IJCE - · PDF fileGiven this upsurge of interest and the market forecast, ... (BioMEMS) has increased greatly the scope and value of microfluidic devices by making them

Department of Chemical Engineering C. V. Raman College of Engineering Bidyanagar, Mahura, JanlaBhubaneswar-752 054, India E-mail: [email protected]

MICROFLUIDIC PROCESSES: BLENDING NEW CHEMISTRY WITH NEW ENGINEERIN

Pratap R. Patnaik

ABSTRACT

Microfluidic devices are emerging rapidly as a preferred way to produce materials with specific propertiesor promote chemical/biological reactions that require stringent control. The use of microtubes providesmany advantages over conventional equipment in terms of transfer processes and control. Theseadvantages have enabled microfluidic devices to have wide applications, covering semiconductors, drugdelivery, enzymatic reactions, the recovery of sensitive biomolecules, food products, photocatalysis andbiosensors.

To be practically useful and economically viable, a microfluidic device may have to combine severalmicrounits on a single chip in a functionally effective way. This is not easy, partly because of limitedunderstanding of some micro-processes and partly due to the difficulties in optimizing an integratedmulti-unit micro-process. A good micro-process therefore has to blend the chemistry with the chemicalengineering. This is the focus of the present review, which discusses the major chemical systems formicro-reactions, the types of micro-reactors and other equipment, integration methodologies and somesignificant applications.

Keywords: Microfluidic processes; microreactors; chemistry and engineering; integrated labon-a-chip units; modeling; applications.

1. INTRODUCTION

Microfluidic devices have experienced a phenomenal growth of interest, research andapplications during the last decade. This growth has been driven by many factors, notablygreater understanding of the underlying chemistry, the design of new equipment that optimizemixing and transport processes, and novel applications that require special nanomaterials whichare difficult to manufacture by conventional methods. Thus, microfluidic technologies havespanned reaction environments such as microemulsions, micellar systems and polyelectrolytecapsules [Shchukin & Sokhurukov 2004], enzymatic and cellular microreactors [Matosevic etal 2010; Miyazaki et al 2008], different reactor configurations [Doku et al 2005; Song et al.2008], and applications covering analytical chemistry, diagnostics, drug discovery, biosensingand combinatorial synthesis [Aurox et al. 2002; Ehrfeld 1999; Hessel et al. 2009; Nguyen &Werely 2002].

INTERNATIONAL JOURNAL OF CHEMICAL ENGINEERING4(1) (2011): 27-57

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28 International Journal of Chemical Engineering (IJCE) • ISSN: 0974-5793

The commercial potential of microfluidic reactors is demonstrated by their rapidly growingapplications in areas such as on-line process optimizations [Garcia et al. 2000], optical resolutionof racemic mixtures [Honda et al. 2007], vesicles for controlled and targeted delivery of drugs[Modi & Pandya 2011; Ranquin et al. 2005], and the synthesis and identification of high-valuebiological products [Duan et al. 2006; Roberge et al. 2008].

The market for microfluidics was estimated to be λ1.98 billion in 2008 [Mindbranch 2010],with an expected annual growth of 15.5%. Given this upsurge of interest and the market forecast,some companies have already tapped into the microfluidic business. Reports indicate thatDolomite (2010) is developing large-scale systems comprising multi-layered droplet-generatingmicrofluidic devices, Microfluidics Corporation (2010) has provided integrated equipmentsolutions to the pharmaceutical and chemical industries, and Sigma Aldrich (2010) is marketinga microreactor assembly that is also being used in-house for the production of certain finechemicals.

The proliferation of both research and applications of microfluidic reactions and reactors,in either stand-alone mode or integrated with other compatible small-scale units has beengalvanized by the advantages of such systems and by advances in enabling areas, mainly micro-electro-mechanical manufacturing systems (MEMS). Extension to biological systems(BioMEMS) has increased greatly the scope and value of microfluidic devices by making themapplicable in which areas of medical diagnostics, sensor technology, micro-battery developmentand drug delivery [Ferrari et al. 2006]. Health care applications alone are forecast to grow from$ 1.2 billion in 2009 to $ 4.5 Billion in 2015 [IFSA 2011], making it one of the most lucrativeareas for BioMEMS.

The many benefits of microreactors include their low cost, high efficiency and easyrepeatability [Ehrenfeld et al. 2000; Hessel et al. 2004]. Since the processes are carried out innarrow capillary tubes with high aspect ratios, accurate control and efficient heat dissipation repossible, thereby reducing the consumption of reactants and generation of waste products andenhancing operational safety [Hessel et al. 2004, 2009; Wang & Holladay 2005]. In addition,microreactors offer the possibility of monitoring and controlling reaction and flow parametersother than traditional parameters such as bulk flow rates, concentrations and pressure [de Mello2006].

Some of the advantages of microfluidic devices are due to the flow being laminar, withmixing occurring mainly by diffusion. However, often diffusive mixing alone may not besufficient to enable intimate contact between two or more fluids. Thus a certain degree ofdisruption of laminar flow may be required, and many studies have addressed the issue ofcontrolled mixing. Methods to achieve controlled mixing include coalescing channels [Dokuet al. 2005], micromixers of different designs [Erickson & Li 2002, Seong & Cooks 2002,Strook et al. 2002], and controlled droplet fusion [Hung et al. 2006]. However, optimal mixingremains a key unresolved aspect of microreactor design, especially when two or more phasesare involved [Commenge et al. 2002; Doku et al. 2005].

Multi-phase microreactors and nanoreactors present both new challenges and fascinatingopportunities. The possibility of size reduction beyond the micro-scale allows the synthesis ofnovel and useful nanomaterials with properties radically different from those possible thoughtraditional manufacturing methods, However, processes to synthesize nanoparticles require

Microfluidic Processes: Blending New Chemistry with New Engineering 29

control systems that are more stringent and complex than required for large rectors. A keyrequirement is that the nanoparticles should have a narrow size dispersion; traditional approachesrequire multiple purification steps, which increases the cost of production. Methods such aslaser vaporization, sputtering, metal evaporation and electron beam lithography [Song et al.2003, 2008] provide viable and cost-effective alternatives. Monodispersity is of course justone requirement. The properties also depend on other factors such as crystal growth and kinetics,both of which are sensitive to the operating conditions [Chan et al. 2003; Lee et al. 2006].

In spite of these complexities, the numerous benefits of micro-and nano-reactors continueto drive both fundamental understanding and new applications. One reason sometimes advancedas a weakness of these reactors is their low throughputs. This drawback may, however, beovercome by using many reactors (hundreds or sometimes even thousands) in parallel (callednumbering-up) [Ehrfeld et al. 2000; Hessel et al. 2004; Miyazaki et al. 2008]. Parallel processingtoo has its attendant problems, notably equal distribution of the reactants among all the tubesand uniform dissipation of heat from all the tubes. However, given the advantages, thesedifficulties are surmountable and do not constitute an impediment to the growth of microfluidictechnology, especially in the context of the synthesis of valuable nanomaterials that requirespecial processing conditions.

In this communication, the principal features of microfluidic reactors are overviewed,followed by their many advantages and weaknesses, current strategies that blend nanochemistrywith compatible reactor designs, quantitative modeling (that is still at an early stage), and somemajor applications.

2. MICROFLUIDIC REACTORS: AN OVERVIEW

Microfluidic reactions occur inside narrow tubes or channels, and they are usually operated incontinuous flow. The flow is inherently laminar, the many source of mixing is diffusion driven,and the driving force applied may be mechanical or electro-osmotic. Since the reactions areconfined to small narrow regions, accurate and sophisticated control is both possible andnecessary. Sophisticated monitoring and control are necessary because these devices are usuallyemployed to synthesize special-purpose nanomaterials endowed with specific physical, chemical,biological or magnetic properties that should be within narrow ranges.

