Review

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Trends in Micro-/Nanorobotics: Materials Development,

Actuation, Localization, and System Integration
for Biomedical Applications
Ben Wang, Kostas Kostarelos, Bradley J. Nelson, and Li Zhang*

1. Introduction
Micro-/nanorobots (m-bots) have attracted significant interest due to their
suitability for applications in biomedical engineering and environmental The concept of miniature robots that can
remediation. Particularly, their applications in in vivo diagnosis and inter- be actuated and localized inside the human
body to help the diagnosis and treatment of
vention have been the focus of extensive research in recent years with var-
diseases has been popular for decades.[1–7]
ious clinical imaging techniques being applied for localization and tracking. Indeed, this was exactly the theme of the
The successful integration of well-designed m-bots with surface function- movie Fantastic Voyage (1966), in which a
alization, remote actuation systems, and imaging techniques becomes the submarine and its crew were shrunk to the
crucial step toward biomedical applications, especially for the in vivo uses. microscale so that they can voyage inside
This review thus addresses four different aspects of biomedical m-bots: a patient’s body for treatment of a blood
clot. As nanoscience and nanotechnology
design/fabrication, functionalization, actuation, and localization. The
are developing rapidly, functional nanoma-
biomedical applications of the m-bots in diagnosis, sensing, microsurgery, terials form a bridge between robotics and
targeted drug/cell delivery, thrombus ablation, and wound healing are nanomedicine through applications that
reviewed from these viewpoints. The developed biomedical m-bot systems feature the execution of assigned tasks in
are comprehensively compared and evaluated based on their characteris- an on-demand manner through remote
control by a programmable energy input.[1,4]
tics. The current challenges and the directions of future research in this
Unlike traditional robots[8] that are larger in
field are summarized. size, microrobots characteristically possess
sizes less than 1 mm while nanorobots have
sizes less than 1 µm. When the size of an
object is reduced to the micro-/nanoscale, unexpected challenges
Dr. B. Wang, Prof. L. Zhang may appear and thus, the propulsion of micro-/nano-objects
Department of Mechanical and Automation Engineering
The Chinese University of Hong Kong in liquid environment is not as straightforward as those at the
Shatin N.T., Hong Kong, China macroscale. Owing to their small size, m-bots can access com-
E-mail: lizhang@mae.cuhk.edu.hk plex and narrow regions inside human body, such as the distal of
Dr. B. Wang cerebral vessels and bile duct, which are sometimes inaccessible
College of Chemistry and Environmental Engineering with existing minimally invasive medical devices and traditional
Shenzhen University
Shenzhen 518060, China
robots, while being minimally invasive. Up to now, several micro-
Prof. K. Kostarelos
and nanoscale robots of different designs, types of functionaliza-
Nanomedicine Lab tion, modes of actuations, and imaging strategies for localization
Faculty of Biology, Medicine & Health and feedback have been reported for biomedical applications.[9–14]
The University of Manchester It is worth mentioning that another type of nanorobot, known
AV Hill Building, Manchester M13 9PT, UK as molecular motor, has also been developed with proven poten-
Prof. K. Kostarelos tial for targeted drug delivery. As a typical molecular motor,
Catalan Institute of Nanoscience and Nanotechnology (ICN2)
Campus UAB, Bellaterra, Barcelona, Spain DNA nanorobots are generally fabricated as initially folded
Prof. B. J. Nelson structures with DNA aptamer-based locks. The locked DNA
Institute of Robotics and Intelligent Systems (IRIS) structure can be mechanically opened by certain proteins in the
ETH Zurich cells by the specific recognition of the sensing strand, typically
Tannenstrasse 3, Zurich CH-8092, Switzerland the aptamer, causing the release of inner payloads for thera-
Prof. L. Zhang peutic purposes.[15–18] The targeting ability of DNA nanorobots
CUHK T Stone Robotics Institute
The Chinese University of Hong Kong
primarily depends on the protein recognition of the aptamer
Shatin N.T., Hong Kong, China whereas the targeting ability of programmed energy powered
The ORCID identification number(s) for the author(s) of this article m-bots depends either on the energy supply strategies or the
can be found under https://doi.org/10.1002/adma.202002047. combined effect of energy supply and site recognition. Though
molecular motors exhibit the typical ­features of robots to some
DOI: 10.1002/adma.202002047 extent, they are different from m-bots in that their function is

