Micromotors for “Chemistry-on-the-Fly” - ACS Publications - American

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Cite This: J. Am. Chem. Soc. 2018, 140, 3810−3820

Micromotors for “Chemistry-on-the-Fly”

Emil Karshalev, Berta Esteban-Fernández de Á vila, and Joseph Wang* Department of NanoEngineering, University of California San Diego, La Jolla, California 92093, United States micro- or nanometers (in one or more dimensions), are capable of performing a particular task while propelling autonomously in solution.3,4 At these microscopic scales, viscous forces dominate over inertial forces, and thus, a small object such as a micromotor would experience swimming in water as a person would experience swimming in molasses.5 To overcome this challenge, nature has evolved ways to produce nonreciprocal or asymmetric swimming techniques, such as the flexible oar or corkscrew behavior seen in many microscopic organisms.6 Inspired by these natural phenomena, scientists conceived the first artificial self-propelled microswimmers which move by the asymmetric decomposition of H2O2 fuel into O2 and H2O on the Pt end of a Pt/Au nanowire.7 This results in gradient of reaction products and leads to propulsion of the wire. Later, more powerful propulsion methods were developed, based on hollow microtubes or asymmetric microparticles which produce bubble thrust via a chemical reaction to release a gaseous byproduct or by harnessing energy from magnetic, electric, or acoustic fields.3,8−12 These artificial swimmers have been designed to display high speed at microscopic scales and in different environments. Such continuous movement of the micromotor leads to built-in sample solution mixing, enhancing the speed of the chemical reactions.13,14 Fluid mixing is very important for enhancing the speed and yield of a wide range of chemical processes. Besides this intrinsic microscale mixing ability of micromotors, the surface of these self-propelled microdevices can play an important role in dynamic chemical reactions. On one hand, the micromotor surface material can represent an active reactor which is moving along the sample and accelerating the corresponding chemical processes. Besides the locally induced mixing, such movement enables these reactive swimmers to cover larger portion of the treated solution. Considering their rich surface chemistry, mobile microreactors can participate in multiple “on-the-fly” reactions at the same time. Mobile micro/nanomotors enable also the fast and effective dispersion of the reactive materials around the sample leading to enhanced reaction rates. On the other hand, the versatility of micromotor materials and structures facilitates their surface functionalization with reactive agents or specific receptors which are rapidly transported through the sample solutions, improving contact with the corresponding target molecules.15,16 The multitude of propulsion strategies and surface reactivities of modern microscale motors can lead to diverse mobile chemical platforms that can benefit a broad array of chemical processes. In this perspective, we will present an overview of micromotors as mobile scaffolds for performing “chemistryon-the-fly” and describe key micromachine strategies and recent

ABSTRACT: This perspective reviews mobile micro/ nanomotor scaffolds for performing “chemistry-on-the-fly”. Synthetic nano/micromotors offer great versatility and distinct advantages in diverse chemical applications owing to their efficient propulsion and facile surface functionalization that allow these mobile platforms to move and disperse reactive materials across the solution. Such dynamic microreactors have led to accelerated chemical processes, including organic pollutant degradation, metal chelation, biorecognition, redox chemistry, chemical “writing”, and a variety of other chemical transformations. Representative examples of such micromotor-enhanced chemical reactions are discussed, focusing on the specific chemical role of these mobile microreactors. The advantages, gaps and limitations of using micromotors as mobile chemical platforms are discussed, concluding with the future prospects of this emerging field. We envision that artificial nano/micromotors will become attractive dynamic tools for speeding up and enhancing “on-the-fly” chemical reactions.

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INTRODUCTION Today, technology and society are moving at an ever increasing pace. The electronics industry, for example, has been doubling the number of transistors on integrated circuits approximately every 2 years,1 with new smart phones and fitness watches introduced annually. The remarkable turnover speed of the electronics and software industries is pushing many other disciplines, including chemistry, to keep up. More and more chemical processes and analyses are required to go mobile. With more stringent environmental laws and growing societal awareness fast response to ecological disasters is crucial. For example, large-scale water detoxification or oil spill cleanup require a fast response and rapid chemical reactions. On the other hand, chemistry is moving onto textiles and epidermal devices.2 Such wearable devices can sense chemical biomarkers in sweat and tears or deliver therapeutics, but require fast reaction times, along with small sample volumes and miniaturized equipment. Furthermore, these devices are meant for the lay person and require straightforward data analysis and readouts to prevent incorrect interpretation. Finally, this chemistry is performed “on-the-go” in field settings, and hence can no longer rely on bulky instrumentation in fully staffed laboratories. Society demands faster, simpler, and cheaper. With these rapidly growing trends of faster speed and increased mobile, microscopic, self-propelled devices appear as suitable candidates to enhance chemical processes. Commonly called micromotors, these small-scale devices, on the order of © 2018 American Chemical Society

Received: January 3, 2018 Published: February 22, 2018 3810

DOI: 10.1021/jacs.8b00088 J. Am. Chem. Soc. 2018, 140, 3810−3820

Perspective

Journal of the American Chemical Society

Figure 1. Micromotors for “chemistry-on-the-fly”. Examples of various types of mobile chemistry micromotors applications, including metal-ion chelation and sequestration (top left), photocatalysis and photodegradation of chemical and biological warfare agents on an active surface (top right), surface binding for chemical recognition and sensing (bottom right), and selective recognition of biomolecules for sensing, imaging, conversion and delivery (bottom left).

