Current Opinion in Colloid & Interface Science xxx (2015) xxx–xxx

COCIS-00980; No of Pages 10

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Current Opinion in Colloid & Interface Science

j ourna l homepage: www.e lsev ie r .com/ locate /coc is

Active colloids: Progress and challenges towards realisingautonomous applications

S.J. Ebbens 1

Department of Chemical and Biological Engineering, University of Sheffield, Sheffield, UK

E-mail address: s.ebbens@sheffield.ac.uk.1 Tel.: +44 114 2227589; fax: +44 114 2227501.

http://dx.doi.org/10.1016/j.cocis.2015.10.0031359-0294/© 2015 The Author. Published by Elsevier Ltd.

Please cite this article as: Ebbens SJ, Active coface Sci (2015), http://dx.doi.org/10.1016/j.c

a b s t r a c t

a r t i c l e i n f o

Article history:Received 31 July 2015Received in revised form 29 September 2015Accepted 8 October 2015Available online xxxx

Keyword:Active colloids

Active colloids are small scale materials capable of producing enhanced motion within fluid environments.The field of active colloids has grown rapidly over the last ten years and is approaching maturity where viableapplications arewithin reach. In this review, recent advances are surveyedwith a strong emphasis on developmentsthat can enable autonomous applications, where colloids execute useful tasks without external interventions. Theseapplications are likely to prove transformative as the resulting technologies will be significantly less complex thancurrent methods. A survey of the requirements to achieve autonomous applications is provided, consideringguidance, solution compatibilities, manufacture and function; with reference to recent developments in thesecapacities. Following on from this, progress towards applications in environmental remediation, lab-on-a-chipmicrofluidics and in vivo drug delivery is highlighted.

© 2015 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

1.1. Background

Generating and controlling autonomous motion within a fluidenvironment is an essential component for many proposed nanometreandmicron-scale technologies.While some ability to transportmaterialswithin a fluid environment is provided by Brownian diffusion andosmotic effects, in many cases these phenomena do not display therequired speed or directionality. Fluidic transport problems are alsofaced in nature, as evidenced by the complex structures that haveevolved to augment passive diffusion. For example, protein motors areused to transport attached cargo along microtubule tracks within cells[1], achieving directed motion at scales where trajectories are otherwiserapidly randomised by Brownian effects. In addition there are manyexamples of larger, micron sized cells, such as spermatozoa, Escherichiacoli and algae, that can produce enhancedmotion by “swimming”withinfluids. These cells can also navigate based on well documented sensingmechanisms such as chemotaxis [2] and gravitaxis [3]. Partially inspiredby these natural examples, and motivated by the burgeoning need totransport and organise material at small scales in order to realise newapplications, attention has increasingly focused on producing syntheticdevices capable of similar autonomous motion behaviour.

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lloids: Progress and challengeocis.2015.10.003

Two strands in the development of autonomously moving syntheticdevices can be followed. At first it seemed that mimicking thedeformation based swimming of the motile cells mentioned above is apromising strategy. Thismotivated the development of colloidal assem-blies that could be manipulated to produce motion, that can be tracedfrom a famous early examplewhere a chain ofmagnetic beads executedspermatozoa like deformations [4], through simpler realisationsinvolving fewer components [5]. However, so far the limitationsimposed by low Reynolds number, requiring that deformationsequences are non-time-reversible [6], have necessitated the appli-cation of external actuating fields, such as magnetic fields or light,in order to generate synthetic motion from deformations. Whilethese actuated colloidal devices are of significant fundamental interest,applying external field gradients to individual magnetic colloids alsoallows them to be efficiently transported, rotated, and manipulated[7], and so the unique benefits for using more complex deformationswimming to enable applications are hard to isolate. In this context, asecond approach, which is less obviously, if at all, utilised in nature;based on the ability of chemically active colloids to modify their localenvironment, has proven to meet the requirement of autonomy. Anearly example for this concept, to produce motion by chemical activity,was reported by Whitesides, where asymmetrically distributedplatinum catalyst allowed a centimetre scale device to autonomouslymove along a meniscus by generating a surface tension gradient whiledecomposing hydrogen peroxide fuel [8]. The general concept of anasymmetrically distributed reaction generatingmotion has subsequentlybeen elaborated upon andminiaturised to lead to the development of the

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range of materials termed active colloids which are discussed here.Active colloids are so named to distinguish them from conventionalpassive colloids which exhibit purely Brownian transport behaviour.

1.2. Autonomous active colloids

The range of strategies by which surface reactions can producemotion has been the subject of several comprehensive reviews whichthe reader is directed towards, for example those by Kapral [9] andSen [10]. As a broad classification, active colloids can be groupedaccording to geometry, and propulsion mechanism, however it isworth bearing in mind that for some examples the mechanism hasbeen the subject of debate, and it is also possible that multiple mech-anisms contribute to the observed motion. The earliest examples ofsmall scale chemically active colloids were bi-metallic nanorods,Fig. 1a [11]. These rods produce enhanced motion by catalyticallydecomposing hydrogen peroxide fuel via an electrophoreticmechanism[12]. Many studies have reported a range of phenomena for thesedevices, including correlations between rod composition and motionvelocity [13], the effect of solution properties on speed, and collectivebehaviour [14]. A further much studied category of active colloids,first postulated theoretically [15], are spherical Janus swimmers,Fig. 1b [16]. A common example of these devices is made by coating

Fig. 1. Active colloids. (a) Schematic for a bi-metallic nanorod [12]. (b) Schematic for aspherical Janus active colloid. (c) Still frames from a video for a moving bubble producingspherical Janus active colloid [26]. (d) Schematic and still frames from a video for amovingbubble producing tubular active colloid [27•].