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mostly limited to conformational motion. This review deals batch of micro- and nanorobots is important, and the motion
with the following aspects of energy powered m-bots: design, control of a batch of m-bots differs widely from that of indi-
functionalization, actuation, localization, and application. vidual m-bots. Individual m-bots inside the swarming integra-
To navigate the miniature robots in a low Reynolds number tion are not only governed by the external applied field/energy,
environment where the inertia is negligible compared to the but also influenced by their neighboring bots. In recent years,
viscous force, special strategies should be designed for locomo- in addition to studying individual m-bots, the motion control of
tion. Generally, micro- and nanorobots can be divided into bio- swarms has also been widely studied as they offer several advan-
logical, artificial, and biohybrid types depending on the mate- tages for practical biomedical applications.[41–43] First, swarm
rial with which they are made. Biological m-bots are made of motion and control of m-bots are promising for the delivery of
natural biological materials and show exceptional biocompat- large doses of drugs, cargo materials, or cells, as well as energy
ibility. Artificial m-bots may either be self-propelled or driven such as the heat based on photothermal conversion and mag-
by an external field depending on the energy supplied. Self-pro- netic thermal conversion. Second, the swarming pattern may,
pelled micro- and nanorobots generate the driving force directly as an entity, provide much better imaging contrast than that
from the surroundings and their driving mechanisms can be provided by individual agents at the micro- or nanoscale due
cataloged into self-electrophoresis-, self-thermophoresis-, self- to the accumulative effect, thereby facilitating the localiza-
diffusiophoresis- and microbubble-based propulsion.[19] The tion.[44] Therefore, apart from the individual micro- and nanoro-
self-propulsion of m-bots is very attractive, however, some of bots, the collective behavior of batches of m-bots and their
the chemical fuels in the surrounding environment seriously application for in vivo delivery are separately discussed.
restricted their practical applications in biomedical engineering As shown in Figure 1, in this review, we examine five aspects of
due to the cytotoxicity of the fuels.[20–24] In contrast to self-pro- m-bots, namely, their design, functionalization, actuation, locali-
pelled m-bots, external-field-propelled micro- and nanoscale zation, and applications. The design of the m-bots is defined by
robots, a type of m-bots that can be controlled using a remote, their chemistry and geometry. The functionalization of the m-bots
external field for steering and propulsion, has the advantage is depending on the types of cargos/molecules that are either
that it does not require the presence of chemical fuels inside physically anchored or chemically conjugated on the surface of the
the fluid environment.[25] External fields contain magnetic m-bots. The actuation is systematically summarized according to
fields, electric fields, light, ultrasonic waves, Marangoni effect, the type of energy for the propulsion, and the bots may be pro-
and so forth.[26] Biohybrid m-bots combine the advantages of pelled using magnetic fields, ultrasonic fields, light, electric fields,
natural organisms, such as their geometry, auto-fluorescent fuel, heat, and the Marangoni effect. There are also hybrid m-bots
properties, and biocompatibility, with the multifunctionality of and those propelled based on the collective behavior of the m-bots.
artificial m-bots that results from the use of different materials. The collective behavior of m-bots is dependent not only on the
M-bots have many attractive practical applications, such as propulsion under the applied energy field, but also on the internal
cargo manipulation,[27,28] environmental remediation,[29–34] and interactions between the individual m-bots. For in vivo tracking
targeted therapy,[35,36] and so on.[37,38] Surface functionalization purpose, the localization of the m-bots is discussed based on the
is of critical importance for achieving biocompatibility and ther- adopted medical imaging techniques and are classified into fluo-
apeutic efficiency. Specific functionalization processes based rescent imaging, MRI, US imaging, and radionuclide imaging.
on both physical absorption and chemical grafting should be The applications, especially for the in vivo use of the m-bots, have
selected to endow the surface of the m-bots with certain poly- been reviewed in terms of the following aspects: diagnostics, iso-
mers, proteins, and quantum dots (QDs) for completing var- lation and cell growth, targeted therapy with peroral and injected
ious biomedical and environmental tasks. manners, thrombus ablation, and other bioapplications.
Localization of the m-bots, especially for the in vivo situa-
tion, is also crucial for biomedical applications. A variety of
imaging techniques, including fluorescent imaging (FI), com- 2. Design of m-Bots
puted tomography (CT), magnetic resonance imaging (MRI),
ultrasonic (US) imaging, positron emission tomography (PET), 2.1. Structure and Chemistry
and single-photon emission computed tomography (SPECT),
have been investigated with regard to the localization of micro- Micro- and nanorobots can be divided into biological, artifi-
and nanoscale robots. Benefiting from the synergy of localiza- cial, and biohybrid types. Typical dimensions of a micro- and
tion and navigation, the resultant micro-/nanoscale robots can nanorobot can vary from dozens of nanometers to dozens of
not only be tracked in real time in vitro and even in vivo, but micrometers. Biological and biohybrid m-bots commonly con-
also be used toward targeted delivery and therapy in specific tain natural organisms and are highly biocompatible; how-
locations with vision-based control. Moreover, the introduction ever, the difficulty in shaping them presents a considerable
of the movement of the micro-/nanoagents may also enhance limitation. The majority of the m-bots are artificial m-bots,
­
the imaging contrast when compared with the static micro-/ which are fabricated using either a top-down or a bottom-
nanoagents. The combination of medical imaging techniques up strategy. Top-down strategies applied for m-bots fabrica-
and actuation of the m-bots offers a brand-new active tool for tion include physical vapor deposition (direct deposition and
targeting specific sites and performing medical procedures in a glancing angle deposition), roll-up technique for the fabrica-
minimally invasive fashion.[39,40] tion of micro/-nanotubes and helical microrobots, and 3D
In a practical situation, the individual micro- and nanorobots printing techniques such as direct laser writing.[69] The bottom-
may not have the capability to deliver enough drugs and cure up strategies applied for m-bots fabrication include electro-
the disease completely. Thus, the synergy and cooperation of a chemical/electroless deposition, wet chemical synthesis, and

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Figure 1. Schematic illustration of the types of m-bots for biomedical applications, classified into the design, functionalization, actuation, and localiza-
tion (four aspects). Further details of the four aspects are depicted using images for a visual introduction. The in vivo applications of the m-bots are
listed in the outer ring, including diagnosis, isolating and guided cell growth, microsurgery, targeted drug delivery, targeted cell delivery, thrombus
ablation, and wound healing, and others. Figure created by the authors with the insets reproduced from the following references. Helical: Reproduced
with permission.[45] Copyright 2012, Wiley-VCH; Tubular: Reproduced with permission.[46] Copyright 2014, American Chemical Society. Rod-like: Repro-
duced with permission.[47] Copyright 2017, Wiley-VCH. Ni/Au: Reproduced with permission.[48] Copyright 2005, Royal Society of Chemistry. Au/TiO2:
Reproduced with permission.[49] Copyright 2016, American Chemical Society. Pt/SiO2: Reproduced with permission.[50] Copyright 2010, Wiley-VCH. Ag/Cu:
Reproduced with permission.[51] Copyright 2016, Royal Society of Chemistry. Ag/Zeolite: Reproduced with permission.[52] Copyright 2015, Wiley-VCH.
Soft matter: Reproduced with permission.[53] Copyright 2016, Wiley-VCH. Smart materials: Reproduced with permission.[54] Copyright 2009, National
Academy of Sciences. Functionalization, Dye: Reproduced with permission.[44] Copyright 2015, Wiley-VCH. Polymer: Reproduced with permission.[55]
Copyright 2014, American Chemical Society. QDs: Reproduced with permission.[56] Copyright 2015, Royal Society of Chemistry. Protein: Reproduced with
permission.[57] Copyright 2011, Wiley-VCH. Actuation, Electric: Reproduced with permission.[58] Copyright 2016, Springer Nature. Self-propelled: Repro-
duced with permission.[59] Copyright 2018, Wiley-VCH. Ultrasonic: Reproduced with permission.[60] Copyright 2012, Wiley-VCH. Light: Reproduced with
permission.[61] Copyright 2016, Wiley-VCH. Thermal: Reproduced with permission.[62] Copyright 2017, American Chemical Society; Marangoni effect.
Reproduced with permission.[63] Copyright 2017, Wiley-VCH. Localization, FI and MRI: Reproduced with permission.[64] Copyright 2017, AAAS. CT and
SPECT: Reproduced with permission.[65] Copyright 2017, Royal Society of Chemistry. US: Reproduced with permission.[66] Copyright 2014, SAGE. PET:
Reproduced with permission.[68] Copyright 2015, American Chemical Society.

self-assembly process. All fabrication methods of the m-bots to unpredictable surroundings when they are used for biomed-
will run through the review. ical applications.[87–97] Soft m-bots can be further classified into
The design of the artificial m-bots includes the structural active soft matter and smart materials.
design and component design. On the basis of structure, artifi- Active soft matter refers to the soft-bodied m-bots fabricated
cial m-bots may be divided into rigid and soft, and on the basis using the polymers and organic components. The modulus and
of their appearance, into micro-/nanospheres, rigid/flexible stiffness of the soft matter is generally comparable to real bio-
nanowires, micro-/nanotubes, helical m-bots, and microbullets, logical cells, tissues, and organs, making the as-fabricated m-bots
as shown in Figure 2.[70–86] Rigid m-bots have been extensively resemble biological material more closely and thus, making them
investigated in the past decades, while the attention has been more suitable for biomedical applications. Some of the soft-bodied
shifted to soft m-bots in recent years due to their overwhelming robots can change shape during the navigation.[98] Smart materials
advantages that can interface with the human body and adapt do not simply integrate soft matter into their design, but is also