Figure 2. Advantages of micromotors for performing “chemistry-on-the-fly”. Examples of the main types of micromotors currently used by the micromotor community including structures such as conical tubes, helices, core−shell Janus particles, and nanowires (left column). These selfpropelled active structures present certain advantages for doing chemistry in motion such as possessing a mobile binding surface or reaction platform, micromotor signaling and communication via chemical means, and enhanced material dispersion (middle column). Real life examples of micromotors for performing “chemistry-on-the-fly” such as biomarker recognition and delivery (Adapted with permission.24 Copyright 2011, American Chemical Society), enzyme-functionalized nanomotors for “writing-on-the-fly” (Adapted with permission.25 Copyright 2010, Royal Society of Chemistry), micromotor chemical communication via release of Ag ions (Adapted with permission.17 Copyright 2018, Wiley-VCH), and the continual release of HRP enzyme for H2O2 detection (Adapted with permission.26 Copyright 2015, American Chemical Society) (right column).

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continuous movement. This affords the user improved control since the reaction sites can be built directly on the micromotor or attached to it and detached at a later time. The continuous movement of receptor-functionalized micromotors within the sample solution increases contact with target analytes, reducing recognition times. We can also envision the catalyst moving around the reactant solution, instead of the other way around, to increase molecular contact and reaction yield. Additionally, chemical communication can take place between moving micromotors to affect their movement or trigger reactions, giving the chemist further control of the reaction conditions.17 Furthermore, microswimmers can form swarms because of collective behavior produced by chemical gradients or interactions with external fields.18−22 Such swarms can produce large-scale effects while maintaining the advantages of micrometer-sized motors. A swarm of autonomously moving micromotors can act as an efficient fluid pump for enhanced mixing, deliver large drug doses, or clean large volumes of contaminated solution, and can be readily collected upon completing their task. Micromotors, as was mentioned earlier, enhance the mass transport within a solution, even within microscale samples, due to their continuous movement.23 Propulsion at this scale forces the solution to move around the micromotor and in the case of bubble-propelled micromotors bubbles enhances the transport of reagents or uniform dispersion of desired materials.13 Overall, the use of micromotors presents chemists and chemical engineers with new tools for increasing the productivity, speed, and yield of their processes. There are already examples of micromotors in a variety of fields and applications which take advantage of the aforementioned properties of self-propelled structures to perform “chemistry-on-the-fly”. One such example (shown in Figure 2, right column, first panel) involves Ti/Ni/Au/Pt microrockets modified with a single-strand DNA capture probe via thiol chemistry on their outer Au surface for “on-the-fly” DNA hybridization in complex samples.24 The Pt catalyzed H2O2 degradation provided O2 bubbles for thrust on the inside of the microrocket, enabling efficient propulsion in biological media. The Ni segment enabled navigation within multiple locations inside a microfluidic platform by magnetic manipulation. These DNA-modified microrockets exhibited selective and fast hybridization of their target DNA sequence. Micromotors can also act as the catalyst for a chemical reaction. In this case, Manesh et al. used a Pt/Ni/Au−Ag nanowire to “write” surface features of polyaniline (PANI) in real time.25 The nanowire micromotor propels chemically in the presence of H2O2 at its Pt end. On the Au side, immobilized horseradish peroxidase (HRP) enzyme oxidizes the aniline monomer in the presence of H2O2. Such localized electropolymerization of aniline monomers results in defined PANI surface microstructures on the substrate surface through a controlled movement and accurate positioning of the HRP-modified nanomotor, as illustrated in Figure 2 (right column, second panel). Chemical communication is another attractive trait possessed by micromotors. Chen et al. devised a combination of polystyrene (PS)/Ni/Au/Ag and SiO2/Pt activator and activated micromotors, respectively (Figure 2, right column, third panel).17 In a H2O2-rich solution the activator releases Ag ions while simultaneously producing superoxide radicals (O2•−) which later reduce the ionic Ag on the Pt surface of the activated micromotors dramatically enhancing their catalytic properties toward H2O2 degradation through electronic and geometrical

advances aimed at increasing the yield and speed of different chemical and biochemical transformations. Our goal is to inspire future research efforts in the field of micromotors at the intersection of engineering and chemistry to advance chemical processes and technology to the next level. A visual overview of such micromotor strategies is presented in Figure 1. Here we present some of the most common microswimmer designs with several typical chemical applications they are used for. For example, the large surface area, coupled with robust propulsion, makes micromotors favorable candidates for heavy metal removal, chelation, and remediation from polluted waters (Figure 1, top left). Light-sensitive materials incorporated into micromotor design endow them with photocatalytic capabilities to degrade organic and biological contaminants such as pesticides, dyes, or bacterial spores (Figure 1, top right). Micromotors can be functionalized with responsive materials, acting as logic gates in response to target biomolecules, such as the boronic acid/sugar reaction (Figure 1, bottom right). Microscopic motors, functionalized with bioreceptors, offer promise as mobile sensing platforms for fast, small volume detection of biomarker concentration, enzyme activity, and nucleic acid identification (Figure 1, bottom left). In the following sections, we will outline the unique properties of selfpropelled microdevices and their inherent advantages for performing chemical reactions, sequestration, detection, and so forth, while “on-the-move”. We provide representative examples from the application-rich micromotor literature and present a detailed case-by-case explanation of each type of micromotor and its specific chemical role. Finally, we will conclude with a look at the pertinent challenges, drawbacks and limitations which are posed to micromotors as mobile chemical platforms and provide and outlook on their expanding influence in the future.