Please cite this article as: Ebbens SJ, Active colloids: Progress and challengeface Sci (2015), http://dx.doi.org/10.1016/j.cocis.2015.10.003

one hemisphere of a conventional colloid with a catalytic material,for example a platinum hemisphere decomposing dissolved hydrogenperoxide fuel. Janus colloids were initially thought to produce motionby pure self-diffusiophoresis, however recently experiments havesuggested that an electrokinetic mechanism [17], related to thatproposed for nanorods, may dominate. Again, extensive experimentshave reported motion production across a range of colloidal sizes [18•,19], for different materials [20], and investigated phenomena such asself-assembly [21]. For all reported bimetallic nanorod experiments,and the smaller sized examples for active Janus colloids, motion isproduced without detectable bubble nucleation and release occurringat the colloid surface, despite the chemical reactions often producing agaseous product. However, as devices get larger and less curved, theenergetic penalty associated with bubble nucleation reduces [22], andexamples of bubble propulsion, where motion clearly results frommomentum transfer due to bubbles growing and detaching fromthe active surface are seen. Some examples of bubble swimmersinclude larger, more reactive spherical Janus colloids, Fig. 1c, madefor example by partially masking an inner chemically active colloidwith an inert overlayer [23]. In contrast to the smaller non-bubblingspherical colloids it has also been found that asymmetrical chemicalactivity is not a requirement to produce motion: uniformly chemicallyactive colloids can also produce bubble propulsion [24,23]. The finalmuch studied active colloid examples are rolled-up nanotubes [25],also termednano-rockets, Fig. 1d. This swimmer type contains chemicallyactive material localised inside a tubular structure, which generatesbubbles that are expelled from one of the two open ends of the tube,resulting in rapid motion.

Despite this apparent diversity, all these active colloids possess thesalient feature of producing motion powered solely by dissolved fueland so offer the potential to be exploited for autonomous small scaletransport applications.

1.3. Scope of review: emphasis on autonomy

This review focuses on advances made in the last three yearsthat have the potential to contribute to the development of autonomousapplications for active colloids. The remit of this review is consequentlyfocused on active colloids that are not reliant on the application of exter-nal directing fields in order to perform a given task. This focus reflectsthe authors' viewpoint that any application that requires significantexternal control does not fully exploit the autonomous, unactuatedmotion capability that motivates interest in active colloids [28]. Due tothis, the emerging class of active colloids that have a propulsion mech-anism requiring external actuation are not discussed. These includeexamples such as thermophoretic devices [29] which are locally heatedwith a laser beam, and other examples based onde-mixing [30], electro-phoresis [31], and ultrasonic agitation [32]. In addition, the review willendeavour to clearly indicate when tasks have to date only be achieved,by a “hybrid” approach: where an intrinsically autonomous motionproducing device is steered or otherwise actuated by an external field[33]. While externally driven and controlled active colloids can enableapplications, these are likely to be via relatively complex technologiesrequiring significant additional control and monitoring infrastructure.In contrast, by perusing the goal to retain autonomy in active colloiddevelopments, simpler applications may be realised, and this is thestrong focus of this perspective.

In this context, initially a “wish-list” for the functionality that willbe required to produce fully autonomous applications is outlined.These features are compared with the currently reported behaviourfor existing devices. Particular emphasis is placed on recognising thatat present, as outlined above, there are a range of demonstrated activecolloid propulsion mechanisms, each having relative advantages anddisadvantages. Reviewing the state of the field without recognisingthis diversity has the danger of understating the challenges that mustbe met in order to implement a viable new technology based on active

s towards realising autonomous applications, Curr Opin Colloid Inter-

Fig. 2. Gravitaxis behaviour in active colloids. (a) 3D trajectory for a catalytic active Janussphere (see Fig. 1b) moving in free solution show an upwards bias [36••]. (b) Schematicshowing an L-shaped light driven colloid on an inclined plane. (c) (1): control experimentshowing sedimentation (2–6) as light intensity is increased an upwards bias in trajectoriesis seen (2–4), while at very high illuminations complex spiralling is observed (5,6) [37].

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colloids. Having assessed the general prognosis for applications, recentdemonstrations for active colloid utility in three application areas:environmental remediation, lab-on-a-chip transport, and in vivodrug delivery and repair are discussed and the remaining challengesto develop these concepts into working technologies are highlighted.

2. Functional requirements for autonomous activecolloid applications

This section describes the toolkit of features that will be required torealise autonomous applications for active colloids. The salient featuresof direction control, solution compatibility, ease of manufacture andability to performuseful functions are all discussed in turnwith referenceto recent developments.

