfoil shape and hence, it can be said thatthe gaps within the airfoil post array operate as a guide for thecarried particles. Consequently, there will be little effect on thedeformation process of soft particles.

3.3. The applied forces on post surface

Accurate computation of the forces affecting the particles iscrucial for precise determination of the path of micrometer sizedparticles in microchannels. In general, fluids possess internalstresses due to a fluid pressure, P, and stresses due to viscousforces. To quantify the forces that are applied on soft cells, wenumerically have calculated fluid normal force (Fn) and tangentialforce (Ft) to the post wall as depicted in Fig. 9, where circular,diamond and airfoil post designs have been examined accordingto Eqs. (2) and (3). Tangential forces were found by summing themeasurements of the shear force components at post surface A

that faced soft cells, which are definitely carried by fluid flow.

Ft ¼

ZAZ @u

@ydA ð2Þ

where Ft is the measured tangential force, Z is fluid viscosity andqu/qy represents velocity gradient.

Fn ¼

ZA

2Z @u

@ndA ð3Þ

where Fn is the normal force at which pressure force acting on asmall area dA and n is the outward normal vector on the boundary.

Fig. 10 shows the resulted forces as a function of Reynoldsnumber. We observed that as the input flow velocity increases, theresulted forces increase substantially. As shown in Fig. 10(a), thenormal forces at airfoil post surface are much lower than both ofthe diamond and circular shapes. For example, at Re¼0.308 theresulted normal force at airfoil post surface was five times lowerthan that at circular one, and less than the diamond post by morethan two times. Hence, soft particles that might stop by the airfoilpost would exhibit much lower possibility of getting deformed.Remember that the reported results are related to the optimizedairfoil post of 13 mm thickness, where the measured normal forceat its surface decreased almost by 58% compared to an airfoil

diamond and airfoil post surfaces that faced input flow versus Reynolds number.

M. Al-Fandi et al. / Robotics and Computer-Integrated Manufacturing 27 (2011) 237–244244

post of 20 mm thickness. For comparison purposes, normal forceswere measured at designs of circular and diamond post surfaces of13 mm diameter each. However, we observed no significant changescompared to that were obtained at 20 mm diameter of such posts.

On the other hand, the resulted tangential forces at airfoil postwere obviously much greater than the other designs. Fig. 10(b)illustrates that the tangential forces increase extrusively asReynolds number increases. Also, let us consider the values atRe¼0.308; the results show that airfoil performs tangential forcesthat are about two times greater than that for circular post andaround three times greater than that at diamond one. Accordingly,this gives clear evidence that soft cells will behave and slipsmoothly, avoiding any collision complications.

From the above analysis, it is obvious that airfoil post array ishighly recommended to be more reliable and effective than the otherdesigns in maintaining the normal shape of soft particles/micro-organisms. The important finding is that the airfoil post demonstrateda distinguishable behavior of fluid flow around it, where the flowexerts minimum variation of velocity gradient, very low normal forcesto the airfoil post surface and high values of tangential forces. Thisimplies high potential for airfoil posts to overcome the complicationsencountered during the separation of soft biological microorganisms,thereby increasing the separation efficiency.

4. Conclusions

In this paper, we developed new post shape designs: diamondand airfoil posts. The goal is to overcome the deformation andsticking complications of soft cells that are usually encounteredby using the conventional circular post microfluidic separationarrays. Numerical simulations were utilized to evaluate theperformance of the proposed diamond and airfoil post arrays.For completeness, comparisons between diamond, airfoil andcircular posts were conducted numerically in parallel with sometype of optimization regarding the complex airfoil design.

The simulation results showed that due to the design itself ofthe airfoil post, the fluid flow behavior minimizes any possibilityof deformation and clogging problems through the separation ofsoft microorganisms. In particular, at airfoil post array, the flowexerts minimum variation of velocity gradient, very low normalforces at the airfoil post surface and higher values of tangentialforces compared to circular and diamond designs.

These important findings permit us to conclude that airfoilshape is recommended for the predicted behavior of soft cellseparation at low Reynolds number, in a manner that prevents thetargeted particles from getting deformed, stuck or clogged duringtheir motion. In other words, the simulation work demonstratedthe efficiency and robustness of airfoil shape as an obstacle inmicroseparation arrays that would provide much greater controlduring the separation of deformable cells.

Acknowledgments

This work is partially supported by Jordan University ofScience and Technology (Award No. 83/2008). Special gratitude

goes to Dr. Jonas Tegenfeldt and Dr. Jason Beech from the Divisionof Solid State Physics at Lund University for the valuablediscussions and for allowing us to utilize their laboratory toperform the experimental work. The authors also acknowledgethe European commission Erasmus Mundus mobility program forpartially supporting this research.

Appendix A. Supplementary data

Supplementary data associated with this article can be foundin the online version at doi:10.1016/j.rcim.2010.06.003.

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