While most microfluidic devices are constructed on the general principles of MEMS, i.e.,micro-electro-mechanical systems, one of the most interesting and popular approaches is tomimic biomineralization processes. A general MEMS architecture has four components:microsensors, microactuators, microelectronics, and microstructures. Of these, the creation ofspecific nanostructures with desired morphology and properties is the focus of microfluidicengineering, and the challenge is to design a MEMS architecture that accomplishes this objectivemost efficiently [Korvink & Paul 2006; Hessel et al. 2009].

There is no direct and straight forward methodology to design the best MEMS architecturefor a given application. This is due partly to the limited understanding of some key facets of thefluid dynamics and transport phenomena, and partly to the need to integrate a microreactorwith other micro-components so as to develop a comprehensive and functional piece ofequipment. Such integration may require some of stand-alone optimal features to be


compromised in the larger interest of an effective multi-component device. For example,Taniguchi et al. (2008) developed a microreactor system integrated with micropumps,micromixers and a temperature regulator to optimize small scale chemical synthesis processes.Each unit had to function in consonance with other units, implying that the design parametersof each had to be functionally compatible with those of other components. Their design alsohad a novel magnetic actuator in the micromixer, for which the MEMS approach was used.Hartman and coworkers (2010) reported an interesting study in which a continuous-flow multi-step Heck synthesis was demonstrated by integrating microreactors, liquid-liquid extractionand microfluidic distillation. As with Taniguchi et al., the interacting micro-units had to beoptimized in tandem so that the system as a whole generated the best performance. More suchexamples have been discussed by McMullen and Jensen (2010) for reaction automation and byMarre and Jensen (2010) for nanostructures in microdevices.

Song et al. (2008) go further to suggest that a microfluidic reactor often has to be integratedwith micromixtures, microscale heat exchangers, micropumps, microsensors, microextractorsand microactuators. This task becomes more daunting if all these devices are to be integratedon a single chip, which is the ultimate objective. Nevertheless, microchip-based integrateddevices have already be fabricated for three or four components, even though both design andfabrication strategies have yet to be standardized [Chan et al. 2003; Edel et al. 2002; Nissila etal 2009]. These devices differ in the components that are combined as well as in their applications,indicating the versatility and robustness of on-chip micro-integration designs and procedures.

It has been stated above that many microfluidic reactors are based on laminar flow withdiffusion as the main source of micromixing. While laminar flow allows ease of operation andcontrol, source applications require more intimate mixing and/or more effective heat and masstransfer. This is particularly important for strongly exothermic reactions, as in gas phase catalyticsystems [Nobuaki et al. 2007], and where mass transfer across two or more phases may becomerate-limiting [Doku et al. 2005]. Many methods have been proposed to reduce laminarity andincreasing micromixing. Commercial methods include micromixers using physical orelectrokinetic methods [ Erickson & Li 2002; Seong and Crooks 2002], zigzag microchannels[Mengeaud et al. 2002], coalescing channels [ Doku et al. 2005] and controlled fusion of fluiddroplets [ Hung et al. 2006]. One useful departure from laminar flow that shows considerablepromise of performance improvement is laminar segmentation. The idea here is to introducecontrolled segmentation into laminar flow such that an optimum level of mixing is obtained.Such controlled mixing has been shown to promote product yield and selectivity in bothgas-phase catalytic rectories [Nobuaki et al. 2007] and gas-liquid reactions, [Ahmed-Omer etal. 2008; Oskooei & Sinton 2010] suggesting that, as a logical extension, this should also favorthree-phase gas-liquid-solid reactions. Computation fluid dynamics simulations [Harries et al.2003; Kashid et al. 2007] support this view but experimental verification is awaited.

Shchukin and Sokhurukov (2004) have pointed out that micro-scale and nano-scale reactorsmay be classified broadly into two types. They may be either (a) individual standalone reactorsor (b) inter-connected with neighboring reactors. From a chemical engineering perspective, thelatter have greater direct practical relevance, and hence a major portion of microreactor studiespertain to these reactors. Shchukin and Sokhurukov (2004) therefore reviewed the former typeof microreactors, drawing attention to their importance and complexities in synthesizing


nanostructures. Microemulsions, micellar systems, multi-layer organic films and polyelectrolytecapsules are the major kinds of individual (disconnected) micro-and nano-reactors. The absenceof linkages between individual microreactors prevents aggregations of particles and thus enablesa prescribed size distribution of nanoparticles to be synthesized. While non-interacting arraysof microreactors way be functionally effective, scaling up to economically viable levels ofproduction usually requires synchronized interactions so as to have efficient transport of reactants,products and energy. Thus, emulsions or micelles or capsules often function within a capillarymicroreactor. While such configurations have wide practical utility [Hessel et al. 2004, 2009;Ostafin and Landfester 2009], they are also difficult to model and optimize. These aspects arediscussed separately in the sectors that follow.

3. NON-INTERACTING MICROFLUIDIC SYSTEMS

On a microscopic scale, systems such as vesicles, micelles, emulsion droplets, liposomes andpolyelectrolyte capsules function as microreactors themselves. This is an attractive observationsince it enables upscaling of microfluidic processes by manipulating the medium of reaction,either instead of or in addition to stacking many tubes in parallel. Since the micelles or emulsiondroplets are much smaller than the microreactor channels, the surface to volume ratios aremuch larger and hence allow considerably greater enhancements than might be possible byexpanded parallel processing (or numbering-up). In spite of these advantages, there have beenfar fewer studies of these individual miniature reactors than of inter-linked arrays ofmicrocapillaries. A brief overview is provided below of some of the major types of such reactors.

3.1. Microemulsions

These are among the most widely used types of chemical microreactors. Both direct and reverseemulsions have been employed [Jiao & Burgess, 2001; Kent & Saunders 2001; Landfester etal. 2000]. There owe three common methods to prepare reactive microemulsions. One methodis to dissolve both the starting reactants in disperse media; alternately, one of the reactants maybe a constituent of the surfactant. The third method involves so-called micellar exchange betweentwo or more emulsion droplets containing dissolved reactants.

Much of the research on microemulsions has focused on the preparation of metal oxides[Li et al. 2002; Lee et al. 2003; Gomez-Lopera 2001] in reverse water-in-oil emulsions. Theprocess involves micellar exchange by dissolving a metal salt in an aqueous phase inside themicrodroplet and adding a base to the oil phase. Inorganic nanomaterials too can be prepared inreverse microemulsions, as shown for calcium carbonate [Li & Mann 2002] and barium sulfate[Niemann et al. 2008].

Microemulsions are particularly effective for enzymatic hydrolysis, where high substrateconcentrations and product yield are possible [Miyazaki et al. 2008; Miyazaki & Maeda 2006].A related significant area of application is in food grade products. Glatter et al. (2001) basedtheir research on the fact that surfactants containing sugar components and fatty acids satisfyfood standards. Their system consisted of the sucrose monoester of stearic acid in the aqueousphase and a 1:1 mixture of n-tetradecane and 1-butanol in the oil phase. Flanagan et al. (2006)also focused on edible surfactants and their ability to form microemulsions with soya bean oil,which is rich in protein.


Microemulsion reactors are easy to fabricate and operate but they have limitations such asthe narrow range of nanomaterials that can be synthesized, the lack of mild control over thereaction(s) and the absence of a rigid, stabilizing shell. When these features are critical, othersystems may be used.

3.2. Micellar reactors

Micelles arise from the thermodynamically stable organization of surfactants, which encapsulatea nanosized water core in contact with their hydrophilic head groups [ Shchukin & Sokhurukov2004]. The extremely small size of the micellar core makes it feasible to synthesize nanomaterialswith narrow size distributions. One class of applications where this feature has been exploitedis for semiconductors with marked quantum-size effects, e.g. ZnSe [Quinlan et al. 2000], CdS[Pileni 2000] and CdTe [Ingert & Pileni 2001], by using ion-exchange reactions in reversemicelles. The nanoparticles made by this method had average diameters between 3 and 6 nm.