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WHY MICROMOTORS? Microscale machines possess certain inherent advantages as platforms for “chemistry-on-the-fly”. First of all, developments in micromotors have produced a wide variety of designs, shapes and propulsion strategies to be employed in numerous environments. The main classes of such micromotors are displayed in Figure 2 (left column). Microrockets and Janus particles which propel with highly efficient bubble thrust offer high speeds, along with motion-induced solution mixing, and possess large area for further surface functionalization. On the other hand, these chemically powered motors require particular fuels or release ionic species as a result of their propulsion reactions which could be disadvantageous for the chemical process of interest. Micromotors can alternatively be actuated by external forces, such as magnetic or acoustic fields, for accurate localization and navigation. These fuel-free micromotors require additional equipment for generating the external fields. Metallic nanowire motors, which use phoretic mechanisms for motion, are limited to low ionic strength, nonbiological environments but can access very small domains due to their nanoscale dimensions. Thus, the diverse designs and materials, coupled with their efficient movement, make micromotors an attractive platform for performing chemistry in solution, whether within microfluidic channels or in large liquid reservoirs or reactors. In the center column of Figure 2, we illustrate some of the main advantages of micromotors for such mobile chemistry applications. For example, micromotors can act as a mobile surface binding or reaction platforms to capture target analytes or catalyze specific reactions during their 3812


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Figure 3. Examples of inorganic reactions, photocatalysis, and surface chemistry using micromotors. (A) Micromotor strategy for photocatalytic degradation of CBWA based on light-activated TiO2/Au/Mg microspheres that propel autonomously in natural water and generate highly reactive oxygen species responsible for the efficient decontamination processes. Inset: absorbance spectra showing the efficient motor-induced degradation of methyl paraoxon (green) vs appropriate controls; see ref. 28 for details. Adapted with permission.28 Copyright 2014, American Chemical Society. (B) Schematic process for the degradation of polluted water into oxidized byproducts and CO2 by multifunctional H2O2-propelled Fe/Pt micromotors. The remediation of polluted water is achieved by the combination of Fe2+ ions with peroxide, generating HO· radicals, which degrade organic pollutants via the Fenton reaction. Adapted with permission.29 Copyright 2013, American Chemical Society. (C) Schematic representation of the structure of ZrO2/rGO micromotors for selective capture of nerve agents. These functional micromotors swim in a complex sample and preferentially remove organophosphate compounds. Adapted with permission.30 Copyright 2015, American Chemical Society. (D) Self-propelled micromotors for “on-the fly” removal of Zn, Cd, and Pb metals via DMSA chelation. Inset: stripping voltammogram of seawater spiked with 500 μg/ L Zn(II), Pb(II), and Cd(II) treated with unmodified (red line) and DMSA-modified (green line) Mg micromotors. Adapted with permission.31 Copyright 2016, Royal Society of Chemistry. (E) Acid-powered Mg-based micromotors spontaneously neutralize the gastric acid of the stomach while providing pH-responsive payload release. Plot demonstrates the pH of the stomach contents as a function of time after treatment with Mg micromotors. Adapted with permission.33 Copyright 2017, Wiley-VCH. (F) Flexible magnetic nanoswimmers for biocatalytic patterning of complex surface microstructures. Right: SEM images of helical patterns obtained with different magnetic-field rotation frequencies: 7.5 (top) and 12 (bottom) Hz. (Adapted with permission.34 Copyright 2013, Royal Society of Chemistry).

movement. These are only a few examples that demonstrate the versatile and diverse capabilities of micromotors for incorporation into applications for “on-the-fly” chemistry. In the following sections, we will provide an in depth description of nano/micromotor-based “chemistry-on-the-fly” approaches in a case by case basis along with current bottlenecks and limitations to micromotor “on-the-fly” strategies.

effects. Communication between individual entities is widely spread in biology and is even necessary for complex life to exist. However, such chemical signaling between synthetic micromotors is in its infancy, yet shows great potential for implementing greater control over chemical processes and reactions locally and in situ. Finally, self-propelled motors can become useful agitators and dispersing agents. MorenoGuzman et al. demonstrated this with their Marangoni effect propelled HRP dispersing motors (Figure 2, right column, fourth panel).26 The motor platform is used for the detection of H2O2 in aqueous media by the oxidation of 3,3′,5,5′tetramethylbenzidine (TMB) by HRP. Motion was achieved by the asymmetric release of sodium dodecyl sulfate (SDS) surfactant from one of the openings of the motor which establishes a surface tension gradient resulting in fluid rushing in to equilibrate the surface tension. The peroxide detection was aided by the continual release of fresh enzyme into solution and the increased fluid convection caused by the micromotor

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“ON-THE-FLY” DECONTAMINATION, SEQUESTRATION, AND NEUTRALIZATION: MICROMOTOR-BASED INORGANIC, PHOTOCATALYTIC, AND SURFACE REACTIONS Functional micro/nanomachines can benefit a variety of reactions and chemical processes. Numerous studies have shown the potential of micromotors as “on-the-fly” chemistry platforms for photocatlysis, environmental cleanup and sequestration, and inorganic reactions among others. In this section we will summarize some of the most promising 3813