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Figure 2. a) Periodic table (partial) shows the elements favored in the composition design of m-bots. The highlighted elements with the orange boxes
represent the elements that are frequently applied for design of m-bots. b) FESEM image of an artificial bacterial flagellum. Reproduced with permis-
sion.[109] Copyright 2009, American Chemical Society. c) SEM image of the microwalker. Scale bar is 10 µm. Reproduced with permission.[110] Copyright
2015, Wiley-VCH. d) SEM image of a cylindrical-shaped microrobot. Reproduced with permission.[111] Copyright 2015, Wiley-VCH. e) SEM image of a
Janus sporopollenin exine capsules micromotor partially coated with Pt. Reproduced with permission.[112] Copyright 2017, American Chemical Society.
f) SEM image shows the Pt-coated microbead with a TiO2 arm. Reproduced with permission.[113] Copyright 2011, American Chemical Society. g) TEM
image of a single carbonaceous nanobottle motor. Reproduced with permission.[114] Copyright 2018, Wiley-VCH. h) TEM image of a T7 AuNS (PAH/
PSS)20 PtNP microengine. Reproduced with permission.[46] Copyright 2014, American Chemical Society. i) SEM image of a representative red blood
cell membrane-coated magnesium Janus micromotor. Reproduced with permission.[115] Copyright 2015, Wiley-VCH. j) SEM image of the burr-like
porous spherical microrobot. Reproduced with permission.[116] Copyright 2018, AAAS. k) SEM image of torpedoes microrobots. Reproduced under a
Creative Commons Attribution 4.0 International License.[117] Copyright 2017, The Authors, published by Springer Nature. l) TEM image of an individual
Janus nanotree. Reproduced with permission.[85] Copyright 2016, Springer Nature. m) SEM images of 3D printed microcapsule (top) and microsyringe
(bottom). Scale bar is 20 µm. Reproduced with permission.[118] Copyright 2015, Wiley-VCH. n) SEM image shows the U-shaped microrobot that can
be actuated by magnetic field gradient. Reproduced with permission.[119] Copyright 2013, SAGE. o) SEM image of the hematite peanut microparticles.
Scale bar is 1 µm. Reproduced with permission.[120] Copyright 2013, American Chemical Society. p) SEM image shows the rolled-up polyelectrolyte mul-
tilayer microrockets. Scale bar is 10 µm. Reproduced with permission.[59] Copyright 2018, Wiley-VCH. q) SEM image of a multilinked artificial nanofish.
Scale bar is 800 nm. Reproduced with permission.[53] Copyright 2016, Wiley-VCH. r) SEM images of two types of untethered magnetic microgripper
that are deformable based on magnetic torque and magnetic force, respectively. Scale bar is 500 µm. Reproduced with permission.[121] Copyright 2014,
Wiley-VCH. s) Optical image of a flagellated soft microrobot. Scale bar is 500 µm. Reproduced under a Creative Commons Attribution 4.0 International
License.[122] Copyright 2016, The Authors, published by Springer Nature. t) SEM image of a thermo-biochemically actuated microgripper. Reproduced
with permission.[54] Copyright 2009, National Academy of Sciences.

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adaptable and changeable throughout their entire structure (such As for the larger m-bots, they may be captured by the immune
as spring-mass systems) or at the predesigned hinges (such as seg- cells in the circulatory system such as the monocytes, leukocytes,
mented micro-/nanostructures with several soft joints)[99–101] when platelets, and dendritic cells, and in the tissues/organs such as the
they are exposed to external stimuli like heat, light, ultrasound, resident phagocytes. The resident phagocytes are of various types
magnetic field, electric field, and mechanical force. Li et al.[102] and exist in many organs, including the Kupffer cells in the liver,
developed a magnetic nanorobot with two soft linking arms that alveolar macrophages in the lung, and B cells in the spleen.[106,107]
can perform “freestyle” swimming even in liquids with low Reyn- Accordingly, the size of the micro-/nanomachines should be taken
olds number. The degrees of freedom of these soft robots during into consideration for clearance during the design of the m-bots.
motion are much higher than that of the rigid robots. In addition, the size of the m-bots can also affect the localiza-
The component design of the m-bots should also depend tion and motion during the remote control. The motion of the
on the propulsion regime. In the case of magnetically actuated microscale robots and nanoscale robots is quite different. As the
m-bots, magnetic materials such as Fe3O4, Ni, γ-Fe2O3, and robot size decreases, the interference caused by Brownian motion
FePt,[28,45,54,103] should be considered. For bubble-propelled becomes increasingly obvious. The random changes in the
m-bots in the environment that contains fuel, catalytic ­materials direction of motion, caused by Brownian motion of the nanoro-
such as Au, Pt, Ag, MnO2, TiO2, and enzyme may need be used bots, make the trajectories much more disorganized and disor-
to obtain asymmetric bubble propulsion. In self-propelled m-bots dered than that of the microrobots. The trajectories originate
without bubble release, robots with anisotropic geometry or com- from the guided actuation, and in some cases, should be assessed
position, commonly called Janus particles, are usually applied. by analyzing the statistics, instead of by intuitive evaluation.[108]
Currently, the design and fabrication of micro- and nanorobots
mainly depend on ≈20 elements and most of them are the tran-
sition metals with a few coming from main group, as shown 3. Functionalization of m-Bots
in Figure 2a (the frequently used elements in m-bot design are
highlighted with orange boxes). In the future, design and fabrica- The functionalization of the m-bots is a crucial step to endow the
tion may be realized by exploring other multifunctional elements. m-bots with extra functionalities to perform distinct tasks other
than navigation. For bioapplications, the functionalization process
2.2. Biocompatibility and Biodegradability can be applied not only toward targeted delivery/therapy but also
for the visualization and tracking (i.e., localization) of the m-bots
The biocompatibility and biodegradability of the building blocks both in vitro and in vivo. Moreover, the functionalization process
of the micro-/nanomachines should be also satisfied during the also improves the biocompatibility and prevents the immune
design stage, which can be deduced according to the elemen- system from recognizing m-bots as foreign objects and attacking
tary properties. Generally, biodegradable materials are pre- them, which would increase the retention time in vivo. To date,
ferred during the design since they disappeared gradually after several functionalization strategies and methods have been
use without any postremoval process. These materials can be explored for specific bioapplications via both physical absorption
degraded into noncytotoxic solute in the biological environment and chemical bonding to absorb and anchor molecules of drugs,
and show little harm to the human body while they are controlled polymers, proteins, and QDs onto the m-bots.[123,124,125]
to a moderate amount. In fact, when limited to the relatively mild Wang et al.[126] proposed a self-propelled Au/Ni/PANI/Pt
environment of the biological environment, only a small part microtubular device via a template-based method and followed it
of the materials shows biodegradability. Several biodegradable up with functionalization with concanavalin A lectin bioreceptor
micro-/nanomachines have been developed as building blocks/ for the recognition of Escherichia coli. The authors found that the
functional layers for in vivo uses, such as the inorganic materials m-bots are extremely effective for the easy real-time isolation
like Mg, Zn, and CaCO3, and organic materials such as polydopa- of E. coli in a fuel-enhanced environment and clinical samples
mine, polysaccharides, liposomes, and hydrogel gelatin methacry- as illustrated in Figure 3a. The captured E. coli could also be
loyl,[104] which will be illustrated based on the different catalogs of released from the tubular microrobots in the solution with low
applications in the Section 6. In most cases, the applied materials pH because of the dissociation of the sugar-lectin complex. Apart
cannot be maintained to be biodegradable because of the diverse from the protein, the grafting of polymer on the m-bots can also
requirements for actuation, imaging, and applications. Anyhow, facilitate their bioapplications. Guan et al.[55] developed Mg/Pt-
the building blocks of the micro-/nanomachines should fulfill the poly(n-isopropylacrylamide) (PNIPAM) Janus micromotors that
minimum requirement of biocompatibility during the design. show autonomous motion in simulated body fluids and blood
plasma and can effectively uptake, transport, and affect the tem-
perature-controlled release of drugs due to the partially function-
2.3. Robot Size alized thermoresponsive PNIPAM polymer layers (Figure 3d).
Other polymers, such as PEG, have been widely applied for the
The size of the robots may be another important aspect for bio- functionalization of m-bots for the enhancement of the bio-
medical applications since it directly determines the final direction compatibility. To further enhance the biocompatibility and pre-
in which the m-bots have proceeded in vivo. There are several bio- vent the immune system from recognizing the micro-/nanode-
logical barriers such as the blood-brain barrier, vascular endothelial vices as foreign molecules and attacking them, the researchers
barrier, and glomeruli filter that prevent the passage of m-bots of developed strategies to coat the micro-/nanodevices with cell
specific sizes.[105] For the nanorobots with a small enough size, they membranes.[127–132] Conversely, bacteria membranes can be also
may be discharged from the body with the kidney removal regime. utilized for coating the m-bots to enhance the phagocytosis by