Quantum-sized semiconductors are by no means the only class, or even the dominant class,of nanoparticles manufactured in micellar rectors. TiO

2 and SiO

2 nanoparticles, either

individually or in combination with noble metals such as Pd and Pt, have also been made[Bae et al. 2002]. Other metals such as Co, Cu, Fe, Ag and Au have also been synthesized asnanoparticles in micellar reactors, thereby demonstrating the versatility of these nanoreactors.The basic procedure involves introducing metal ions into a micelle core and then reducingthem by either a strong, soluble reducing agent (e.g. NaBH

4) or gaseous H

2. NaBH

4 generates

small metal particles whereas large particles are formed with H2 as the reducing agent.

Nanoparticles made in this manner exhibit higher catalytic activity than normal metal catalysts.

Two strong areas where micellar nanoreactors have proven to be effective synthesizers arein enzymatic reactions and biological materials. Enymes solubilized in reverse micelles shoeenhanced activity and improved substrate specificity [Klyachko & Levashov 2003; Orlich &Schomaker 2002]; this has been attributed to many factors including increased conformationalrigidity of the enzyme, a reduction in substrate inhibition, and stabilization of the transitionstate. The ability to tailor the structure and properties of biological nanoparticles through reversemicelles has tremendous potential for the development of new drug delivery systems [Matsumara2008] and novel protein crystals [Thachepan et al. 2010], and for control of the properties ofviral caspids [ Michel et al. 2006]. This is exemplified by the work of Vrignaud et al. (2011).For two anti-cancer drugs, they showed that their new technology could solubilize the hydrophiliccontents in the oily core along with the lipophilic contents. Such advances have attractedcommercial interest, with Soligenix (2011) developing the LPMTM (Lipid Polymer Micelle)technology for the delivery of peptides and nucleic acids in the stomach and small intestine.

While there are many profitable applications of micellar nanoreactors, an underlying problemthat needs to be solved is the limited and weak control of the size distribution and permeabilityof the micellar network [ Faure et al. 2006].

3.3. Multilayer Organic Films

In addition to the limitations outlined above, it is also not possible to carry out sequentialreactions inside a micelle or an emulsion droplet. Here the layer-by-layer (LbL) approach ofdeveloping a multi-layer polymeric microreactor offers a feasible alternative. The method was


pioneered by Tillman and coworkers (1989), who produced multi-layered films via covalentadsorption of molecules with specific functional groups. Although such selfassembled layerswere quite stable, the requirement of chemical affinity between adsorbent molecules and theadsorbate layers limited the choice of molecules. Subsequently, Decher et al. (1992) and Lvovet al. (1993) expanded this method to make it possible to build layered heterostructures withfine control over specific properties. Their method significantly widened applications of theLbL technique to polymeric nanocrystals [Zucolotto et al. 2005], metal and semiconductornanoparticles [Cassagneau & Fendler 1999; Fendler 1996], dendrimers [Sun et al. 2003] and,significantly, a number of enzymes, proteins, DNA, cell membranes and viruses [Caruso &Mohawald 1999; He et al. 1998]

The LbL technique has become popular for many reasons. It allows the facile, cheap andenvironmentally friendly processing of both simple and complex structures. Simple variationsof the pH and the ionic strength of the medium enable the thickness of the layers, permeability,surface wettability, and the number of unbound functional groups to be controlled [Lutkenhaus& Hammond 2007]. The LbL technique is also usable with both hydrophilic and hydrophobicsubstrates [Stockton & Rubner 1997], and the films may be deposited directly on to colloidalsuspensions [Clark et al. 1997; Ichinose et al. 1998].

A major advantage of LbL films is their suitability for immobilization to biological moleculeswith preservation of activity over long durations. This has made it possible to immobilize anumber of proteins and enzymes, with both diagnostic and therapeutic applications [ Crespilhoet al. 2005]. This is illustrated by the work of Galeska et al. (2001) and Yang et al. (2006). Theformer immobilized humic acids in LbL films to prepare semipermeable membranes forelectrochemical sensing of glucose, whereas Yang et al. prepared amperometric biosensorsform LbL films of horseradish peroxidase to detect phenolic compounds in micromolar ranges.

The versatility of multilayer LbL films is also exemplified by the use of metalhexacyanoferrate films as redox mediators. Such films have been investigated for a variety ofapplications such as catalytic oxidation of NADH [Xun et al. 2003], oxidation of dopamine[Chen et al. 2008] and as glucose biosensors [Jaiswal et al. 2003; Zhao et al. 2005].

Many of these applications, as well as weak areas for further development, have beenreviewed by Crespilho et al. (2006). An alluring development that might push the boundariesof LbL films is the ability to build three-dimensional nano-structures using charged particles.For example, Seo et al. (2008) showed for multilayer films based upon hydrogen bondingbetween hydrophobically modified poly(ethylene oxide) and poly(acrylic acid) that athreedimensional surface structure appeared above a critical number of layer pairs fordip-assisted LbL method but not for the spin-assisted method. An altogether different area ofapplication has been pointed out by Facca and coworkers (2008), who showed that complexthreedimensional LbL structures can be constructed for various types of cells, proteins, peptidesand DNA. The ultimate aim of their work is to reconstruct biological tissue with specifiedproperties. This study and that of Seo et al. (2008) indicate that three-dimensional LbLnanostructures can be constructed for highly selective and problem-specific applications.


3.4. Polyelectrolyte Capsules

Pharmaceuticals and therapeutic molecules, such as proteins and peptides, require suitablecarriers to deliver the drugs safely to their target sites without being broken down en route byproteolytic enzymes. In addition, the drug should be released only when required so that it isnot wasted or causes harmful effects at other times. Ocular implants for dry eyes and insulincapsules inserted under the skin are common examples. These capsules should release theircontents at controlled rates upon being activated by physical, chemical or biological triggers.

Polyelectrolyte capsules provide a convenient and effective way to achieve such stimulant-induced controlled delivery. These capsules are made by LbL coating of polyelectrolyte filmson sacrificial templates, which decompose and release the entrapped nanoparticles [De Guestet al. 2007; Sokhurukov 2001] upon being triggered by different stimuli. For example, chemicaltriggers work by altering the electrostatic interactions between successive polyelectrolyte layers;this may be achieved by a simple change in the pH of the environment. Another chemicaltrigger may be the ionic strength of the environment that causes the polyelectrolyte shell toswell and eventually dissolve.

A major advantage of polyectrolyte systems is their multifunctionality. The walls of acapsule can be functionalized with fluorescent, magnetic, and heatable colloidal nanoparticles,while its cavity can be loaded with cargo molecules. Depending on the triggering mechanism,the cargo molecules are released whenever needed [GiI et al. 2008]. In Gil et al.’s (2009) study,for example, the capsules were filled with a nonactive prodrug, a self-quenched fluorescence-labeled protein. Upon uptake by living cells, the walls of the capsules were degraded anddigested by intra-cellular proteases. The proteases then reached the inner protein cargo,fragmented the molecules and thus revoked self-quenching of the fluorescent dye. In this waynonactive (non-fluorescent) molecules were converted into active molecules.

The permeability of polyelectrolyte capsules may be varied over wide ranges, therebyenabling control of the fluxes of molecules across the layers so that a desired selectivity isachieved [Antipov et al. 2002; Antipov & Sokhurukov 2004; Modi & Pandya 2011]. The capsulewall is usually permeable for macromolecules and nanoparticles at low pH (< 3) or high ionicstrength, and it disallows these molecule at high pH (> 9). Thus, the pH again provides a simpletrigger to drive cargo particles across the capsule walls. Antipov and associates (2002)investigated the pH trigger for different polyelectrolytes adsorbed layer-bylayer onto the surfacesof melamine formaldehyde and CdCO

3 particles. The capsules were impermeable at pH > 8 but

at pH < 6 the macromolecules could permeate the interior of the capsules. While pH manipulationis a common technique for permeability control, other methods such as depositing polymersinside the microcapsule walls have also keen employed [Ghan et al. 2004].