2.1. Direction control

For most autonomous active colloids, Brownian randomisation ofposition and orientation results in trajectories that become randomisedover relatively short time periods. Considering the examples introducedabove in turn: non-bubbling spherical Janus swimmers trajectories havebeen reported to become diffusive due to Brownian rotations over atime period of 10 s of seconds [16]. Nanorods and nanotubes showgreater persistence of motion, due to asymmetric drag forces, but areeventually randomised, and for spherical bubble swimmers the chaoticnature of the bubble release process also leads to highly randomisedtrajectories [24]. While this random enhanced motion can be exploitedfor some applications; for example speeding up capture or neutralisationof an evenly distributed cargo/contaminant, it is likely that many usefulapplicationswill require the direction of motion to be further controlled.For example, having gathered a cargo, this may need to be transportedtowards a specific location. The importance of imparting directionalityis further evident when considering lab-on-a-chip systems wherepumps and valves, or other actuated fluid manipulation methods, arecurrently required to enable sequential operations. In order for activecolloids to provide a viable flow free alternative, the ability to controltransit though a device will be required. Developing methods to inducethis directionality to the motion of active colloids has consequentlybeen the focus of recent experimental attention.

An obvious way to impart directionality to asymmetric activecolloids with a well-defined link between their orientation and propul-sion direction, is to generate a constraining torque with sufficient energyto prevent Brownian rotation. This can be achieved relatively trivially byincorporating amagnetic component into the device, and then externallyapplying a sufficiently strong magnetic field [34,35]. However this isclearly not an autonomous approach. Alternatively, two recent studieshave shown that a constraining torque can also be generated by the inter-action of active colloids with the Earths' gravitational field. The first studyconsidered catalytic spherical Janus swimmers. As these active colloidsare made by coating one side of a colloid with a dense metal (Platinum),they possess considerable mass asymmetry. Depending on the size of thecolloid and the thickness of the deposited metal, this mass asymmetryresults in a propensity for the heavy catalytically active hemisphere topoint downwards. Because the propulsion vector for these swimmers isorientated away from the platinum cap (Fig. 1b), this results in autono-mous upwardsmotion: termed positive gravitaxis, Fig. 2a [36••]. A similarmechanism is also used by bottom heavy algae to navigate aquaticenvironments. In a second study, shape-anisotropy was found to alsoresult in autonomous gravitaxis, Fig. 2b + c. In this latter example thepropulsion mechanism relied on laser illumination, but extending thisfinding to chemically powered devices should be straightforward. [37]The utility of gravitaxis is clear, as it provides a mechanism to break theotherwise isotropic motion for active colloids and impart a well-definedand controllable propulsion direction without the need to apply control-ling fields. These findings could be exploited to rapidly concentratecolloids from a 3D volume to a 2D interface, and also open the potential

Please cite this article as: Ebbens SJ, Active colloids: Progress and challengeface Sci (2015), http://dx.doi.org/10.1016/j.cocis.2015.10.003

to execute serial processes by designing suitable vertically arrangedchambers, or inclined surfaces. Furthermore, the degree of gravitaxiscan be potentially be altered by cargo attachment, fuel concentrationand other solution properties allowing dynamic responses in the naviga-tion behaviour and enable sensing capabilities.

An alternative emerging route to overcome the randomisation ofactive colloid trajectories is to exploit interactions with physicalstructures. Self-motile cells have been observed to display a rangeof interactions with surfaces, resulting in them accumulating at planarinterfaces [38], and when exposed to more sophisticated patterning,rectification and sorting according to motion characteristics has beenreported [39]. In a similar fashion, the interactions between activecolloids and patterned surfaces have recently been considered. In twoindependent studies, bimetallic nanorods [40••] and Janus spheres [41]have displayed circling behaviour around the base of the colloidalobstacles, Fig. 3a. These trajectory modifications were explained bysteric and hydrodynamic interactions. Heart shaped structures havealso been demonstrated to autonomously localise nanotube swimmersat sharp cusps due to steric effects, Fig. 3b [42••]. Taken together, thesedevelopments suggest the potential to develop a new type of smallscale fluid transport where active colloids are autonomously guidedallowing the development of new applications that require predictabletransit of material through a fluidic environment without the need forflows or other external control.

An additional strategy for achieving autonomous directional controlfor active colloids is inspired by the ability of self-motile organisms suchas E. coli to display chemotaxis i.e. navigate in response to solution com-position gradients [2]. To achieve this function, E. coli rely on temporallysensing local levels of the target chemical and then adjusting theirflagella to execute running and tumbling trajectories. While such com-plex sensing and response is not possible for current active colloids,there are several examples of active colloids accumulating in responseto a gradient in the fuel molecules that drive their motion. The first

s towards realising autonomous applications, Curr Opin Colloid Inter-

Fig. 3. Physical guidance for active colloids. (a) Bimetallic nanorods orbit larger sphericalcolloids [40••]. (b) Nanotube swimmers progressively autonomously accumulate at theapex of a heart shaped cell [42].