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Figure 3. a) Schematic of the functionalization procedure of protein (concanavalin A lectin bioreceptor) on the microtube for the recognition of E. coli.
Reproduced with permission.[126] Copyright 2012, American Chemical Society. b) Schematic of the fabrication of the hybrid neutrophil microrobots com-
posed with mesoporous silica NPs coated with E. coli membranes. Reproduced with permission.[133] Copyright 2017, Wiley-VCH. c) Schematic of the
functionalization procedure of the CdTe QDs on to the tubular micromotor via electrostatic self-assembly process. Schematic and fluorescent images
of a QDs functionalized microrobot before and after 30 s locomotion in solutions containing Hg2+ (3 mg L−1) and Pb2++Cu2+ (5 mg L−1), demonstrating
the selective detection of the Hg2+. Scale bar is 2 mm. Reproduced with permission.[56] Copyright 2015, Royal Society of Chemistry. d) Schematic of the
temperature-caused controlled drug releasing by Mg/Pt-PNIPAM Janus micromotors. Reproduced with permission.[55] Copyright 2014, American Chemical
Society. e) Schematic of the poly(3-aminophenylboronicacid)/Ni/Pt microrocket and the interaction with glucose and yeast cell along with fructose triggered
release of the cell. Reproduced with permission.[134] Copyright 2012, American Chemical Society.

the phagocytic cell. He et al.[133] developed a kind of chemotaxis- anchored onto the magnetic microparticles by Maier et al.[135]
guided hybrid neutrophil microrobots fabricated from the cam- using a self-assembly process to the flexible tails which made the
ouflaging approach of the drug-loaded mesoporous silica NPs microswimmer easily steerable by the external magnetic field.
with the E. coli membranes and followed it by phagocytosis by In addition to the organic agents and organisms, the inorganic
the neutrophils because of their characteristic chemotaxis capa- functional nanoparticles can also be anchored to the m-bots with
bility (Figure 3b). This type of chemotaxis-guided hybrid neutro- ease. Sanchez et al.[56] proposed tubular microrobots which were
phil microrobots exhibit good cellular activity and motility, and functionalized with QDs via electrostatic self-assembly for the
can be applied for enhanced neutrophil-guided drug delivery real-time optical visualization due to the fluorescence property of
for targeted therapy. The functionalization of the m-bots with the QDs (Figure 3c).
the cells on them was also proposed by Wang et al.,[134] who pro-
posed a poly(3-aminophenylboronic acid)/Ni/Pt microtube func-
tionalized by a boronic acid-based outer layer with an inner plat- 4. Actuation of m-Bots
inum layer. The outer boronic acid layer could perform selective
monosaccharide recognition while the inner platinum worked The actuation of m-bots is essentially the energy conversion
for catalyst-based propulsion. The resultant microrobots could that transforms various energy, such as magnetic energy,
recognize and bind to the yeast cells and glucose and trans- electric energy, light energy, and chemical energy to kinetic
­
port them in the media (Figure 3e). The DNA flagella was also energy. The kinetic energy of m-bots can be used for several

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Table 1. Summary of the features of the mainstream actuation systems toward the biomedical applications.

Actuation field Features Notice for biomedical applications

Magnetic field High penetration of tissue and body Attenuation with distance
Multiple motion modes for adapting different environments, including Applicable for the patients without metal implants
corkscrew motion in suspended environment and tumbling motion in (such as pacemaker)
boundary condition
Collective motion of the magnetic agents for collaborative purpose in
realizing an assigned task and dynamic contrast
Precise and multi-dof control of the tiny robots
Safe and good biocompatibility
Acoustic field High penetration of tissue and body Heat generation during the actuation
Broad selectivity of the motor materials
Fast response and long lifetime
Locally aggregating effect
Can trigger instantaneous ejection of tiny agents with ultrahigh speed
Good biocompatibility
Safe
Light field Can be focused and scattered for collaborative tasks by multiple agents Applicable for superficial tissue
High motion speed of individual robot Suitable for sensing and diagnosis
Fuel Biochemical fuels such as enzyme-triggered biocatalytic reaction are Bubble-propelled motors (e.g., Mg and CaCO3) are
safe and biocompatible promising in the gastrointestinal disease and wound
No external actuation system/setup is required healing with low cytotoxicity and no further removal is
High motion speed required for clearance
Chemotaxis
Electric field Contact free and the low-cost of the set-up Applicable in ionic media such as the interstitial fluid
and blood
Marangoni effect Surface energy guided motion of the tiny agents in contact free mode Applicable for in vitro applications
Magnetic field + Acoustic field High penetration of tissue and body Applicable for the patients without any metal implants
Collective behavior with locally enhanced contrast and dose
Reversible swarming behavior
Safe
Untethered
Good biocompatibility
Magnetic field + Fuel Steerable with high motion speed Combine the high speed of fuel powered motion and
High penetration of tissue and body high precision of magnetic field actuation
Untethered Applicable for the patients without any metal implants