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acid−base Lewis interaction. Again, the selective binding capability and contaminant removal is enhanced by the selfpropelled motion of these ZrO2/rGO/Pt microrockets which enhances the fluid transport and interaction between the ZrO2 surface and MP. Besides the detoxification of organic and biological pollutants from contaminated wastewater, micromotors are viable candidates for efficient collection of heavy metals from industrial waste waters. Uygun et al. coated Mg microparticles with a thin Au hemispheric cap that was subsequently functionalized with the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). DMSA exhibits high selectivity for 2+ valence toxic metallic species, such as Zn (II), Cd (II), and Pb (II) (Figure 3D).31 Stripping voltammetric data show that both lake and tap water containing 500 μg/L of these 3 heavy metals can be effectively cleaned by DMSA-functionalized Mg−Au Janus micromotors. In contrast, a negligible removal of these metals was observed using the unmodified micromotors (no DMSA). These results demonstrate that micromotors are attractive platforms for “on-the-fly” surface mediated chelation and adsorption reactions. The Au micromotor surface provides a versatile interface toward modification with diverse functionalities. Continuing with the use of micromotors for environmental remediation, Pumera’s group developed biocompatible and degradable nanomotors, composed of a zerovalent Fe core and ultrathin FeIII oxide shell.32 These Fe0-based Janus nanomotors were fuelled by their decomposition in citric acid, leading to a continuous asymmetric bubble propulsion. These nanomotors acted as dynamic reducing agents to decontaminate environmental pollutants, as demonstrated by the enhanced degradation of toxic azo-dyes. In addition to developing an organic pollutant neutralization strategy, these Fe0-based micromotors attempt to address the motor scalability challenge. To make micromotors effective participants in a large-scale chemical processes they have to be low cost and easy to produce. This report utilizes a large scale manufacturing process where iron(III) oxyhydroxide precursor is reduced in a hydrogen environment at 400 °C followed by coolling down in a 2% oxygen environment to form the ultrathin iron(III) oxide. This process is used commercially, thus demonstrating the capability of manufacturing micromotors on a kg/ton scale. However, for many other motor designs and materials, scalability remains a concern, as will be addressed in later sections. Besides their use for environmental and industrial reactions/ processes, micromotors have exhibited promise for “on-the-fly” chemical reactions in living systems. One such important reaction is the neutralization of gastric fluid. Many proteinbased drugs and antibiotics suffer from denaturation or degradation in the highly acidic stomach environment, and require preadministration of proton pump inhibitors (PPIs) which have numerous side effects. Aiming to find less aggressive treatment, the Wang group has devised a Mg-based Janus micromotor which can interact with gastric fluid to neutralize the stomach pH to ∼7 with subsequent pH-dependent release of a drug.33 Figure 3E shows the scheme for the operation of this biocompatible micromotor. The core−shell structure includes a Mg core with an Au shell and a pH-responsive enteric coating loaded with an antibiotic drug. The rapid reaction between the highly acidic gastric environment and Mg consumes 2 protons for every Mg atom, leading to a fast depletion of the protons and consecutive pH neutralization. Upon reaching neutral pH, the enteric coating is dissolved,

strategies utilizing such mobile chemistry microsystems, explore their enhanced chemical capabilities, and evaluate their performance relative to passive chemistry techniques. Chemical and biological warfare agents are of great concern to the public health due to their highly acute toxicity.27 In an effort to combat these threats Li et al. developed a mobile micromotor platform to photocatalytically degrade such warfare agents directly in solution (see Figure 3A).28 The micromotor is based on a reactive Mg core covered by Au nanoparticles (NPs) and a TiO2 shell, respectively. The Mg core, assisted by the microgalvanic corrosion by noble Au NPs, reacts with seawater and produces H2 bubbles that enables rapid movement. At the same time, the outer TiO2 is irradiated with UV light, producing reactive oxygen species, such as OH•, O2•−, O2H•, and OH−, which are effective at oxidizing organic and biological contaminants into nonharmful products. The main advantage of the micromotor system comes from its inherent motion. The mobile cleaning platform provides enhanced fluid mixing through H2 bubble production, without the need of external stirring, while the movement of the active TiO2 enhances contact with contaminants. Thus, Mg/Au/TiO2 micromotors resulted in faster degradation of the nerve agent simulant methyl paraoxon (MP) and inactivation of Bacillius globigii spores compared to static micromotors or motors with non UV-responsive shell (Al2O3 instead of TiO2) (inset, Figure 3A). Organophosphorous nerve agents can also be detoxified efficiently without any motor functionalization.14 Such detoxification processes commonly rely on H2O2-rich media for in situ generation of OOH- nucleophiles. The repeated movement of multiple micromotors and corresponsding motorinduced fluid transport across a peroxide-activated contaminated sample results in detoxification of these chemical threats under mild conditions. Microrockets have also been utilized for well-known chemical reactions, such as the Fenton reaction. The Fenton reaction, involving the oxidation of organic pollutants by iron(II) and hydrogen peroxide, is widely used for the treatment of chemical wastewater. The Schmidt group fabricated a rolled-up structure consisting of an inner layer of Pt and outer layer of Fe (see Figure 3B).29 As the microrocket propels in H2O2 solution (through the Pt catalytic breakdown of H2O2 and O2 bubble generation) Fe2+ ions are released (from the outer layer) and react with H2O2. This reaction produces the OH• radical which is a highly reactive and capable of oxidizing organic pollutants into nonharmful byproducts. Under static conditions (Fe tubes without propulsion), the micromotors led to a limited decontamination (e.g., of 30% of the initial rhodamine 6G after a 5 h treatment). In contrast, moving Pt/Fe microrockets under the same conditions resulted in full decomposition of the dye in 5 h, reflecting the strong mixing and continuous movement of these microtubes. The bubble ejection led also to a fluid pumping phenomenon that increased further the decontamination process. Singh et al. tackled the neutralization of chemical warfare agents by selective binding of their phosphate group to the ZrO2 moieties of a ZrO2/reduced graphene oxide (rGO)/Pt microrockets (Figure 3C).30 These microrockets are electrochemically grown in a template membrane. Thin layers of rGO are grown as the high surface area template over which nano domains of ZrO2 can nucleate and grow. The ZrO2 NP formation thus enables high contact area for the selective binding of phosphate containing MP which occurs by the sharing of electrons with the electronically deficient zirconia via 3814