Apart from regulating permeability, pH may also be used to drive chemical reactions insidethe capsules. The influence of a pH gradient has been used for the precipitation of acidic dyesin a capsule filled with negatively charged poly( styrene sulfonate) [Sokhurukov 2001].A similar procedure has been used to synthesize polytungstinic acids and nanosized WO

3

[Shchukin et al. 2003] by suspending capsules loaded with poly(styrene sulfonate) in a NaWO4

solution for 24 h.


Table 1Applications of Different Microreaction Systems

Reaction system Applications References

Microemulsions Metal oxides Lee et al. (2003); Niemann et al. (2008)

Enzymatic hydrolysis Miyazaki & Maeda (2006); Miyazaki et al. (2008)

Enhanced oil recovery Shah (1998); Santanna et al. (2009)

Textile coating and finishing Barni et al. (1991); de Castro Daritas et al. (2004)

Cosmetics Azeem et al. (2008); Friberg (1997)

Food products Flanagan et al. (2006); Glatter et al. (2001)

Pharmaceuticals Hazra et al. (1998); Jain et al. (1998)

Environmental remediation Baran et al. (1998); Haegel et al. (2000)

Chemical reactions Candau et al. (1998); Moulik et al. (1999)

Chemical sensors Xu et al. (2000); Yoon et al. (2007)

Reverse micelles Semiconductors Ingert & Pileni (2001); Xiang et al. (2010)

Metal oxides Bae et al. (2002); Ganguly et al. (2005)

Enzymatic reactions Klyachko & Levashov (2003); Orlich

& Schomaker (2002)

Drug delivery Matsumura 2008; Vrignaud et al. (2011)

Proteins and viral caspids Michel et al. (2006); Thachepan et al. (2010)

DNA and protein anlyses Davis et al. (1996); Park et al. (2003)

Molecular dynamics Allen et al. (2000); Levinger & Swafford (2009)

Extraction of biomolecules Hemavathi et al. (2008); Shinshi et al. (2006)

Multilayer (L-b-L) Polymeric nanocrystals Rogach et al. (2000); Zucolotto et al. (2005)films

Semiconductors Cassagneau (1999); Fendler (1996)

Dendrimers dos Santos et al. (2006); Sun et al. (2003)

Biological molecules Carusso & Mohwald (1999); He et al. (1998)

Enzyme immobilization Galeska et al. (2001); Zhao et al. (2005)

Redox mediator Chen et al. (2008); Zhao et al. (2005)

3-D nanostructures Facca et al. (2008); Seo et al. (2008)

Polyelectrolyte Controlled drug delivery De Geest et al. (2007); Gil et al. (2008, 2009)capsules

Chemical reactions Shchukin et al. (2003); Choi et al. (2005)

Photocatalysis Pan et al. (2009); Shchukin et al. (2003)

Precipitations Antipov et al. (2003); Nolte et al. (2004)

Molecular dynamics Chakraborty et al. (2010); Saphiannikova et al. (2003)

Therapeutic molecules Corbitt et al. (2009); Rivera-Gil et al. (2009)


Polyelectrolyte capsules may also be used to facilitate ion-exchange and photocatalyticreactions, thus underlining their versatility. Shchukin et al. [2003] demonstrated the biomimeticsynthesis if calcium hydroxyapatite inside poly (allylamine)/poly(styrene sulfonate) capsulesby an ion-exchange process. Choi et al. (2005) went further and synthesized two types ofnanoparticles within the same capsules; their relative quantities could be controlled by thecopolymer ratio and the number of reaction cycles. Photocatalytic reactions inside polyelectrolytecapsules have been demonstrated for the preparation of TiO

2 nanoparticles [Shchukin et al.

2003]. In an interesting departure from conventional photocatalysis, Pan and coworkers (2009)prepared fiber photocatalysts of TiO

2 by electrospinning in combination with LbL technology;

the follow fibers of TiO2/ polyelectrolyte by electrospinning in combination with LbL technology;

the hollow fibers of TiO2/ polyelectrolyte had greater surface-to-volume ratio and higher catalytic

activity than conventional LbL films.

A new and growing area of application is the processing of bioactive molecules. Corbittand coworkers (2009) encapsulated Cobetia marina and Pseudomonas aeroginosa, separately,in microcapsules comprising alternating layers of oppositely charged poly (phenylene ethylene)-type conjugated polyelectrolytes. Strong antimicrobial activity was observed upon exposureto whit light irradiation. Rivera-Gil et al. (2009) also used multilayer polyelectrolyte capsulesbut filled them with a nonactive prodrug, a self-quenched fluorescence-labeled protein. Onuptake of the capsules by living cells, proteolytic fragmentation of the prodrug converted it toan active form. Such in vivo activation preserves drug activity and delivers the active drug onlyat the target sites.

The wide variety of applications of individual noninteracting microreactors and nanoreactors(which are summarized in Table 1) augers well for nanotechnology, but it also underscores thelimited knowledge we have for each kind of such reactor, thus making it sometimes difficult tochoose the most suitable configuration. This difficulty is exacerbated when stand-alonenanoreactors are embedded in microchannels, where transport processes become prominent.The latter problem is analyzed in the next section.

4. MICROREACTORS WITH FLOW AND REACTIONS

In many practical situations, the design and operation of microfluidic devices has to accommodateflow processes in addition to chemical or biological reactions. Flow in microchannels is usuallylaminar, and diffusion is the dominant mode of mixing [Hessel et al. 2004; Miyzaki & Maeda2006, Song et al. 2008]. However, sometimes more intense mixing than is possible by diffusionalone is desired; then additional micromixing devices are incorporated, and these are discussedlater.

The presence of mixing ipso facto implies that most practical designs of microreactorsinclude interactions between individual reactor elements (or so-called nanoreactors). Theseinteractions may be expected to alter the product patterns and reactor stability that would haveresulted in non-interacting reactors. While the effects of flow, micromixing and diffusion onlarge reactors have been analyzed in detail, this is still a recent area of micro fluidics.


There are broadly two kinds of microreactor devices: (a) chip-type microreactors and (b)2microcapillary devices. Chip-type microreactors offer easy control of fluid dynamics andintegration of many processes on one physical device. Microcapillaries form networks of flowchannels; this enables versatile control of flow and diffusion but it also makes it difficult tointegrate a network with other units on a single chip. Thus, both kinds of microreactors haveadvantages and limitations, which are discussed have.

4.1. Chip-Type Microreactors: Analytic Applications

Lab-on-clip microreactors are rapidly gaining popularity owing to their integrated architecturethat combines a number of microdevices into a functioning process. The architecture way betailored to specific needs. For solution-based chemistry, the networks of channels of themicroreactors are connected to a services of reservoirs containing chemical regents to form aminiature laboratory on a chip. For electrokinetically driven processes, electrodes are implantedin the appropriate reservoirs, and sequences of voltages are applied under automated computercontrol.

This background should suggest that chip-type microreactors rely on MEMS or BioMEMStechnologies for their fabrication and are ideally suited for analytical applications. There are avariety of such applications. Garcia-Egido et al. (2003) prepared and studied combinatoriallibraries of pyrazoles by means of a Knorr reaction of 1,3-dicarbonyl compounds with hydrazines.Of more direct use in analytical work are micro-total analysis systems (µ-TAS). For manyyears, µ-TAS has formed a dominant fraction of lab-on a-clip microreactor applications, rangingfrom direct analyses such as those of chemical components in enzyme-catalyzed reactions[Chandrasekaran & Packirisamy 2006] noninvasive on-line monitoring of chemical reactions[Mozharov et al. 2010] to more elaborate devices that combine microfluidic reactors with massspectrometry [Fidalgo et al. 2009] or a MALDI-TOF [Sim et al. 2006].