types of specific motion forms such as rectilinear motion, cir- like cargo manipulation and transportation, targeted/directed
cular motion, and spiral motion. According to the forms of the therapy, and environmental remediation. Since low-intensity
supplied energies, the m-bots can be divided into self-propelled magnetic fields are regarded as harmless to living organisms,
and external field-propelled types. In self-propelled m-bots, m-bots actuated and steered by external magnetic fields show
the energy is generally supplied by water, H2O2 solution, and great promise for in vivo applications. Basically, the magnetic
acidic solutions. The reported m-bots actuated by the concen- force (F) and magnetic torque (T) on a magnetic object inside a
tration gradient, self-electrophoresis, and bubbles all belong magnetic field can be expressed as[137]
to the chemical-powered/self-propelled m-bots. The external
field-propelled m-bots are powered by the external magnetic/ F = V (M·∇ )B (1)
electric/ultrasonic field and do not need chemical fuels inside T = VM × B (2)
the environment, making them much more suitable for bioap-
plication compared with the chemical-powered ones. Table 1 Therein, V is the volume of the magnetic object, M repre-
summarizes the features of mainstream actuation systems for sents the magnetization and B represents the magnetic flux
biomedical applications. The following sections will pay more density. From the above equations, we can conclude that the
attention to the introduction of the m-bot actuation based on magnetic force on a magnetic object is zero under a uniform
the requirements of the biomedical applications. magnetic field. The magnetic torque on the magnetic object
depends on the direction of the magnetic dipole moment and
the external magnetic field. In order to obtain a continuous
4.1. Magnetic Field-Propelled m-Bots motion of a magnetic object, the magnetic field must be either
temporal-varying or spatial-varying. Rotating, oscillating, and
Magnetic field-propelled m-bots can transform magnetic energy pulsed magnetic fields belong to the category of temporal-var-
into mechanical energy in the form of the magnetic field gra- ying magnetic fields, while gradient magnetic field is a typical
dient and magnetic torque, to realize their specific applications spatial-varying magnetic field. Based on the type of magnetic

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Figure 4. a) FESEM image of the artificial bacterial flagella with InGaAs/GaAs/Cr helical tail. The scale bar is 4 µm. Reproduced with permission.[143] Copyright
2006, American Chemical Society. b) SEM image shows the helical nanorobots fabricated by GLAD and the trajectories of individual nanoswimmers navigate
the preprogrammed “R@H” tracks in solution. Reproduced with permission.[144] Copyright 2009, American Chemical Society. c) Fabrication procedure of
helical microrobots by direct laser writing and the SEM images of the prepared microrobots. Reproduced with permission.[45] Copyright 2012, Wiley-VCH.
d) Schematic of the fabrication process of helical microstructures by template-based electrodeposition and SEM image of large numbers of Pd nanosprings
fabricated based on commercial AAO template. Reproduced with permission.[153] Copyright 2011, American Chemical Society. e) Fabrication process of the
porous hollow microhelices by biotemplate method and the SEM and TEM images f) of the prepared sample. Reproduced with permission.[155] Copyright
2015, Wiley-VCH. g) Schematic of the fabrication of the helical microrobots. SEM image of the prepared helical microrobots. Scale bar is 300 µm. Confocal
laser scanning microscopy image of the prepared Janus helical microrobots. Magnetic rotation and corkscrew motion of the helical microrobots incorporated
with magnetic NPs. Reproduced with permission.[157] Copyright 2017, Wiley-VCH. h) Schematic of the magnetic tumbling microrobots and the tumbling
modes (lengthwise tumble and sideways tumble can be performed depending on the alignment of the magnetic agents) under a rotating magnetic field.
Optical images show different geometries of the magnetic tumbling microrobots. Optical image shows the programmable trajectory of a rounded rectangle
tumbling microrobot with “P” shape. Navigation of the tumbling microrobots on various terrains (flat paper, cylindrical bumps, knurled surface, and hon-
eycomb terrain) in dry environment with field strength of 10 mT and frequency of 0.5 Hz. Reproduced under the terms of the Creative Commons CC-BY
license.[167] Copyright 2018, The Authors, published by MDPI.

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field, and inspired by the motion of natural microorganisms, recent years, several research groups have developed much
various magnetic field-actuated m-bots/actuators have been simpler designs and structures that perform well under a
developed,[136–141] including the m-bots driven by the magnetic rotating field without any boundary, including the ensemble
force (F) and the magnetic torque (T). of beads,[158–160] planar structures,[161–163] and even randomly
With the simple magnetic force (F) generated with a nonuni- arranged clusters.[104–106] In comparison with the helical m-bots,
form magnetic field, the magnetic objects can be actuated along these simpler designs and structures possess their advantage in
the direction of magnetic field, regardless of their geometry that they can be mass produced due to the simple designs and
and structure. Another typical magnetic field-actuated m-bot fabrication approaches.
is the magnetic torque-(T) powered propulsion in a uniform In a practical situation, the magnetic micro-/nanoagents may
magnetic field with changing field direction. Artificial bacte- not reside in a suspended state and have boundary interactions
rial flagellum is a kind of typical magnetic m-bot that can be with respective boundaries of the confined spaces. The mag-
actuated under a uniform rotating magnetic field. The theory netic micro-/nanoagents can, therefore, be navigated using an
related to the magnetization and propulsion of helical m-bots external magnetic field; this is true even in a uniform case, in
under a rotating magnetic field is well established by Morozov the form of tumbling/rolling which benefits from the boundary
and Leshansky.[142] The helical m-bots are either made of uni- interaction forces. Cappelleri et al.[167] developed magnetic tum-
formly magnetic materials or composed of magnetic heads bling microrobots by photolithography with various geomet-
and helical tails. In 2006, Zhang et al.[143] fabricated a micro- rical shapes that can be navigated on complex surface topog-
artificial bacterial flagellum that contains a magnetic Cr/ raphies with precise trajectory (Figure 4h). The microtumblers
Ni/Au head and an InGaAs/GaAs helical tail based on the use friction to grip the surface and move forward. They can not
self-crimping technique (Figure 4a). The artificial bacterial only tumble into the valleys but also climb steep inclines. Apart
flagellum can be actuated to move ahead, turn a corner, and from the actuation and control of individual microrobots, mag-
move back under a uniform rotating magnetic field with netic tumbling is also applicable for the swarming of a batch
a translational speed of 4.6 µm s−1 in DI water. Thereafter, of m-bots (will be introduced in Section 6.6). This mode of
researchers have developed many other methods, such as ­magnetic motion shows its advantages in universality in terms
glancing angle deposition (GLAD) (Figure 4b),[144–146] direct laser of a wide selection of magnetic-objects and applicability of var-
writing (Figure 4c),[45,147–151] ­ template-based electrodeposition ious surface topographies.
(Figure 4d),[152–154] natural-template method (Figure 4e,f),[155,156]
flow lithography integrated microfluidic spinning and spiraling
system (Figure 4g)[157] to fabricate the magnetic helical robots 4.2. Ultrasonic Field-Propelled m-Bots
with smaller size[144] and environment oriental properties.[122]
Fischer et al.[144,146,147] fabricated a nanoscale helical swimmer Ultrasound field, when used as external energy input to m-bots,
with a diameter of only 200–300 nm and a length of only 1–2 µm can realize noninvasive and on-demand motion control with
using the GLAD technique. It is the smallest helical robot fabri- long lifetime and good biocompatibility. Control and actua-
cated to date, and can be precisely controlled under a magnetic tion of the m-bots by ultrasound, therefore attracted extensive
field to reach a speed of 40 µm s−1. Zhang and Nelson et al.[45] attention during the past decades.[168–175] The m-bots suspended
developed the direct laser writing method to fabricate helical in the solution are driven by the acoustic radiation forces that
microswimmers one by one on a substrate, followed by the consist of a primary radiation force (responsible for the migra-
vapor deposition of Ni and Ti. Magnetic microswimmers show tion of m-bots) and a secondary radiation force (responsible for
good biocompatibility and can be actuated in water with a speed the repulsion and attraction between the m-bots).[168] The ultra-
of up to 180 µm s−1. Park et al.[153] also fabricated the Pt helical sound field-related actuation is adaptable for various m-bots
structure by electrodeposition on the anodic aluminum oxide including the propulsion of metallic nanowires and tubular
template. Gao et al.[154] applied spiral xylem vessel plant fibers as microagents, rotation of microbeads, and the patterning of
the natural template and fabricated the microhelical swimmers nanoparticles.[168] Mallouk et al.[169] developed a kind of nano-
after the e-beam evaporation process of Ti/Ni. Yan et al.[155] used wire via template-assisted electrodeposition on the AAO sub-
Spirulina as the biotemplate to fabricate the biocompatible strate, and the nanowire could be levitated into node plane with
helical microrobots via a coprecipitation method. The flow-
­ an adjustable random motion speed by the MHz frequency
lithography integrated microfluidic spinning and spiraling acoustic waves through the variation of the amplitude and fre-
system was also designed by Zhao et al.[157] for the continuous quency of the acoustic wave. The asymmetry of the nanorods in
generation of helical microrobots. With the method, the length, the composition/geometry can lead to unidirectional motion of
diameter, and pitch of the helical microrobots could be pre- the nanorobots, which is attributed to the self-acoustophoresis
cisely controlled. The helical microrobots could be imparted mechanism. Ultrasound can also offer precise and reversible
with Janus, triplex, and core–shell structures with ease from control of the motion speed of the chemical-powered m-bots.
the fast-online gelation and polymerization by UV illumina- Wang et al.[170] found that the bubble-propelled microrobots
tion. After spatially controlling the encapsulation of NPs in the respond to the ultrasound field instantaneously for the speed
helical structure, the helical microrobots could be actuated not modulation. While the ultrasound field is applied on the bub-
only in the manner of fuel-free magnetic rotation and cork- bling tubular microrobots, the generated O2 inside the catalytic
screw motion but also through fuel-catalyzed bubble propulsion tubular microrobots is ejected immediately without the growth
mode. Although the helical magnetic m-bots can be efficiently process and the gas was driven to the nodes/antinodes, causing
propelled under a uniform rotating field, the design and fab- the microrobots to stop. Different from the rigid m-bots, Nelson
rication procedures are complicated and time-consuming. In et al.[171] described a flexible nanoswimmer composed of a rigid