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Figure 4. Examples of biomolecule-mediated reactions using micromotors: On-the-fly bioreactions. (A) Microrocket with “built-in” boronic acid recognition of sugars. Schematic representation of a poly(3-aminophenylboronic acid) (PAPBA)/Ni/Pt microrocket and its “on-the-fly” interaction with glucose. Inset: microscope image showing the carbohydrate-sensitive microrocket transporting multiple yeast cells. Reproduced with permission.40 Copyright 2012, American Chemical Society. (B) Schematic illustration showing the pH-triggered insulin release nanomachine approach based on US-propelled mesoporous silica/Au nanomotors. Glucose responsive gated insulin containing nanocontainers. Steps involved in the insulin release mechanism: the PBA functionalized MS segment is capped with pH-sensitive nanovalves based on the GOx gating trigger molecule that leads to the autonomous insulin delivery in the presence of glucose. Zoom in showing how the protonation of the PBA groups induces the opening of the pH-driven gate and uncapping of the insulin-loaded nanovalves. Inset: plot showing the normalized insulin release from the GOx/ In/MS-Au nanomotors as a function of glucose concentration. Reproduced with permission.41 Copyright 2017, Royal Society of Chemistry. (C) Self-propelled carbonic anhydrase (CA) functionalized micromotors offer efficient CO2 sequestration. Reproduced with permission.42 Copyright 2015, Wiley-VCH. (D) Micromotor-based biosensing strategy for mycotoxins detection in food samples using rGO/PtNPs micromotors combined with specific dye-labeled aptamers. Reproduced with permission.46 Copyright 2017, American Chemical Society. (E) Schematic showing the approach for specific intracellular detection of miRNA-21 in intact cancer cells using US−propelled ssDNA@GO-functionalized nanomotors (top). Fluorescence images of MCF-7 cell before and after nanomotor internalization (bottom: left and right, respectively). Reproduced with permission.47 Copyright 2015, American Chemical Society. (F) Dynamic microtubes with immobilized DNA can selectively bind to Hg(II) in aqueous environments. Reproduced with permission.48 Copyright 2016, Elsevier.

GOx reaction, acts as a reducing agent for the localized catalytic reduction of AuCl4− ions to helical Au microwires on the glass substrate.

releasing autonomously its therapeutic payload. With optimal amount of the micromotors, stomach acid neutralization can be achieved in as little as ∼20 min in mice models, compared to 30−60 min using common PPIs. A micromotor with these capabilities has multiple advantages over current treatments involving administration of several drugs which passively diffuse in the stomach. First, all of the needed components are packed into a single microscale motor platform. Second, the selfpropelled behavior of the micromotor promotes fluid transport and speeds up the neutralization even with small amounts of micromotors (only 5 mg per mouse), eliminating the necessity of PPIs preadministration. Finally, the motor movement leads to their enhanced retention on the stomach walls which improves drug penetration into the tissue. Along with removal of harmful elements from contaminated waters or neutralization of acidic conditions in vivo, micromotors can be used for additive chemistry. One such example is the self-propelled metallic nanowire reported by Manesh et al. which can directly “write” helical 3D Au features on surfaces.34 The composition of the writing micromotor and the scheme for its operation are presented in Figure 3F. This nanomotor chemical “writing” protocol relies on the controlled magnetic field enabled movement of an enzyme glucose oxidase (GOx) functionalized nanomotor in the presence of its glucose substrate and AuCl4−. The H2O2, produced by the localized

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BIOMOLECULE-MEDIATED REACTIONS USING MICROMOTORS: “ON-THE-FLY” BIOREACTIONS The autonomous and rapid movement of micro/nanoscale motors has been also utilized to accelerate biochemical reactions mediated by different biomolecules. As it has been introduced above, the continuous movement of micromotors leads to a built-in mixing in sample solutions, which enhances the speed of the biochemical reactions.13 Furthermore, the different structures and materials used in the fabrication of micro/nanomotors offer versatility toward the modification of the motor structure with chemical ligands or its functionalization with specific receptors. Such combination of micro/ nanomotor propulsion with the possibility of modifying the motor surface with biomolecules using different chemical strategies offers multiple advantages toward the development of diverse “on-the-fly” reactions. For example, numerous reports have demonstrated that the continuous movement of micro/ nanomotors functionalized with specific bioreceptors through the sample can enhance target binding efficiency and sensitivity,13,35 allowing direct “on-the-fly” identification and isolation of different biological targets.36−38 Figure 4 displays 3815