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example of chemotaxis for active colloids was reported for bimetallicnanorods by the Sen group in 2007 [14]. However, more recentlychemotaxis was investigated in more detail by establishing welldefined fuel gradients using a microfluidic channel. In this study itwas found that both Janus active colloids and tubular bubble swimmersshowed a tendency to move towards higher fuel concentration regions[43]. Similar to the original nanorod report, so called “match-stick”shaped swimmers were also observed to move towards higher fuelregions [44]. Interestingly, these experiments are in disagreementwith predictions for the direction of chemotaxis made by simulations[45], and the exactmechanism for these phenomena is unclear (readersare directed towards the review by Golestanian [46] for a description ofpossible scenarios). The benefit to applications for this approach is thepotential for active colloids to autonomously follow signals, to allowdelivery of cargo in a particular region or accumulate to perform aspecific task. To achieve this it is desirable to expand the range of che-motaxis inducing signals. Solution properties including conductivity[47] and certain small molecules [48] are known to modulate propul-sion velocity, and so should also allow a chemotaxis response. Indeed,one very recent report has demonstrated that metal organic framework

Please cite this article as: Ebbens SJ, Active colloids: Progress and challengeface Sci (2015), http://dx.doi.org/10.1016/j.cocis.2015.10.003

swimmers powered by peptide assembly can be autonomously directedtowards a target based on the interaction of the propulsionmechanismswith local pH gradients [49••]. In addition, size changes in a responsivematerial incorporatedwithin the active colloid have also been proposedto allow chemotaxis within a uniform fuel concentration solution [45].

2.2. Solution compatibilities

Another key requirement for using active colloids to enable futureapplications is that they can produce autonomous motion within awide range of solution compositions. However, a restriction for manycurrent active colloids is the requirement for a dissolved fuel source.The most common fuel for active colloids is hydrogen peroxide, oftencatalytically decomposed by platinum.While this combination providesan experimentally convenient room temperature catalytic reaction, theapplicability for real world applications is limited due to the potentialfor the highly chemically active fuel molecules to be incompatiblewith other material contained within the solution in which active col-loids are to be deployed. An example is human blood; which containscatalase, the biological enzymatic equivalent of platinum, whichwould also compete to decompose hydrogen peroxide fuel. In addition,the evolution of oxygen gas, a by-product of the hydrogen peroxide de-composition, is undesirable, as at high active colloid volume fractionsconvection inducing gas bubbles are inevitably produced which wouldhamper the directional control approaches described above. Fuel deple-tion also limits the duration of active colloid propulsion at high activecolloid densities.

One approach to overcome these problems is to use different cata-lyst and fuel combinations. For example, a significant improvement inefficiency, which potentially ameliorates fuel depletion and bubbleformation issues was recently demonstrated for active silica Januscolloids using an Iridium catalyst to decompose hydrazine [50]. Ratherthan the 1–10% fuel contents required for the Pt–H2O2 system,enhanced motion was observed for N2H4 at 0.0000001% fuel. However,it is more desirable to remove the need to add fuel, and instead producemotion driven by the solution in which the active colloids are to bedeployed. Examples of this type of active colloid are starting to appear,for example a manganese based Janus swimmer will produce enhancedhydrogen bubble propelled-motion within sea water, due to the transi-tion metals' corrosion properties in the presence of high chloride ionconcentrations [51•]. However, in common with many bubble propul-sion examples, this demonstration still required the addition of a surfac-tant to the swimming solution, and in contrast to the Pt and Ir examplesthe driving reaction is no longer catalytic, so the reacting part of thecolloid is consumed, limiting the motion producing period to just overa minute.

Another solution compatibility issue faced by some active colloidalsystems is that the propulsion mechanism is quenched by the additionof small levels of dissolved salt. A reduction in propulsion velocitywith solution ionic strength was reported at the early stage of develop-ment for bimetallic nano-rod swimmers, and a similar limitation hasrecently been found for single metal Janus active colloids [47,17]. Thisreduction in propulsion velocity does not correspond solely to a reduc-tion in themotion producing reaction rate, but instead reflects a relianceof the propulsion mechanisms on self-generated ionic flows. In thecontext of current understanding of propulsion mechanisms for singlemetal Janus colloids this observation has led to the conclusion that amajor component of propulsion velocity is generated by an electro-kinetic mechanism [17], as opposed to the originally suggestedself-diffusiophoresis [52]. Bubble propulsive swimmers do not sufferfrom the same general limitation, as bubble release is not stronglyhindered by increased ionic strength, although this device type arestill subject to a variety of other solution compatibility issues [53].

It is clear that despite a variety of approaches to improving thesolution compatibility for active colloids, at present a number of obstaclesto a widely deployable active colloidal system still exist: electrokinetic

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swimmers require low salt concentrations, bubble propulsion often re-quires surfactants and recent fuel-free alternatives require materials tobe consumed in order to generate motion.