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Figure 5. a) Schematic illustration of the fabrication procedure of microcannons by template electrodeposition and the loading of cargos by infiltrating
them inside a gel matrix into the interior of the microcannons. b) Schematic illustration of the firing of nanobullets inside the microcannons. c) SEM
images show the microcannons loaded with nanobullets before and after the US triggered firing. d) Fluorescence images show the fluorophore loaded
in microcannons before and after the US triggered firing. Reproduced with permission.[176] Copyright 2016, American Chemical Society.

bimetallic head and a flexible tail. The flexible microswimmer images and fluorescent images of the microcannons before and
can be propelled by the small-amplitude oscillation of its flex- after the US pulse trigger action. The strategy not only offered
ible tail in both the standing and traveling acoustic waves which a controlled firing method of nanobullets from a microstruc-
may facilitate in vivo uses of the US-propelled m-bots since it is ture but also provided improved accessibility to target locations
may be hard to form predictable standing waves in vivo. and enhanced tissue penetration for in vivo applications.
Apart from the sustainable actuation of the m-bots, the
ultrasound field could trigger an instantaneous ejection of the
micro-/nanoobjects with ultrahigh instantaneous speed, which 4.3. Light-Propelled m-Bots
might be in favor of the penetration of the tissue barriers.
Wang et al.[176] developed a controlled and powerful microb- Light, as an environment friendly and renewable energy source,
allistic tool that realized the loading and firing of nanobullets, shows its unique merits in the actuation of m-bots based on the
such as silica and fluorescent microspheres, using electro- light-sensitive molecules and atoms.[177,178] Compared with other
chemically fabricated microcannons (Figure 5a) via acoustical external fields such as magnetic, electric, and ultrasonic, the light
trigger action. The focused ultrasound pulse could cause the field is generally a highly localized field with a focused light beam
spontaneous evaporation of the perfluorocarbon emulsions of that is favorable for conducting collaborative tasks by a group
the nanobullets; the nanobullets were ejected at a remarkably of m-bots, which is intensively reviewed in Section 4.7.[179–182]
high speed, as shown in Figure 5b. Figure 5c,d shows the SEM Due to the limitation of the penetration depth of the tissue, the

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Figure 6. a) Schematic of the fabrication procedure of TiO2/Si Janus nanotree. b) False-colored SEM image of the Janus nanotree forest prepared
on Si substrate. c) Schematic of the propulsion mechanism of the Janus nanotree under illumination. The photoexcited minority carriers drive
the photoelectrochemical reaction on the nanotree surface and the electric field generated by the unbalanced ions propels the charged nanotree
forward. d) Controlled locomotion of a nanotree. e) Superimposed images of the top two images show the original and 3-[2-(2-aminoethylamino)-
ethylamino]-propyltrimethoxysilane- (AEEA, positive charged) treated Janus nanotrees migrate in tail-forward form with positive phototaxis. The
bottom left image shows the 2-(4-chlorosulfonylphenyl)ethyltrimethoxysilane (CSPTMS, negative charged) treated Janus nanotree migrates in
head-forward form with negative phototaxis. The right bottom image shows the Pt NPs coated Janus nanotree migrates in head-forward form with
positive phototaxis. Reproduced with permission.[85] Copyright 2016, Springer Nature.