Owing to the high costs of the analytical equipment linked to microreactors, such macromicrocombinations make economic sense only for high-value applications. Most applications howperform to biological molecules, typical examples being in the areas of exploration of noveltherapeutic molecules [Dittrich & Manz 2006], synthesis of novel proteins [Yamamoto et al.2002], and investigation of drug-protein interactions [Lombardi & Dittrich 2011].

Lately the applications of lab-on-a-clip microfluidic devices have expanded beyond processanalysis to actual synthesis of nanomaterials. This is a promising development, particularlyfrom the perspective of combining manufacturing microdevices with analytical microdeviceson a single integrated chip. While this level of micro-integration is speculative at present, theapplications described below suggest that it may become feasible in the foreseeable future.

4.2. Chip-Type Microreactors: Process Applications

The applicability of lab-on-a-chip microreactors for the synthesis of nanomaterials adds anotherdimension to their usefulness. At the laboratory scale, drug discovery [Matsumura 2008], proteinsynthesis [Marre & Jensen 2010] and combinatorial chemistry [Garcia-Egido et al. 2003] havebeen aided by these reactors. Recent designs have used chip-type reactors with parallel reactantflows in a multi-level network that allows multi-step syntheses with a small footprint and theability to vary process parameters in a short time-scale [Hessel & Lowe 2010; Hessel et al. 2004].


A popular application for lab-on-a-chip microreactors is in the Paal-Knorr synthesis reactionsince it can generate products with a wide range of biological activities. The reaction essentiallycomprises the synthesis of substituted pyrroles by reacting an α-amino-ketone with a compoundcontaining a methylene group α- to a carbonyl group. Different authors have addressed differentaspects of the Knorr reaction. From a commercial point of view, fast scale-up from the laboratoryto a pilot or production plant is of primary interest, and this is facilitated by chip-typemicroreactors [Hessel et al. 2008; Nieuwland et al. 2011]. Not surprisingly therefore, industrialinterest has followed these observations. GlaxoSmithKline (GSK) reported the synthesis of a3 × 7 library using the Knorr reaction of different 1,3-dicarbonyl compounds and hyrazines topyrazoles [Garcia-Egido et al. 2003]. GSK also generated a 2 × 2 library for a domino reactiondescribed in detail elsewhere [Fernandez-Suarez et al. 2002].

Integrated lab-on-ca-chip microreactors have also been used in multi-phase catalysis, wherekinetic data analysis and modeling were performed for asymmetric syntheses. As an example,de Bellefon and coworkers (2000, 2002) monitored steric, solubility and electronic effects onreactivity for the isomerization of ally alcohol derivatives. Recently, Sato and coworkers (2009)described a high efficient chemoselective N-acylation of various amines and anilines by waterat both ambient and subcritical temperatures; their process achieved high yields and selectivity(> 95%) without using any catalyst.

An interesting variation in chip design was employed by Bula et al. (2007) to follow theprogress of parallel reactions. They investigated the kinetics of Knoevenagel condensationunder different reaction conditions in four parallel microchannels with different residence times.They used a special topology of the reaction coils to overcome the differences in pressure dropamong channels of different lengths, and chemical quenching at specific locations to createidentical conditions in all reaction coils.

The scale-up features of chip-type microreactors are interlinked with their ability to promoteprocess intensification. This applies to both liquid-phase and gas-phase reactions. Waterkampet al.’s (2007) study illustrates how a microreactor can overcome the weaknesses of aconventional macroreactor for the manufacture of ionic liquids. They intensified the productionof 1-butyl-3-methylimidazolium bromide by combining a microstructured mixer withmicrocapillary tubes. The design and the high surface-to-volume ratios allowed excellenttemperature control, resulting in product purity greater than 99% and more than twenty-foldincrease in space-time yield compared to a conventional batch process. Mills and associates(2008) simulated the gas phase oxidation of ammonia over a 0.1 µm Pt catalyst by using MEMSfabrication techniques to construct a computer chassis that mimicked a microreactor. Withclosed loop PID control at 200Hz, the degree of oxidation was more than an order of magnitudehigher than for a conventional fixed-bed reactor. Much of the theory, the continuing developmentsand earlier examples are described by Wang and Holladay (2005).

The combination of rapid scale-up and process intensification has obvious commercialimplications. Merck operated a production process involving an organometallic reaction, witha 20% increase in yield over its earlier batch process [Koummradt et al. 2000]. More recently,the Clariant Company published its work on the production of an azo pigment in a microreactorequipped with micromixers [Wille et al. 2004]. Owing to the improved mixing characteristics,pigments with superior brightness, color-fastness or transparency could be produced. Clariant


also established a pilot plant for the synthesis of phenyl boronic acid by a Grignard reaction[Hessel et al. 2004]; a microreactor.micromixer unit achieved a yield of about 90%, comparedto less than 65% in the best batch reactor.

4.3. Microcapillary Reactors

Microcapillary reactors consist of arrays of micro-tubes arranged in either twodimensional orthree-dimensional structures. The inter-meshing of the capillaries favors micromixing and thetopology of an array may be designed to achieve an optimum level of mixing that maximizesproduct yield or selectivity. Optimum mixing discussed in detail in a later section.

Although an array of micro-capillaries can be quite complex, most arrays are composed ofcertain basic types of capillary contacting arrangements. One basic configuration is the Y-typereactor channel; this is preferred for two immiscible liquids, such as water and an organicsolvent. Phase contract, diffusion-based dispersion and chemical/biochemical reaction occur atthe Y-junction. This simple design can generate surprisingly large interfacial areas and highconversions, sometimes close to 100% [Hisamoto et al. 2001]. An alternation to this is theT-type of contactor; here one liquid is injected as an sequence of pulses (segmented flow) intoa continuous stream of the other liquid. Thus, unlike the single interface of the Y-junction,there is a sequence of liquid-liquid interfaces travelling downstream; this improves interfacialtransport and thus reduces mass transfer limitations. Further improvement is possible by changingthe lipophilic properties of the non-polar liquid by adding quaternary ammonium salts orsurfactants so thatmicroemulsions are created [Landfester et al. 2000; Shchukin & Sokhurukov 2004].

T-type contractors are also usable for gas liquid microreactors. Either of two modes ofcontacting may be employed. In one mode, the two streams are fed cocurrently; however,while the gas flows continuously, the liquid inflow is pulsed, thereby generating a segmentedtwo phase stream beyond the T-junction. Alternately, the gas and liquid streams may befed counter-currently, again generating a segmented stream. In yet another configuration,Ganan-Calvo et al. [2001] supplied the gas continuously through a capillary tube to form alarge bubble near a small orifice through which a cocurrent stream of liquid is pumped in. Theremit is a train of uniform microbubbles originating at a constant frequency.

While the Y-type and T-type mixers form so.called fundamental building blocks, recentvariations in both design and stacking arrangement have generated very large specific interfacialareas (10,000-50,000 m2/m3, with consequent increases in product yield for many two.phaseorganic syntheses [Gokhale et al. 2005; Hornung et al. 2010; Kobayashi et al. 2006].

Gas liquid-solid microreactors are understandably more difficult to analyze, design andoptimize. Thus, although there are fewer applications than for liquid-liquid and gas.liquidsystems, they cover a wide spectrum of products and a variety of configurations. These reactors,as also two-phase microchannel reactors, have often relied on slug flow or annular flow inmonolithic reactors to achieve high conversions and high throughputs. The applicability androbustness of the new microchannel reactors under demanding conditions is illustrated byFischer-Tropsch synthesis. This involves a highly exothermic conversion of syngas to a rangeof hydrocarbons. Owing to the strong dependence of product distribution in temperature, eachproduct pattern requires maintaining a specific temperature; this is achieved more effectivelyby an array of microchannels than by a standard packed-bed reactor [Tonkovich et al . 2008].