2.3. Manufacture

While research into active colloids is currently at the lab-scale, torealise applications it is important that some attention is devoted tothe cost and scalability of production. Few of the common lab basedmethods to produce the active colloids used in research programmesare currently either financially viable or scalable, as they often requireboth access to expensive instrumentation and expensivemetal catalystsand result in very small batches of colloids. Much of the cost associatedwith manufacturing active colloids is the effort required to generatethe asymmetry needed to produce propulsion. For example, bimetallicnano-rod manufacture requires an expensive porous template, and amultistage electrochemical process, while producing Janus structuresmost often exploits the directionality of thermal metal evaporation,performed using expensive high vacuum apparatus. While nanotubebubble swimmers do not require a Janus structure, localising catalystwithin the interior of a nanotubular structure remains challenging toscale up. However, bubble propulsion can also result from symmetricalactivity at the outer surface of colloidal bodies. One recent example usedthis to manufacture a bubble swimmer using a solution based processwhere the platinum catalyst self-assembled onto a polymer lamellabody [54]. Despite being easier to make, the drawback with thesesymmetrical bubbling devices is that their trajectories are chaotic, andthey exhibit short persistence lengths, making them hard to harnessfor autonomous directed transport. [24] An extension then, is to developsolution based methods to not only produce chemical activity, but alsoto impart the asymmetry which leads to directional motion. Oneapproach to achieve this is to exploit Pickering emulsions, where awax like material is mixed with colloids, resulting in a suspension oflargerwax particles intowhich the smaller colloids are partially embed-ded. This allows solution chemistry to be carried out selectively on theexposed surface of the colloids, providing a simple and scalable routeto asymmetrically chemically active structures. Despite the potentialfor this method, it has to date only been used in one prominent exam-ple, where selective amination of one side of the active colloid enableddecoration with the enzyme catalase, resulting in bubble propulsionvia decomposition of hydrogen peroxide [55•]. Considering materialcosts, recognition of the potential to source readily available enzymesto power active colloid motion was highlighted in a study thatdemonstrated that sufficient catalase was contained in various unpro-cessed plant materials to produce bubble propulsion, which could befurther directionally controlled by applying an impermeable mask toone side [56•].

2.4. Function

The final key requirement for active colloids is that in additionto being able to autonomously produce motion and be appropriatelydirected, they must possess the capacity to perform a useful function.Most visions for the future applications for active colloids have focusedon transport, and so the ability to attach cargo, ranging from smallmolecules to micron sized components, at the surface of active colloidshas achieved considerable attention. The promising aspects of thesereports is the demonstration that active colloids of all major types(rods, tubes and Janus spheres) are compatiblewith additional chemicalfunctionalization stages required to attach cargo. A particularly impor-tant older autonomous example is the demonstration of dynamic selec-tive protein loading onto a bubble propulsive nanotube [57••]. However,frequently these transport demonstrations have been at the expense ofautonomy, with cargo release requiring external actuation [58], andcargo loading being performed as a separate stage before directedtransport commenced. Illustratively, a recent example for cargo

Please cite this article as: Ebbens SJ, Active colloids: Progress and challengeface Sci (2015), http://dx.doi.org/10.1016/j.cocis.2015.10.003

transport function from the Sanchez group, shows the potential toexploit the porosity of silica Janus colloids. In separate stages,this work showed small molecules could be diffusively loaded intoexposed pores, that active colloid transport could be used in conjunctionwith physical guidance to concentrate the colloids at an enhanced rate ina well-defined location, and that sustained release from the poreswas also possible [18•]. While clearly showing future potential, accom-plishing the loading and release phases autonomously in synergy withactive transport was not possible. Incorporating responsive materialsto gate release behaviour from the pore was consequently suggested asa future extension to address this issue. In addition to transport,some researchers have demonstrated more easily obtainable func-tions that rely simply on existing features of active colloids, an exam-ple being the demonstration that bubble propulsive nanotubesenhance mixing rates considerably due to a combination of bubblegeneration and enhanced motion [59•]. Other autonomous functionsinclude the very recent development of catalyst powered spiralshaped devices that can potentially drill into soft materials [60].

3. Current application areas

The remainder of the review further illustrates the extent to whichthe existing active colloids meet the challenge of demonstrating auton-omous applications in three different areas, each requiring a differentcombination of the attributes discussed above.

3.1. Environmental applications

Each application area for active colloids will require differingfeatures from the existing toolkit of demonstrated capabilities to beused in order to realise a new autonomous technology. One areathat has been attracting recent attention is environmental remediation.The concept is that active colloids can perform a function such asneutralisation of a harmful agent, taking advantage of enhancedmotionto result inmore frequent contactwith the contaminants. For this appli-cation, less demand is placed on the ability to direct active colloidstowards a target, as it is viable to deploy them specifically at the siteof contamination, which will often be locally homogenously dispersed.However, the ability to produce fuel free motion is likely to be key, asthe idea of releasing an additional chemical fuel into a contaminatedenvironment is unlikely to be palatable. Two examples from the Wanggroup have used fuel-free bubble propulsive motors to demonstrateremediation functionality. One example combines the ability ofmanganese colloids to produce motion in seawater discussedabove, with a functional photocatalytic layer of titanium dioxidecapable of decomposing an anthrax mimic contaminant along withother chemical warfare agents. This study illustrated that theenhanced motion improved solution mixing as well as self-cleaningthe functional surface, allowing a much increased rate of decontam-ination, Fig. 4i [61••]. A second example using a similar motor particleshowed that adding a hydrophobic coating enabled the function ofoil droplet collection, Fig. 4ii [51•]. This study usedmagnetic steering,however this does not appear to be crucial in order to perform the oilcollection function. In both cases, while the active colloidmotionwasfuel free within chlorine rich aquatic solutions, a surfactant additivewas required to instigate motion. This limitation does not howeverappear to be universal for all bubble propulsion, for example platinumbased bubble swimmers decomposing hydrogen peroxide can producemotion without any additives [23]. Potentially engineering the surfaceroughness in these systems to increase the local gas evolution rate canovercome the need to add surfactant and realise truly autonomousdemonstration of an environmental clean-up task. Environmentallyrelevant functions have also been demonstrated for nanotube activecolloids, for example using Fenton oxidation to degrade organiccontaminants, however these colloids did require added fuel tofunction [62].