light-propelled micro-/nanomachines are extremely suitable for i­llumination direction of the outer light source via a self-elec-
diagnosis and treatment at near-skin positions. The structures of trophoresis with photoelectrochemical reaction that generates
the m-bots contain Janus ­spherical micro-/nanoparticles,[183–188] anions and cations at opposite ends of the nanotree and mimics
rod/wire-like m-bots,[189–191] tubular micro-/nanomotors, and the phototaxis of natural motile algae (Figure 6b,d). Both the
other irregular structures with diverse motion modes, including positive and the negative phototaxis of the microswimmer can
self-electrophoresis, self-thermophoresis, and self-diffusiopho- be realized by controlling the zeta potential of the photoanode
resis. All the motion generated from the energy conversion of the (Figure 6e).[85] Another example of the self-electrophoresis
external light energy to the mechanical energy of the m-bots due microrobots is the visible-light-driven bismuth oxyiodide (BiOI)
to the light caused nonuniform gradient field (such as concen- based Janus microspheres powered by photocatalytic reactions
tration, thermal field, and electric field) around the m-bots. The reported by Cai et al.[192] The BiOI was selected due to the narrow
nonuniform gradient field can be generated by either the nonu- band gap (17 eV) which makes the materials activated by the vis-
niform light field or the asymmetric structure of the m-bots. As ible light. The propulsion of the microrobots can be controlled
the nonuniform light field can be applied to actuate the particles by adjusting the wavelength and power of the visible light.
which contain the light-sensitive materials, we mainly focus on Apart from the self-electrophoresis driven m-bots, self-ther-
light-propelled m-bots with asymmetrical structures. mophoresis can be also applied for efficient m-bot propulsion.
Tang et al.[85] developed light-propelled microswimmers He et al.[46,61] developed polymer multilayer rockets with tubular
called Janus TiO2/Si nanotrees that were fabricated through a shape through the template-assisted layer-by-layer assembly
partly growth process of TiO2 on the Si nanowire (Figure 6a,b). and deposition of platinum NPs inside and gold shell outside,
The Janus TiO2/Si nanotree can sense and orient itself to the followed by the functionalization of tumor-targeted peptide and

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antifouling polymer on the gold shell. The NIR illumination that enzymes showed propulsion ability after being anchored
can be applied to rapidly trigger the motion of microrobots via onto the artificial micromachines like carbon nanotubes[220]
self-thermophoresis, and the targeted recognition ability and and tubular microrobots.[221,222] Sanchez et al.[223] proposed
treatment of the tumor by the photothermal effect using NIR bubble-free tubular nanojets propelled by an enzyme-triggered
are also demonstrated. biocatalytic reaction that uses urea as the mild fuel. The lon-
Another type of light-propelled m-bots used light as the switch gitudinal self-actuation and excellent biocompatibility make
to promote photocatalysis of the m-bots which can generate gas tubular nanojets promising for bioapplications. Most recently,
bubbles to propel the m-bots. Compared with the self-propelled Mao, Shen, and coworkers[224] developed nitric-oxide-driven
m-bots, external light energy is required for this type of m-bots, nanomotors made of hyperbranched polymide/l-arginine. The
the on/off of the motion is switchable, and the speed of the NO was generated by the conversion of amino acid L-arginine.
motion is controllable. To date, several types of light-triggered The challenge in this field is the combination of the controlled
bubbling m-bots have been reported, such as the UV-propelled propulsion, biological m-bots, and multiple benign fuels into
TiO2-Au Janus microspheres, and UV-driven TiO2 microtube. an uncomplicated design that will enable the actuation and
Guan et al.[193] fabricated a light-controlled bubble-propelled control of the m-bots in a variety of biological media without
tubular TiO2 microrobot that generated O2 in the inner tube any change in the m-bots.[225]
surface by the photocatalysis of H2O2 under UV irradiation. The
motion of the microtube can be triggered by UV with a control-
lable speed by adjusting the intensity of the UV light. 4.5. m-Bots Propelled by Other Types of Fields

Apart from the above-mentioned actuation strategies, several

4.4. Self-Propelled m-Bots other strategies have been also investigated for the ­propulsion of
m-bots. These may require much harsher environment and are
Self-propelled m-bots are fuel dependent that convert chem- not yet suitable for in vivo use. Therefore, here we have lumped
ical energy and biochemical energy from the surrounding them into a single category to provide a brief introduction.
environment to mechanical energy for autonomous propul-
sion. Several aspects of the design should be evaluated for the
self-propelled m-bot system. Particular attention is to be paid 4.5.1. Electric Field-Propelled m-Bots
to the structural design of the m-bots and the component of
the m-bots that are responsible for the chemical/biochemical Just as magnetic field-propelled m-bots must necessarily have
reactions. These m-bots are mainly in the form of bimetallic integrated magnetic materials in their structures, electric
nanowires, tubular microjets, Janus micro-/nanospheres and field-propelled m-bots must be conductive/semi-conductive or
so on.[194–196] For self-propelled m-bots, motility is commonly charged. Electrical actuation has the merit of being contact-
achieved from either the decomposition of a fuel by a catalyst free and inexpensive. Remote driving of the m-bots by DC
or the degradation of the micro/nanorobots in the liquid envi- and AC electric fields is emerging as a new wireless control-
ronment.[194–199] From the literature regarding self-propelled lable and fuel-free actuation method that uses electrophoretic
m-bots, a considerable portion of the research focuses on the motion, electro-osmotic flow, and electrorotation.[226–236] When
catalytic decomposition of hydrogen peroxide (H2O2).[30,200–211] a uniform DC electric field is applied, the charged objects
By integrating proper catalysts onto the m-bots such as Au, Pt, migrate toward the electrode having opposite charge due to
and MnO2, H2O2 can be decomposed to water and oxygen for the Coulomb interactions.[227] When an AC electric field is
gas propulsion.[212,213] Although the H2O2-fueled m-bots could applied, m-bots can be also actuated in a controlled manner.
achieve a much higher propulsion speed than other motors, The AC electric field can be utilized to actuate the objects
hydrogen peroxide is regarded as toxic to the organs and tis- at the microscale as well due to the dielectrophoretic forces; the
sues in the in vivo environment and shows limitation for bio- torque exerted on the objects by the electric field caused dipole
medical applications.[214] moments and electro-osmotic flow.[230,231] The motion of the
Enzyme-based m-bots open up a brand-new strategy to microagents actuated by the DC electric field is typically simple
promote biocompatible self-propelled m-bots for biomedical and cannot adapt to the complex fluid environment with the
applications owing to the good reaction rate and availability roundabout trajectory. In most of the previous works, AC elec-
of various choices in enzyme/fuel combinations. As one of tric fields were applied for m-bot propulsion instead of DC elec-
the special self-propelled m-bots, enzyme-based m-bots com- tric fields.[227,228] Electrorotation of magnetic and nonmagnetic
monly use the enzymes as catalysts in lieu of metals like Au, nanowires with precisely controlled rotational speed can be also
Pt, Ag, and MnO2, and show high activity and biocompat- achieved by four phase-shifted AC voltages with a sequential
ibility.[215–218] Sanchez et al.[84,219] developed a self-propelled phase shift of 90°.[226,236] Wang et al.[229] developed poly(pyrrole)-
Janus nanorobot based on hollow mesoporous silica nanoparti- cadmium (PPy-Cd) and CdSe–Au–CdSe semiconductor nano-
cles which were actuated by biocatalytic reactions based on the wires and actuated them under an external AC electric field by
three types of enzymes fixed on the surface of the Janus nano­ the electro-osmotic flow mechanism to obtain the directional
particles, i.e., catalase, urease, and glucose oxidase. The bio- locomotion of nanowires because of the electro-osmotic flow.
compatible enzyme-based active nanomotors offered exciting Unlike electro-osmotic flow-propelled micromachines, the
potential of using the biological benign fuels for biomedical electric field can also trigger asymmetric bubble production
applications.[219] Some other researchers have also verified via redox reaction at the two faces of the Janus particles. The