Even though microcapillary reactors have been discussed separately here, they are oftenintegrated with other devices in lab-on-a-chip technologies. For instance, the stability of gasliquiddispersions in microchannels may be increased integrating mixing and reaction channels inone microdevice [Hessel & Lowe 2010; Roberge et al. 2008]. Sometimes, this method mayhave to be supplemented by other methods such as the additions of surfactants and glycerol(Doku et al. 2005; Li & Mann 2002; Niemann et al. 2008], and even by replacing the monolithicreactor by other types, e.g. falling film microchannel reactors [Venkalya et al. 2007]. Anotherdevelopment is the use of in-channel integrated micropipette tips, prior to the reaction chamber,for online gas introduction and generation of multiple. line microbubble streams within amicrochannel [Doku et al. 2003].

All configurations of microchannel reactors pose one significant scale-up problem whenmany tubes are employed to increase the throughput (“gnumbering-up”). The problem is toensure that all microtubes receive the same flow rates of all reactants. This problem becomeseven more difficult when there are many feed streams of different phases of fluids, e.g. gasliquidor gas.liquid-liquid. Two solutions have been recommended. One solution is to incorporatecapillary designs that promote internal mixing, and some commercially available devices havebeen shown to be effective micromixers [Lob et al. 2004; Werner et al. 2005]. An alternatesolution has been proposed by Sotowa and coworkers. They suggested the use of “deepmicrochannels.” Whereas a normal microchannel has a width of 100-1000 µm and a depthabout two orders of magnitude larger (i.e., aspect ratios ~100), a deep microchannel has thesame width but it is at least a few millimeters long. The larger depth results in a lower linearvelocity and hence a smaller pressure drop, and the very large aspect ratio enables excellentheat dissipation. Through simulations [Sotowa et al. 2009] and by experimental application tothe hydrolysis of o-nitrophenyl galactopyranoside [Sotowa et al. 2008], they showed theeffectiveness of their designs in achieving high throughputs and high conversions.

Ensuring uniform distribution of the reactants among all microchannels when numbering.upis used remains a problem in deep microchannel reactors. The maldistribution is sensitive tofabrication errors. Since high throughputs are essential for large.scale production, and fabricationerrors are unavoidable, Sotowa et al. [2008, 2011] recommended using a To-type mixer, bafflesand indentations to improve fluid mixing and flow distribution. The To-type mixer is effectivelya conjunction of two T-mixers.

5. MICROMIXING

Since the Reynolds numbers for flow through microcapillaries is ~1, laminar flow is commonlyobserved and mixing occurs largely by diffusion. While this has some advantages, sometimesmore intimate mixing is desired, as in multi-phase reaction systems or highly exothermic catalyticreactions. Then diffusive mixing has to be supplemented by other methods to increase thedegree of mixing.

A number of methods have been recommended to promote and control mixing inmicrocapillaries. While most methods are based on hydrodynamic features, Erickson and Li(2002) exploited the synergistic effects of the electrical double layer field and the surfaceheterogeneity in fluid flow through microchannels to derive conditions on the Reynolds numberthat determine the relative dominance of diffusion, convection and surface heterogeneity. Therebythey suggested strategies to maintain a specified degree of mixing.


A common mechanical method to improve micromixing is the use of microbeads. Drawingon the work of Seong and Crooks (2002), Srinivasan et al. (2010) investigated the bioconjugationefficiency of steptavidin-coupled paramagnetic microbeads and biotincoupled fluorescentmicrobeads in continuous flow micromixers operated at different flow rates. The bindingefficiency was measured by fluorescence emission spectra, which showed maxima at particularflow rates, implying that the most effective level of mixing was between complete mixing andcomplete segregation.

Garstecki et al. (2006) used gas bubbles in place of microbeads in a manner similar tofluidization. They incorporated a micromixer into a portable microfluidic system. The structureof the microchannels ensured mixing of the laminar streams by interaction with gas bubbles.Controlling the rate of gas flow provides a means of controlling the level of micromixing. LikeSrinivasan et al. (2010), Garstecki and coworkers also observed that an intermediate optimumlevel of mixing was the most efficient.

Yamaguchi et al.’s (2004) approach was to divide two inlet streams into 16 smaller streamseach and then merging them five times transversely. Confocal fluorescence microscopy andCFD simulations showed that 90% mixing could be achieved within 1 s after the streams hadbeen merged at a flow rate of 150 µl/min. Intermingling of liquid streams is also the underlyingphenomenon in the chaotic mixers utilized by some investigators. Stroock et al.’s (2002)micromixer used bas-relief structures on the floors of microchannels to disrupt laminar flowand introduce chaotic mixing. The length of the channel required for good mixing growslogarithmically with the Peclet number, and the channels are fabricated easily by planarlithography. Chaotic mixing was also employed recently by Moon et al. (2010) to design anenzymatic microreactor for continuous monitoring of glucose. They studied two kinds ofmicrochannels: (a) with slanted groves and (b) with herringbone groves. As in Yamaguchi etal.’s (2004) work, fluorescence spectra were used to determine the degree of mixing. glucoseconcentrations was determined by rapidly mixing glucose and glucose oxidase, and usingamperometric detection . Her too a moderate flow rate was found to elicit the best performance.

Channel geometry seems to have a significant effect on micromixing, as seen in the studiesdescribed above and in two other novel designs, Mengeaud et al. (2002) suggested a zigzagmicrochannel integrating a Y-shaped inlet port. Below a Reynolds number Re of .80, moleculardiffusion was the predominant cause of mixing, while laminar flow recirculations prevailed athigher values of Re. Fujiwara et al.’s (2007) microreactor combined Mengeaud et al.’s (2002)idea of an odd-shaped channel with Yamaguchi et al.’s (2004) technique of layered mixing ofstreams to propose an asterisk-shaped microchannel which had two inlets and two divergingmixing channels. The latter reduce the molecular diffusion time proportional to the square ofthe mixing length. Since the gap between the two inlets is small in an asterisk-shaped channel,a layered structure could be generated easily.

Like Erickson and Li’s (2002) electrokinetic method, Hung et al.’s (2006) solution to themixing problem also seems to be one of a kind. Through a unique design of microchannels,their device could alternately generate droplets in size ratios 1:5 to 5:1 and fuse them, enablingexact chemical reactions on a picoliter scale on a single chip. They demonstrated that theexclusive fusion of alternate droplets, in their design, with accompanying rapid mixing producesa supersaturated solution of Cd2+ and S2- ions to form CdS nanoparticles in each fused droplet.


A unifying theme of the studies discussed above is the flow of slugs of one fluid through acontinuous stream of another. This is also referred to as segmented flow, implying that segmentsof one fluid (liquid or gas) move sequentially through a continuous phase of another. This hasmany benefits: (i) the usability of strong acids and bases, (ii) more robust ability to handleprecipitates, (iii) flexibility of reaction scale-from micrograms to grams, (iv) tolerance of extremereaction conditions, and (v) ease of reaction automation. These benefits have been shownpractically for different systems and by different methods.

Oskooei and Sinton (2010) created segmented flow in a microchannel for a gas-liquid flowsystem through a design in which a wetted portion of a microchip that shifts downstream to apartially wetted channel that serves to disconnect the liquid plugs. This partial wetting strategyreduces plug-to-plug dispersion and achieves 60% narrowing of the residence time distributionsas compared to a conventional reactor. Similar benefits were observed for a tandem diazotation/fleck reaction [Ahmed et al. 2006] and for the hydrolysis of p-nitrophenyl acetate in toluenewith 0.5 M NaOH [Ahmed et al. 2008]. Jovanov et al. (2010) recently reported significantgains in phase-transfer catalysis for the selective alkylation of phenylacetonitrile in a microreactoroperated in the slug-flow regime. While an increase in the volumetric aqueous-to-organic phaseflow ratio from 1.0 to 6.1 increased the conversion from 40% to 99%, there was a fall inselectivity, again suggesting optimum flow rates of the two phases.