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Fig. 4. Remediation by active colloids. (i) Schematic: a titanium dioxide (grey) coatedmanganese core (yellow) particle produces hydrogen bubbles at an uncoated pore,resulting in fuel free bubble propulsion. The functional titanium layer decomposes anthraxspores when exposed to UV light. Graph shows the autonomous remediation functionefficiency for (a) the situation where colloids are illuminated and producing propulsionand (b) no light (c) moving motors without a functional layer (d) UV light alone(e) staticmotorswith UV light [61••]. (ii) A: Schematic of oil droplet collection by an activecolloid, again a manganese core (grey) produces fuel free motion while a gold surfaceunctionalisedwith an alkane thiol gathers oil droplets B: still frames from videomicroscopyshowing thatmagnetic guidance is used to direct the colloid towards oil droplets, which arethen captured and transported [51•].

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3.2. Lab-on-a-chip applications

Lab-on-a-chip devices have the potential to allow small volumes ofsolution to undergo complex analytical processes at the point of care,enabling rapid diagnosis for medical conditions and reactive responsesto environmental contaminations. However, to execute multistageanalysis procedures it is currently necessary to control the motion ofthe fluid sample through miniature tubing, leading to increasedcomplexity and external power requirements. The goal for active colloidmotors within a lab-on-a-chip device is to instead enable separation,transport and concentration of analytes within flow free miniaturisedfluid networks, a strategy often referred to as static microfluidics.Removing the need to generate and create flows at small scales hasthe potential to considerably simplify lab-on-a-chip devices and sowiden their deployment, however only if active colloid transportcan be autonomous. As discussed above there is little advantage indeploying active colloids if they require guidance by external fields, asin this case the fields may as well be used to also generate fluid flowor colloidal motion. Consequently, deploying the emerging methodssummarised above to autonomously direct active colloids is attractivefor this application. Equally, the demonstrated ability to selectivelyattach cargo such as proteins onto active colloids is encouraging. Theissues of needing to add fuel to support active colloid transport, andpotential solution incompatibilities are also present for lab-on-a-chip

Please cite this article as: Ebbens SJ, Active colloids: Progress and challengeface Sci (2015), http://dx.doi.org/10.1016/j.cocis.2015.10.003

applications, where samples for analysis include biofluids, and poten-tially high salt content environmental samples. In an ideal implementa-tion active colloids will be compatible with an un-adulterated sample.However, it may also be practical to implement initial sample process-ing stages such as the separation of components of a biological fluid,and addition of fuel as part of a lab-on-a-chip technology, thereby less-ening these restrictions. Furthermore, for other important applicationareas such as water testing, solution compatibility challenges are inany case considerably reduced.

Against this background, two separate recent studies illustrate thepotential for deploying active colloids as lab-on-a-chip transporters.The first demonstrates that multi-stage highly specific immunoassayscan be conducted using nanotube swimmers [63••]. A key feature ofthis study is that the active colloids were transferred between differentconnected chambers, enabling a sequential series of chemical processesto be executed to collect and label a specific protein. Active colloidalswimmers pre-functionalised with an antibody for a specific proteinanalyte are loaded into a chamber, then navigated to a second chamberfilled with a mixture of target protein, and other adventitious proteinswhere binding occurs. Finally themotors are driven to a third compart-ment where a second “sandwich” binding colloid functionalised with asecond complementary antibody can label any bound analyte, Fig. 5.The study convincingly shows that antibody functionalization of anactive colloid can enable selective attachment and transport of a specificprotein. This method was also extended to collect a bacterial cell with aspecific protein in its cell wall. To support active colloid motion in thissystem, the entire network of microfluidic chambers was flooded witha solution containing surfactant and peroxide fuel, and the biologicalbinding tolerated these conditions. In addition, the enhanced motionof themotor was found to speed up the protein binding events. Anotherfeature of this work is a consideration of the route to manufacture wasmade, which has led to the use of a polymeric material as the substratefor attaching the bio-recognition molecules, in contrast to other studiesthat require gold substrates. However, the significant missing ingredi-ent from this example is an autonomous guidance function, insteadthe motors are steered using an external magnetic field, which mustbe re-orientated at the correct moment to produce the desired activecolloid path and residence times throughout the device. In this context,a second recent study also concerning nanotube swimmers displaysboth the ability for selective binding (in this case streptavidin used toattach biotinylated components), Fig. 5, and also uses heart shapedfluidic cells to autonomously concentrate the colloids within a spatiallywell-defined region of the cell (see Fig. 3d) [64•]. Unfortunately the twooperations of binding and autonomous concentration by physicalstructures involved manual transfer of the colloids between differentsolutions. However, taken together with the previous example, it isclear that the potential to implement a useful lab-on-a-chip assayautonomously using active colloids is moving closer.