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fresh enzymes led to an accelerated enzymatic conversion, allowing 2 min detection and accurate quantification of Lphenylalanine (L-Phe) in plasma and whole blood and total DAAs in bacteria cultures. The same group has presented recently an enzymemicromotor strategy based on the use of β-galactosidasefunctionalized micromotors for “on-the-move” hydrolysis of lactose in raw milk.44 The micromotors used in this work were prepared by template electrodeposition using multiwalled carbon nanotubes (MW) as outer layer for further functionalization with the enzyme by surface carboxylic groups, and Ni/ Pt NPs for inner layer that allowed efficient self-propulsion in milk without surfactant and convenient magnetic recovery from the sample. Coupling the hydrolytic properties of the immobilized enzyme with autonomous movement of MW/ Ni/Pt NP micromotors resulted in nearly 100% lactose hydrolysis and 2-fold removal efficiency as compared with static conditions and with free enzyme. Micro/nanomotors have been also functionalized with specific receptors for “on-the-fly” biosensing processes. Bioassays in small and ultrasmall sample volumes, where enhanced mass transport by solution stirring is challenging, can particularly benefit from the nanomotor-induced mixing. Several micromotor bioassays have exploited the attractive properties of graphene in combination with specific oligonucleotide or peptide molecules for developing “off-on” micro/ nanomotor-based biosensing strategies. Graphene-based micromotors combined with specific dye-labeled aptamers or DNA probes have thus enabled selective “on-the-move” detection of different target analytes via fluorescence quenching processes.45−48 For example, rGO/Pt microrockets have been used for fast “off-on” fluorescence sensing of ricin B toxin.45 These catalytic micromotors were modified with a specific ricin B aptamer labeled with a fluorescent dye, whose fluorescence was quenched due to π−π interactions with the rGO motor surface. The continuous propulsion of the aptamer-modified rGO/Pt micromotors within the toxin sample accelerated the specific binding of ricin B to the moving aptamer, leading to rapid “off-on” fluorescent switching due to the displacement of the dye-aptamer probe from the rGO- quenching motor surface. In a similar work, unmodified rGO/PtNPs micromotors were employed for simultaneous detection of different mycotoxins in food samples (Figure 4D).46 This strategy also relied on the selective recognition of target mycotoxins (fumonisin B1 (FB1) and ocratoxin A (OTA)) by the specific aptamer toward “on-the-move” “on-off” fluorescence quenching (compared to the quenched fluorescence of the free dye-labeled aptamer in the absence of mycotoxin). This wash-free micromotor approach offered simultaneous and rapid (2 min) “on-the-fly” detection in 1 μL samples. This type of chemical reaction involving graphene− oligonucleotide interactions with fluorescence quenching responses have been performed even inside living cells using US-propelled nanomotors. Figure 4E displays a nanomotorbased “off-on” fluorescence strategy for intracellular detection of endogenous content of target microRNA-21.47 This attractive approach was based on the use of US-propelled GO-modified nanomotors functionalized with a specific singlestranded DNA labeled with a fluorescent dye (dye-ssDNA). In the intracellular space, the presence of the target miRNA resulted in the displacement of the dye-ssDNA probe from the nanomotor surface, and consequently in a fast fluorescence recovery of the quenched dye-ssDNA probe. The micromotor

several examples of micro/nanomotors modified with different chemistries or functionalized with specific bioreceptors which have been used in different biomolecule-mediated reactions. Such movement of the bioreceptor around the sample addresses the limitations associated with the slow analyte transport under quiescent conditions used in such microassays. Micro/nanomotors have been coupled with different glucose responsive systems, involving the use of boronic acid ligands. The complexation of sugars with boronic acid ligands has been widely utilized for different sensing strategies,39 including nanomotor-based approaches. Figure 4A demonstrates a micromotor-based approach for “on-the-fly” selective detection of monosaccharides, based on the sugar recognition capability of the boronic acid−based outer polymeric layer of the motor.40 This strategy relies on poly(3-aminophenylboronic acid) (PAPBA)/Ni/Pt microrockets, coupling the selective monosaccharide recognition of the boronic acid−based outer polymeric layer with the catalytic function of the inner Pt layer. Such micromotors were also applied for “on-the-fly” capture and transport of yeast cells containing sugar residues on their walls (inset, Figure 4A). Effective release of the captured yeast cells, triggered via a competitive sugar binding involving addition of fructose, was demonstrated. More recent efforts showed an autonomous glucoseresponsive “smart” microswimmer for insulin delivery (Figure 4B).41 This strategy was based on the use of ultrasound (US)propelled gold nanowire (AuNW) motors combined with an enzyme-based sensing-effector unit. The Au NWs were coupled with a mesoporous silica (MS) segment, which was gated with pH-responsive phenylboronic acid (PBA)-glucose oxidase (GOx) supramolecular nanovalves responsible for the insulin release. In the presence of glucose, the protonation of the PBA groups triggered the opening of the pH-driven gate and uncapping of the insulin loaded nanovalves. The movement of the insulin-loaded MS-Au nanomotors under an US field led to a noticeable acceleration of the glucose-triggered insulin release compared to static insulin-loaded MS-Au NWs. Such accelerated insulin delivery was attributed to the movement of the responsive nanovalves throughout the glucose solution, as well as to the fluid mixing associated with the nanomotor movement. Micro/nanomotors have also been combined with enzymes demonstrating enhanced biocatalytic reactions. One example, illustrated in Figure 4C, involves self-propelled micromotors functionalized with carbonic anhydrase (CA) that offer accelerated CO2 sequestration.42 The success of this mobile CO2 scrubbing platform relied on the combination of the CO2 hydration capability of CA (to form a bicarbonate ion, followed by CaCO3 precipitation) the micromotor movement increasing contact between scrubber and solution. The hydrodynamics of the self-propelled CA-modified micromotor system and enhanced mass transport of the CO2 substrate led to improvements in the sequestration efficiency and speed. Another micromotor-based enzymatic approach was presented by Escarpa’s group, in which two class-enzyme micromotors were designed for selective detection of various amino acids (AAs).43 In this case, millimeter size-conical motors were self-propelled by the Marangoni effect, where the asymmetric release of surfactant induced fluid convection and rapid dispersion of the class-enzyme D-amino acid oxidase (DAO) and L-amino acid oxidase (LAO) for selective “on-thefly” detection of D-AAs and L-AAs were utilized, respectively. Coupling the motor movement with the continuous release of 3816