The high prices and difficult technologies of biological molecules makes them goodcandidates for microreactors, Jensen (2008) has reviewed many possible applications, such asvaccine development, mammalian cell cultures and integrated biochemical analyses. Kane etal. (2008) have described one application in detail. They developed a microfluidic mixer forrapid measurements of protein folding kinetics using synchrotron radiation circular dichroismspectroscopy. As in other studies discussed above, a special serpentine channel geometry wasused, Their results with cytochrome c showed the possibilities of following protein foldingkinetics and conformational changes by means of microfluidic devices.

These applications (summarized in Table 2) illustrate both the importance of controlledmicromixing and the variety of methods to achieve it. They also show that there is no uniqueway to obtain the best mixing for a given application, and a combination of engineering andingenuity often leads to the best solution.

Table 2Applications of Different Micromixing Strategies

Mixing strategy Application Reference

Microbeads Multi-step enzymatic reaction Srinivasan et al. (2010)Gas bubbles Unspecified Garsteki et al. (2006)Divide and mix streams Polymerization of amino acid NCA Yamaguchi et al. (2004)Chaotic mixing Continuous glucose monitoring Moon et al. (2010)Zigzag channel Different chemicals Mengenaud et al. (2002)Asterisk shaped channel Aqueous dyes Fujiwara et al. (2007)Electrokinetics Aqueous mixing simulations Erickson & Li (2002)Droplet fusion CdS nanoparticle synthesis Hung et al. (2006)Two-phase partial wetting Gas-liquid segmented flow Oskooei & Sinton (2010)Controlled slug flow Alkylation of phenylacetonitrile Jovanov et al. (2010)Serpentine channel Protein folding Kane et al. (2008)


6. MODELING OF MICROREACTORS

Considering the complexities of microemulsions, micelles, polyelectrolyte capsules and flowwith reactions in microcapillary networks, it is understandable that most models have had toincorporate simplifying assumptions or/and use non-analytic methods to solve realistic problems.The choice of assumptions and method of solution seem to depend on the problem, the objective,and possibly the inclination of the research workers. However, some systems have attractedgreater attention than others, and they are briefly discussed below. The examples also illustratethe different methods commonly used to solve microreactor problems.

6.1. Steam Reforming

In view of its industrial importance, the severity of operating conditions, especially temperature,and the complexity of the reactions involved, many authors have studied steam reforming as amodel system for microreactors. Even though the process has been known for many years, itsstudy in microreactors is relatively new. On this time scale, Fazeli and Behnam’s (2007) paperreflects one of the earlier studies. They applied a computational fluid dynamic (CFD) modelfor autothermal reforming of methane to produce hydrogen. A microreactor with a specialgeometry was considered and Langmuir-Hinshelwood kinetics were applied to the chemicalreactions. The model predicted hot spots near the inlets of the microchannel tubes, the eliminationof these spots by suitable air distribution, and consequent performance that exceeded the outputfrom a conventional reformer.

Xinhai et al. (2008) modeled steam reforming of methanol in place of methane. Theirattention was on the effects of two key parameters: (a) the thickness of the catalyst coatings,and (b) the size (diameter) of the microchannels. A thin coating of the reforming catalyst favoredlow CO concentrations in the exit gases, and good mass and heat transfer rates ensurednear-isothermal operation. An experimental setup based on the simulations generated 11Wpower very economically.

Work on the steam reforming of methanol has also been reported by Arzamendi andcoworkers (2009), again using CFD. They integrated the microreformer with the combustionof methanol in a catalytic microchannel reactor for in situ production of hydrogen for portablepower units. Simulations showed that the integrated system could achieve complete reformingand combustion at space velocities up to 50,000 h–1, with more than 99% selectivity for hydrogenat low temperatures of 270-2900C.

6.2. Exothermic Reactions: Iso-Octane Reforming and F-T Synthesis

Karakaya and Avci (2011) attacked a somewhat different, and possibly more complex, reformingproblem. They studied the steam reforming of iso-octane, a surrogate for gasoline, in parallelmicrochannels. As in Arzamendi et al.’s (2009) work with methanol, the heat required for theendothermic reforming reaction is provided by the catalytic combustion of methane, a compoundthat mimicked natural gas.

With a 2-dimensional unit cell model, Karakaya and Avci explored the effects of the thicknessof the wall between microchannels, the lengths of the channels and channel texture (straight-through vs. micro-baffled), as also different materials of construction. It was observed that a


four-fold increase in wall thickness enhanced the yield of hydrogen by 42%. The microchannellength had a more profound effect, doubling of the length increasing hydrogen yield by 110%.The use of micro-baffles had an effect comparable to that of the wall thickness. As in otherstudies, nearly constant temperature, without hot spots, could be maintained through the channellength.

It is of interest to recall here that the beneficial effect of deep microchannels and theintroduction of microbaffles complement the improved mixing and heat transfer reported bySotowa and coworkers (2011) for a similar design.

Another exothermic reaction where a microcapillary reactor has achieved better temperaturecontrol and conversion than in a standard fixed-bed reactor is the Fischer-Tropsch (F-T) synthesis.In a recent review, Guettel et al. (2008) have explained that conventional multi-tubular andbubble column reactors are inefficient for this strongly exothermic reaction. Hencemicrostructured reactors with high catalyst utilization and isothermal operation are increasinglybeing preferred. Gumslu and Avci (2011) therefore simulated the F-T reactions in a heat-exchanger integrated microchannel network. Similar to the observations of Karakaya and Avci(2011) and Sotowa et al. (2008, 2009, 2011) for the steam reforming of methanol, deep channels,micro-baffles and thicker walls promoted isothermality and higher conversion.

Temperature control being a prime requirement for exothermic reactions, Woehl et al. (2007)addressed this problem alone by employing artificial neural networks (ANNs) to model, designand control the operation of Corning’s microreactors. They claim that ANNs can achieve theseobjectives with greater felicity that CFD.

6.3. NOVEL APPLICATIONS

Some recent developments highlight the power and the versatility of microchannel reactors inbeing amenable to variations in architecture and applications that were possibly outside theiroriginal scope. One example of architectural variation is that of Fang and Yang (2008) for theredox reaction of ascorbic acid. To enhance micromixing and thereby speedup the reaction,they designed what they call a split-and-recombination (SNR) microreactor. This equipmentpossesses an in-plane dividing structure that promotes internal mixing similar to themicro-baffles used by Sotowa et al. (2011) and Karakaya and Avci (2011). Micromixing in theSNR design was more that 200% better than in the slanted-groove micromixer over a widerange of Reynolds members (0.1 < Re < 10). The superior mixing was reflected in a shorterreaction length for the redox reaction between ascorbic acid and iodine solutions.

In a noteworthy departure from conventional applications, Mehta and Lidermann (2006)modeled a perfusion micro-bioreactor for a tissue engineering application. Through a set ofdifferential equations characterizing the bioreactor environment and the concentrations ofcell-secreted soluble autocrine/paracrine growth factors in this environment, they showed thatconvective transport can significantly change the concentration distribution of the signalingmolecules as compared to static culture experiments. The unsteady state model revealed thatspatial gradients in nutrient/growth factor concentrations can lower the working volume of themicroreactor, and thereby reduce productivity. These observations emphasize the significanceof optimum mixing in microreactors employing living cells. The importance of microreactors


for tissue engineering is evident from two other publications, one for the cultivation of livercells (Domansky et al. 2005) and the other for cardiac tissue (Iyer 2008) Both these authorsemphasize the usefulness of artificially growth tissues for both diagnostic and therapeuticpurposes.

Tally et al. (2007) adopted another novel perspective of microreactors, born out of aconfluence of two recent areas of biological research. One area is the use of the principal of“gnatural selection” to sift through huge libraries of genes to select specific members that havecertain desirable properties, e.g. as triggers for the expression of particular disorders. The otherarea is the development of high throughput biochemical and genetic assays and screens byusing in miniaturized assay systems. Tally and coworkers employed microreactors asreaction-based assay systems for large-scale rapid screening of gene libraries. This novelapplication opens exciting possibilities in molecular engineering and drug discovery[Dittrich & Manz 2006].