3.3. In vivo applications

One of the original motivations for the active colloid field was basedon futuristic visions of miniature devicesmovingwith the body to effectrepairs or deliver drugs. To this end, recently, reports of active colloidsbeing deployed within living animals have been published, indicatingthe first steps towards this challenging goal are being made. In thefirst example of in vivo animal model testing for active colloids, bubblepropulsive tube swimmers made from zinc and a polymeric matrixwere administered orally to mice [65••]. Within the acidic environmentof the mouse stomach, the zinc reacts to produce hydrogen bubbles,producing propulsion without the requirement for external fuel orother additives. The effect of this active motion was to drive the tubeswimmers into the stomach lining, thereby enhancing their residencetime beyond that for inactive controls. The study also demonstratedthat mixing gold nanoparticles within the matrix of the device allowedthese to be released in the stomach lining as the zinc was degraded,

s towards realising autonomous applications, Curr Opin Colloid Inter-

Fig. 5. Lab-on-a-chip applications for active colloids. (i) Chemical functionalization of a nanotube to allow selective attachment of a specific biological analyte. (a) Schematic representationof the surface functionalization of a half gold covered nanorod (L:R). Thiol attachment introduces a carboxylic acid group; this allows attachment of the commonprotein linking compoundNHS; and subsequent protein binding (b–d) shows sill frames from video microscopy illustrating the selective attachment of fluorescently labelled biotin coated beads to streptavidinattached to the gold half of the nanotube as shown in (a) [64•]. (ii) Transfer of an antibody functionalised nanotube through a microfluidic device (Shown centrally). (1) nanotube leavesinitial reservoir, (2a) nanotubemoveswithin a reservoir containing both target and otherproteinmolecules, and then (2b) leaves to enter a third chamber (3+4). (5) Shows beads taggedwith a second antibody complementary to the target protein attaching to the nanotube, confirming selective pick-up and labelling of the target. All chemistry and propulsionwere autonomous in this example, but magnetic fields were used to guide the device though the interconnecting channels [63••].

7S.J. Ebbens / Current Opinion in Colloid & Interface Science xxx (2015) xxx–xxx

again showing increasing retention compared to conventional adminis-tration, Fig. 6. Assessments of toxicitywere alsomade, with no concernsbeing noted. This suggests a novel route for drug delivery that can leadto a viable application. Additional separate investigations for potentialin vivo toxicity have also been made for gold-platinum nanojetswimmers and these encouragingly confirmed that the viability of acell line was not affected by incubation with the active colloids [66].

Other potential future envisaged in vivo applications for activecolloids could involve themmovingwithin the bloodstream, for exampleto repair arteries. For this reason, and also to move closer to the ability toimplement lab-on-a-chip analysis of blood sampleswithminimal samplepreparation, active colloid motion within fluids containing componentsof blood have been performed. In one report it was found that bloodproteins considerably reduced the mobility for Cu/Pt microtubularmotors, an observation qualitatively assigned to fouling of the catalyticsurface and solution viscosity [67]. However, more promisingly, Fe/Pt

Please cite this article as: Ebbens SJ, Active colloids: Progress and challengeface Sci (2015), http://dx.doi.org/10.1016/j.cocis.2015.10.003

microtubular motors were found to produce motion at physiologicaltemperatures in diluted serum and red-blood cell containing solutions.Raising the temperature of the fluid above ambient served both toincrease catalytic activity and reduce solution viscosity, enhancingthe observed bubble release rate and the resulting propulsionspeeds [68•].

While it is clear that there are in vivo applications such as drugdelivery to the stomach described above that do not require a navigationfunction, it is also apparent that more sophisticated drug delivery andrepair tasks will require active colloids to have the ability to navigateand respond to their surroundings. Autonomous navigation for anymotor type for an in vivo application has yet to be demonstrated.There is however potential for phenomena such as chemotaxis to beused to enable accumulation of devices in response to themany solutiongradients found within the body, while another interesting possibility isto exploit the flows present in the body to align active devices [25,69].

s towards realising autonomous applications, Curr Opin Colloid Inter-

Fig. 6. Autonomous in vivo delivery by active colloids. (a) Reactive nanotubes containingzinc as an interior coating, produce hydrogen bubble powered propulsion in acidic gastricacid conditions, allowing them to embed into the stomach wall of an animal model.(b) Efficiency comparison for the delivery of gold nanoparticles (AuNPs). AuNPs wereretained at an enhanced rate when delivered by the nanotube motors [65••].