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TiO2−Au Janus micromotors

Au-WO3@C Janus micromotor

TiO2/Pt Janus micromotor

Au−B−TiO2 Janus micromotor Pt-black/Ti Janus micromotor

AgNP-coated Au/Fe/Mg Janus micromotors

SAM-coated Au/Ni/PEDOT/Pt micromotors SAM modified Ag/Ni/Ti/Mg Janus micromotors

carbon-Pt Janus micromotors

GOx-functionalized flexible nanowire PAPBA/Ni/Pt-microrocket PBA-Gox-Mesosporous silica-AuNWs L-amino acid oxidase (LAO)- D-amino acid oxidase (DAO)-SDS-filled pipet tips aptamer-GO/Pt micromotors ssDNA-GO-AuNWs DNA-functionalized Au/Pt micromotors fluoresceinamine (FLA)/silica−NH2/Pt Janus micromotor Mg/Au Janus micromotors

ZrO2-rGO/Pt tubular micromotors pH responsive polymer-Au/Mg Janus micromotors

bubble propulsion (H2O2) bubble propulsion (Mg water reaction) bubble propulsion (Mg water reaction) visible light bubble propulsion (H2O2 and NaBH4) light-induced selfelectrophoresis (H2O) light-induced selfdiffusiophoretic (H2O) light-induced selfelectrophoresis

bubble propulsion (Mg water reaction) bubble propulsion (H2O2)

bubble propulsion (H2O2) acoustic propulsion bubble propulsion (H2O2) bubble propulsion (H2O2)

magnetic propulsion bubble propulsion (H2O2) acoustic propulsion Marangoni effect

Marangoni effect bubble propulsion (Mg water reaction) bubble propulsion (NaBH4) bubble propulsion (Mg water reaction) Bubble propulsion (H2O2) bubble propulsion (acid)

HRP-SDS-filled pipet tips TiO2/Au/Mg Janus micromotors

Pd particles-metal films (Ti/Fe/Cr) rolled up microject Au/Ti/Mg Janus micromotors

bubble propulsion (H2O2) diffusiophoresis (N2H4) magnetic propulsion

propulsion mechanism

PEDOT/Pt microrockets Ir/SiO2 Janus micromotor HRP-functionalized nanomotors

micro/nanomotor type

50

H2 bubbles and OH− for diphenyl phthalate (DPP) degradation

micromotors obtain energy from photocatalytic degradation of methyl blue, cresol red, and methyl orange in aqueous solution and exhibit light-induced dye-enhanced motion through self-electrophoretic effects

adsorption and photocatalytic decomposition of sodium-2,6-dichloroindophenol (DCIP) and (RhB) under UV irradiation

Photoactivation of the black TiO2 surface catalytic decomposition of H2O2 and NaBH4 into H2 and O2 byproducts, respectively, used as sources of energy for a hydrogen−oxygen fuel cell photocatalytic degradation of Rhodamine B (RhB) under continuous or pulsed UV irradiation

AgNP-coated Au layer for bacterial adhesion

59

58

57

55 56

54

52 53

51

46 47 48 49

detection of different mycotoxins by specific fluorescent aptamers specific detection of miRNA21 by hybridization with a fluorescent ssDNA microtubes with immobilized DNA can selectively bind to Hg(II) FLA reaction with diethyl chlorophosphate (DCP)

detoxification by adsorption of 2,4-dinitrotoluene (DNT), Pb ions, and degradation of nerve agent stimulant methyl-paroxon and rhodamine 6G capture of oil droplets by hydrophobic interactions with self-assembled layers of alkanes hydrophobic interactions with oil droplets

34 40 41 43

phosphate groups of the organophosphate compounds share e- with the electronically deficient zirconia via acid−base Lewis interaction Mg metal reaction with gastric acid allows temporary neutralization of gastric acid through efficient chemical propulsion in the gastric fluid by rapidly depleting the localized protons production of H2O2 by GOx after the oxidation of glucose reduces gold ions in solution to locally deposit Au in the form of a helix selective monosaccharide recognition of the boronic acid−based outer polymeric layer of the motor glucose-induced protonation of the PBA groups triggers the opening of the pH-driven PABA-GOx gate, releasing the loaded insulin dual enzymatic reaction of DAO and LAO for selective “on the fly” biodetection of D- and L-AAs

32 33

26 28

31

14 18 25

ref

chelation of Zn, Pb, Cd by meso-2,3-dimercaptosuccinic acid (DMSA)

chemical reaction

29

−

oxidative OP degradation via generation of OOH catalytic decomposition of hydrazine fuel at very low levels provides effective motion or pumping capabilities for Janus micromotors localized PANI deposition through the predefined movement of HRP-modified catalytic nanomotors, which break down H2O2 in solution polymerizing aniline HRP enzyme for H2O2 biosensing light-activated TiO2/Au/Mg micromotors generate highly reactive oxygen species responsible for the efficient decontamination processes Fenton reaction; degradation of 4-nitrophenol by NaBH4

Table 1. Representative Examples of “Chemistry-on-the-Fly” Using Micro/Nanomotors