Since many practically useful microdevices integrate microreactors with upstream anddownstream units, all on one microchip [Kessel et al. 2009; McMullen & Jensen 2010; Song etal. 2008], practically useful models have also analyzed such integrated systems. Owing to theircomplexity, the need to eliminate hot spots, and their industrial importance, catalytic rectorshave been the subject of a number of studies. Hari and Theodoropoulos (2004) constructedmulti-scale models of continuous flow microreactors with Pt catalytic walls as an alternative toconventional packed beds. The bulk (gas) phase was described by a reaction-diffusion modeland catalytic activity by kinetic Monte Carlo simulations. The multi-scale approach was validatedby comparing the results with mean.field computations, and the validated microchip ensemblewas shown to be superior to the packed-bed performance.

Vlachos et al. (2006) also employed a multi-scale approach, but their work had a widerscope than that of Hari and Theodoropoulos. They covered the design of experiments, catalystdesign and reactor optimization through a hierarchy of multi-scale models, and illustrated thepower of their approach with two examples: (a) ammonia decomposition on Ru catalyst toproduce hydrogen and (b) water-gas shift reaction on Pt to generate hydrogen from syngas.

The critical role of equidistribution of flow through all the microcapillaries in a multitubularmicroreactor has been emphasized by many workers [Commenge et al. 2002; Hessel et al.2008; Sotowa et al. 2008, 2009]. Saber et al. (2010) therefore investigated this problem forcatalytic reactions occurring at the coated walks of parallel microchannels. Their results supportprevious observations about ensuring equidistribution of flow rates, which is also shown toreduce the overall pressure drop in a network of microchannels.

The use of reverse micelles to synthesize quantum dots with narrow size distributions forthe making of semiconductors [Ingert & Pileni 2001; Pileni 2000; Quinlan et al. 2000;Shestopalov et al. 2004] has already be described above. This process has been modeled byVlachos and coworkers [Chatterjee et al. 2005; Snyder et al. 2005]. They have explained thateven though quantum dots have been synthesized experimentally, the stochastic nature ofdepositions and nucleation has not been well understood. So they used multi-scale stochasticsimulations to understand and model such self-organization processes.


Conclusions and Outlook

In recent years, microfluidics technology has emerged as a powerful and versatile technique toimprove a variety of chemical and biological processes. Both analyses and applications areincreasing so rapidly that any review can discuss only the significant studies within a definedobjective. To get an overview of the scope of microfluidics, and microreactors in particular,without repeating the references cited earlier here, we consider only the most recent applications.Organic syntheses [Kobayashi et al. 2006; Mason et al. 2011] such as heterocyclisations,fluorinations, nitrations, polymerizations, photochemical reactions, catalytic oxidations andreductions, and enzymatic reactions form a major fraction of these applications.

While chemical processes continue to contribute significantly, the most noteworthy emergingapplications are in the health care sector. McCalla and Tripathi (2011) have discussedmicroreactor applications for medical diagnostics. Tests for RNA, DNA and antigens, whichare markers for different diseases, rely on amplification of their low concentrations; microreactorsare ideally suited for this since they use small volumes, consume low energy, and themicrocapillary architecture can be designed to make it sensitive to a particular marker. Thissensitivity and the low costs have led to the commercial development of proteomic analysisplatforms and biosensors [Yeo et al. 2011]. Biosensor applications of microreactors offerimmense benefits for point-of-care analyses of nucleic acids and proteins, but they also posemany technological challenges [Choi et al. 2011].

Besides biosensors, microfluidic devices have entered another traditional biological area-- chemotaxis. While classical methods have revealed many aspects of bacterial chemotaxis,much still remains to be understood. Recent microfluidic studies have provided new insightsinto chemotactic response to conflicting gradients and the large-scale consequences ofchemotaxis, e.g. in fields and oceans [ Ahmed et al. 2010]. These advantages may be translatedinto new microdevices that help in the analysis and manipulation of cell signaling mechanisms,as in cancer metastasis [Ngalim et al. 2010].

Another emerging medical area that has benefited from microfluidic technology is stemcell biology. Conventional techniques for stem cell experiments replicate physiologicalconditions poorly, have imprecise spatial and temporal control, and lack scalability andreproducibility. These weaknesses are greatly mitigated in lab-on-a-chip devices, that allowlarge scale observations of stem cell phenotypes under close-to-physiological conditions, andhigh-throughput screening of cellular responses to a combination of stimuli [Gupta et al. 2010].The potential of microfluidic methods for cancer and stem cell therapies has already led to thepossibility, even at an early stage, of using these technologies to regulate the microenvironmentaround diseased cells so as to design optimum treatment regimens for stem cell therapy to treatcancer patients [Park et al. 2010].

The use of perfusion bioreactors for tissue engineering applications has already been alludedto. Mehta and Lindermann’s (2006) work showed that spatial variations in the concentrationsof nutrients and growth factors can dramatically affect co-cultured cell populations. A broadimplication is that culture conditions in microreactors for tissue growth have to be much morecarefully controlled than in static cultures but yield much better results.


For a feasible micro-chemical or micro-biological process, a microreactor often has to beintegrated with other microdevices on a single chip. These lab-on-a-chip units offer the strongestpossibility for commercial microfluidic processes. Many current studies have thereforeconcentrated on integrated microchips for chemical processes such as the steam reforming ofmethanol [Arzamendi et al. 2009], the oxidation of CO to CO

2 [Hari & Theodoropoulos 2004]

and the synthesis of iron oxide [Marre et al. 2010], analytical applications using Raman[Mozharov et al. 2010] and mass [Fidalgo et al. 2009] spectrometry, and the biologicalapplications described above.

The benefits of integrated microdevices are also moderated by their limitations and theimprovements needed. One fundamental limitation was addressed by Thorsen et al. (2002).This pertains to microfluidic multiplexing, which is the ability to control flow through a largenumber (F) of flow channels by using only a small member (C) of control channels. Thorsenand coworkers solved the problem by analogy with multiplexing in electronic networks; itturns out that C = 2log

2F, so the larger the network of flow channels the greater is the reduction

in C relative to F.

The benefits already seen and the potential for further applications have been translatedinto both commercial products and patents. A recent survey [Hessel et al. 2008] has found thatthe number of patents granted for microreactors per year rose from zero in 1991 to about 350 in2005 and then declined. The decline does not indicate a fall in interest but rather a shift ofemphasis from microdevices to microprocesses; this inference is supported by the steady risein the member of patents for integrated lab-on-a-chip devices, which now account for the largestfraction (4/10) of microprocess patents. There has also been a steady flow of microfluidicproducts into the market. These include Dolomite’s (2010) droplet-generating multi-layereddevices, Microfluidics’ (2010) integrated chips, Sigma-Aldrich’s (2010) microreactor for finechemicals, Novo Nordisk’s micro-bioreactor for cell culture optimization [Smith 20007],Velocys’ (2008) microreactors for process intensification, and Merck’s and Clariant Company’smicro-mixers that ran at ambient temperature chemical process that has earlier been operatedunder cryogenic conditions [Hessel et al. 2006].

The burgeoning research and technologies for a variety of microfluidic devices has inevitablyled to some implausible and conflicting claims. Unfortunately, methods to resolve thesecontradictions are themselves sometimes at variance with one another. Trost’s (2002) conceptof atom economy is one of the simplest ways to compare reaction efficiencies. Subsequently,the original atom economy concept was modified to account for stoichiometric excess, solventusage, catalyst recycling and purification steps. While making the metric more effective andmeaningful, the modified measures also suffer from mutual conflict, redundancy andincompleteness [Andraos 2005a, 2005b]. Thus, while microfluidic technology holds considerablepromise for new devices, products and processes, many important and complex issues have tobe addressed and number of grey areas need to be clarified.


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IJCE - · PDF fileGiven this upsurge of interest and the market forecast, ... (BioMEMS) has increased greatly the scope and value of microfluidic devices by making them