8 S.J. Ebbens / Current Opinion in Colloid & Interface Science xxx (2015) xxx–xxx

4. Future perspective

While this article has focussed on recent experimental efforts to pro-duce autonomous applications for active colloids, these breakthroughshave also been accompanied by a large amount of theoretical andmodelling research. This has clearly contributed significantly to thedevelopment of existing active colloid systems, for example in somecases predicting viable propulsion mechanisms before experimental

Table 1Summary of existing features for the current major types of active colloid.

Swimmer type Navigation capacity D

Geometry Chemistry Bubbles?

Rod Catalytic No External field [72]Chemotaxis [14]Physical guidance [40••]

L

Spherical Janus Catalytic No External field [35]Physical guidance [41]Chemotaxis [43]Gravitaxis [36••]

L

Spherical Janus/SymmetricalActivity

Catalytic Yes None demonstrated A

Spherical Janus Reactive Yes External field [51•] Ao

Tubular Catalytic Yes External field [74]Physical guidance [42••]Chemotaxis [43]

Po

Tubular Reactive Yes External field [27•] A

Please cite this article as: Ebbens SJ, Active colloids: Progress and challengeface Sci (2015), http://dx.doi.org/10.1016/j.cocis.2015.10.003

testing [52]. In this context it appears that developing the active colloidfield beyond the current state of the art will be most efficientlyaccomplished by fully utilising theory and models to overcomeexisting barriers. As highlighted above, two of the most significantattributes for a useful autonomous active colloid system are to bewidely deployable in a range of solutions, and to possess a robustautonomous guidance strategy. Theory and models provide valuableinsight to help address both of these aims. For example, muchtheoretical effort has been devoted to understanding the numerousphysical and chemical properties that determine the propulsionvelocity for a given device [70], and making use of this informationcan consequently ensure that future devices are designed to gener-ate maximum performance from a given driving mechanism subjectto specific solution constraints. In addition, due to the ability fortheory and modelling to access scenarios that are currently hard torealise experimentally, studies using this approach can lead theway for new approaches to guiding active colloids. Of particularinterest is the ability for models and theory to predict collectivebehaviours that may emerge for large numbers of active colloidsbeyond those that can be currently observed due to experimentalrestrictions such as gas evolution or fuel depletion [71]. For example,one recent study shows the general requirements for a catalyst patternedcolloid to be aligned and directed by a chemical gradient, which providesa promising route towards autonomous direction as described above[46]. In addition, the lack of physical constraints then allowed a phasediagram to be generated, predicting a rich variety of multi-body interac-tions under differing fuel concentration and product/reactant diffusionrates that lead to collective motion phenomena. It is these and othertheoretical insights that will inspire experimentalists to perform newexperiments that will further expand the range of guidance methodscurrently available for active colloids, and ensure the continued devel-opment of the field towards future applications.

5. Conclusions

This article has presented a summary of recent advances towardsautonomous applications for active colloids. Both fundamental studiesreporting specific behaviours such as autonomous navigation capacity,and reports that have been presented as steps towards end applicationshave been considered. Table 1 presents an overview of the features andfunctions displayed for the major active colloid types. From this surveyit is apparent that the active colloid field is approaching a maturitywhere viable applications are within grasp. A chief indicator for this is

emonstrated solution compatibilities Functions

ow salt solutions with added peroxide fuel Cargo transport [73]

ow salt solutions with added peroxide fuel Cargo transport [35]

queous solutions with added peroxide fuel Cargo transport [55•]

cidic/basic solutions +ften requires surfactants

Oil clean-up [51•]Chemical remediation [62]

eroxide fuel +ften requires surfactants

Selective “Fly by” capture of proteins+cells [63••]Enhanced mixing [59•]

cidic solutions Cargo transport [27•]In vivo drug delivery [65••]

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9S.J. Ebbens / Current Opinion in Colloid & Interface Science xxx (2015) xxx–xxx

the very recent report where active colloids were found to have thepotential to deliver drugs within a live animal model [65••]. In addition,the state of art concept demonstration for environmental remediation isonly limited by the requirement for added surfactant, which does notappear to be a fundamental obstacle, based on reports for similarmotorsmoving without this additive. Both these demonstrations are intrinsi-cally autonomous: functions can be executed without the applicationof external fields or external monitoring. For lab-on-a-chip applications,such as executing multistage analyte recognition and labelling processes,both the essentials of autonomous guidance and the required selectivecargo attachment chemistry have been separately demonstrated. Equallypromising is the emergence of additional new fundamental autonomousguidance strategies based on gravitational fields, physical structures andchemical signals. It is appears that combining these new approaches tonavigation with the existing ability to collect and transport biologicalmaterials may enable new static microfluidics systems to be realised. Itis also apparent that solution compatibilities remain a key barrier towidely deploy active colloids. In this context it appears that fundamentalstudies to elucidate the absolute theoretical barriers to propulsion mech-anisms, together with continued efforts to utilise biological and syntheticchemical reactions within these constraints has the potential to producefurther gains. Finally, while the engineering considerations for activecolloids such asmaterial costs and scalability have received less attention,it is clear that the emergence of viable applications will increasingly leadto these issues becoming equally central to the development of thisexciting and growing field of research.

Acknowledgements

I acknowledge support from the EPSRC via Career AccelerationFellowship (EP/J002402/1).

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