Journal of the American Chemical Society Perspective


Perspective


millions of micromotors can thus be made at a time, they are still in small (microgram) quantities. However, as mentioned earlier, new strategies are emerging for scaling up micromotor production to kilogram and even ton quantities.32 Despite the major challenges of integrating micromotors into some chemical processes, these microscale mobile chemistry reactors hold considerable promise and offer many potential benefits for “chemistry-on-the-fly”. The production of bubbles and flows around these microscale objects enhances mass transport and induces microscale mixing without the need for external stirring or agitation. This leads to increased reaction rates and accelerated chemical reactions, binding events, or adsorption processes. Unlike common reactive nanoparticles (that are subject to similar scalability issues), micromotors can cover larger portion of the treated sample significantly faster. The capability of micromotors to influence their environment, through release of ionic species or pH neutralization, in response to external triggers, allows for rapid modification of reaction conditions and improved chemical processes. The advantages of rate controlling and acceleration behavior of micromotors can be readily implemented in both small volume reactors and large-scale processes. There are numerous chemical processes and reactions that have not been explored yet in a nanomotor context. Understanding the limitations of existing micromotors in realistic environments will motivate others to fill in the gaps. With proper attention to key challenges and further innovations, the use of nanomotors could thus find broad applications in the production of new chemicals, pollution mitigation, process engineering or energy production. The field of micromotors is moving toward abandonment of toxic peroxide fuels and embracing bio- and environmentally friendly propulsion reactions such as Mg, Zn, Fe water- and acid-powered strategies.53,64−66 This shift in propellants enables operations in a wider range of environments such as seawater, stomach acid, intestinal fluid and other biofluids.67−69 Additional efforts should be devoted to the development of micromotor propulsion based on in situ fuel sources. Also, recent enzyme-functionalized micromotors, powered by their corresponding substrates, may offer an attractive alternative to current fuel-propelled micromotors in relevant biological settings.70 Additionally, advances in micromotor navigation provide control over motion and localization of reaction surfaces for precise interactions between surface reagent, catalyst or receptor with the target reactant or analyte.71,72 The field of micromotors is relatively young, but as outlined in this Perspective it holds considerable promise for incorporation into a variety of chemical and environmental processes. In today’s fast paced world, where speed and simplicity are essential, microsized, self-propelled devices can provide the burst of acceleration needed to push chemistry and chemical technology to the next level. Accordingly, we hope that this perspective will inspire major multidisciplinary research efforts in this exciting area.

propulsion led to enhanced sensitivity and shorter miRNA detection time due to the accelerated internalization process of the nanomotors and their movement inside the cells, which increased the probe-target contact and resulted in a faster miRNA sensing. DNA-functionalized micromotors have not only been used for biosensing strategies, but also for remediation applications. Pumera’s group used DNA-functionalized micromotors as dynamic adsorption platforms for heavy metals removal. In this work, self-propelled micromotors, consisting on an inner Pt catalytic layer for self-propulsion and an Au outer surface for the DNA functionalization, demonstrated selective binding of Hg(II) in aqueous samples (Figure 4F).48 Such metal removal relied on the specific interaction between the target Hg(II) and thymine−thymine (T-T) mismatched DNA to form of highly stable T-Hg(II)-T complexes. The rapid self-propulsion of the DNA-functionalized micromotors resulted in enhanced removal of Hg(II) from contaminated water samples, offering an attractive dynamic decontamination platform.

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CHALLENGES AND OUTLOOK Micromotors are promising candidates for accelerating chemical processes and performing useful reactions in diverse media, hence offering new possibilities for chemical transformations. In this Perspective we have described key strategies and representative examples of using micro/nanomotors for performing “chemistry-on-the-fly”. Some of these approaches and other examples are summarized in Table 1. These recent developments are only the first step toward practical chemical use of micromotors. Yet, translating these recent advances to widespread chemical applications would require major attention to key challenges, limitations and bridging existing gaps. As of today, most micromotors require specialized conditions for their propulsion and operation. These microscale mobile chemistry platforms commonly rely on fuels, such as H2O2, and contain catalytic noble metals, e.g. Pt or Au, which are costly and can generate unwanted byproducts (besides the target chemical product). Most micromotor experiments have been performed in aqueous media while a large portion of chemical processes take place in organic solvent matrices. Operating micromotors in such nonaqueous media would require redesigning existing micromotors to fit the lower surface tension environments of organic solvents.60,61 Furthermore, purification and isolation of products and waste from chemical reactions and processes accounts for ∼50% of all industrial energy consumption and ∼16% of the total US energy consumption. The new mobile chemical microreactors should thus contribute minimally to contamination of the target products or recycling streams.62 Moreover, strategies for efficient recovery or harmless degradation of these micromotors must be improved. Aiming at this, the Sanchez group presented an efficient method for disinfecting and removing Escherichia coli bacteria from contaminated water using self-propelled Mgbased Janus micromotors decorated with silver NPs that were collected magnetically at the end of their mission along with the bound bacteria.57 On the other hand, Chen el al. presented selfdegrading micromotors based on different nontoxic transient materials, which completely disappeared after completing their task, leaving biologically harmless ions.63 Finally, it is important to consider the fabrication and scalability of these mobile chemistry platforms, when moving from laboratory-scale to large-scale productions. Most micromotor fabrication strategies require complex equipment and cleanroom facilities. While

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Joseph Wang: 0000-0002-4921-9674 Notes

The authors declare no competing financial interest. 3818


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ACKNOWLEDGMENTS This work is supported by the Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense (Grant Number HDTRA1-13-1-0002). E.K. acknowledges the Charles Lee Powell Foundation and the University of California, San Diego, for financial support.

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Micromotors for “Chemistry-on-the-Fly” - ACS Publications - American

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