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Figure 7. a) Schematic illustration of the propulsion mechanism of anti-Marangoni and Marangoni effects. b) Illustration of the reversible photoi-
somerization of the photosensitive azobenzene-containing surfactant AzoTAB. c) Time lapse images show the propulsion of a liquid marble (white
arrow) by UV irradiation induced Marangoni effects and anti-Marangoni effect. The purple dot denotes the center of the light spot. Reproduced with
permission.[242] Copyright 2016, Wiley-VCH. d) Translational motion of a PS solid particle on the surface of a liquid crystal film doped with dl-azomenth.
by UV and visible light irradiations. Reproduced with permission.[246] Copyright 2009, Wiley-VCH.

released bubbles can propel the micromotors continuously with caused by the gradient of the interfacial tension. In most cases,
both translational and rotational motions. the Marangoni effect is utilized to actuate the motors and drop-
However, the bioapplications of electric field-propelled lets of the visible scale; however, the study is still instructive
m-bots may be limited due to their short locomotion range that for the design and fabrication of the next-generation m-bots,
is resulted from the rapid attenuation of the electric field with especially for applications at the surface and interface of
the distance, and the electric field may be incompatible[232] with solid, liquid, and air. The Marangoni effect-propulsion occurs
highly ionic media such as the interstitial fluid and blood. chiefly at the liquid/air or solid/liquid interfaces.[237–240] Baigl
et al.[241] developed a technique that can actuate the oil drop-
lets on the water surface for controlled liquid transportation
4.5.2. Marangoni Effect-Propelled m-Bots and high precision droplet coalescence. The authors dissolved
cis-AzoTAB into the solution as this molecule could change
Marangoni effect is a liquid flow motion that occurs on the configuration under light irradiation due to photoisomeriza-
interface between two different phases (e.g., liquid and air), tion (Figure 7a,b), resulting in a change in the surface tension

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www.advancedsciencenews.com www.advmat.de

of the water solution. The local change in the surface tension work demonstrated that the hybrid power actuation of the
would cause the liquid to flow toward the low liquid-tension m-bots can realize the reversible swarming states and collec-
region (Figure 7a). Therefore, the droplet can be transported on tive behaviors, which is hardly possible by the single propul-
demand using the Marangoni effect. Apart from the actuation sion mode.
of the liquid droplets, the actuation of the solid objects and even
the liquid marbles composed of both liquid and solid phases,
can be propelled using the Marangoni flow and anti-Marangoni 4.6.2. Hybrid of Natural Microorganism and the
flow (Figure 7c), as reported by Baigl et al..[242] Kurihara et al.[246] Artificial Microdevices
showed the translational motion of the micro-objects (i.e., PS
microspheres) on the surface of a liquid-crystalline thin film Apart from the artificial m-bots, hybrid m-bots that are a com-
caused by the Marangoni effect. With the irradiation of the sur- bination of natural microorganisms and artificial microdevices
face by UV and visible light, the PS microsphere was actuated have also been developed.[256–263] Sanchez et al.[256] developed
and the direction of motion was dependent on the direction sperm-propelled biohybrid microrobots comprising of a motile
and position of the irradiation (Figure 7d). Besides the actua- sperm cell and a magnetic microtube (Figure 9a). The micro-
tion of the single microrobots, the collective motion of many bio-robots are self-propelled by the sperm cell and steered with
tiny microrobots could be also archived by the Marangoni an external magnetic field (Figure 9c). No toxic fuel is used
effect. Zhao et al.[247] reported a Janus catalytic micromotor that in the system unlike other chemically fueled m-bots. Another
could generate the O2 bubbles in an H2O2 environment. As the sperm-propelled, helical micro-bio-robot actuated and steered
bubbles coalesced and grew, the micromotors moved collec- using a magnetic field was fabricated by 3D direct laser writing
tively toward the bubble and eventually formed an aggregation and subsequent Ni coating by the same research group.[257] The
around the perimeter of the bubble because of the evaporation- sperm-propelled micro-bio-robot could serve as an assistor to
induced Marangoni flow around the bubble. Several other deliver healthy but immotile sperm to an egg, which may aid in
researchers have also demonstrated the existence of M ­ arangoni infertility treatments (Figure 9b,d). Further, they[259] found that
flow-induced propulsion of tiny agents, as described in the these biohybrid microswimmers may also be used as t­argeted
works by Shi et al.[243,244] and Sun et al..[245] Accordingly, the drug delivery carriers. The motile sperm cell in this biohy-
actuation of the objects on the liquid surface is independent on brid microswimmer not only served the purpose of providing
the objects but highly dependent on the liquid surface. Maran- propulsion, but also acted as the carrier. A 3D-printed mag-
goni and anti-Marangoni propulsion are versatile strategies for netic tubular microstructure was used for precisely steering
the actuation of such tiny machines. the sperm and the hitting-induced release of the sperm cell
for drug release, as demonstrated in Figure 9e. Wang et al.[258]
developed an intelligent self-guided biomotor with chemotactic
4.6. Hybrid m-Bots motile behavior, which is prepared by the functionalization
of various nanoscale payloads such as quantum dots, doxoru-
4.6.1. Multiple Energy-Propelled m-Bots bicin hydrochloride drug-coated iron-oxide NPs, and fluores-
cein isothiocyanate-modified Pt nanoparticles with the sperm
Hybrid m-bots use two or more energy sources for their naviga- micromotors. These micromotors can be applied for the tar-
tion and control, and thus, extend the scope of manipulation of geted drug delivery carriers with the transportation of the cargo
the m-bots in complicated and changeable environments.[248–253] guided by the intrinsic chemotaxis of the sperm micromotors.
Wang et al.[253] fabricated a catalytically/magnetically powered Besides, the bacteria biohybrid microswimmers[264–267] were
adaptive nanowire swimmer composed of a flexible multiseg- also proposed by Sitti and Sanchez et al.[264] to propel the micro-
mented Pt–Au–Agflex–Ni nanowire (Figure 8a,b), with the tubes with the motile E. coli in biological media prepared via
Pt–Au and Au–Agflex–Ni portions responsible for catalytic and adhesive bonding of E. coli with the inner side of a microtube
magnetic actuation, respectively. Hybrid m-bots powered by two with a PDA layer. To further increase the loading-carrying effi-
energy sources can switch their mode of motion from catalytic ciency, biocompatibility, and biodegradability, they reported
to magnetic and thus, respond better to the changes in the sur- another bacteria-propelled biohybrid microswimmer that
rounding environment (Figure 8c). Mallouk et al.[112] presented used red blood cells as autologous cargo carriers for active and
a synthetic bimetallic micromotor, which can be actuated with guided drug delivery.[268] The red blood cells loaded with drugs
both the positive and negative rheotaxis property by the hybrid and superparamagnetic iron oxide NPs were fixed on the motile
driving force of the chemical fuel and acoustic field (Figure 8d). bacteria by chemical bonding, and the microswimmers were
Other m-bots actuated with two energy sources, such as UV steered using an external magnetic field. After the treatment,
and NH3, have also been reported.[254] the bacteria can be killed using the on-demand light-activated
In addition to the self-propelled and external field-steered hyperthermia process for the controlling of the bacteria popula-
hybrid m-bots, the motion and direction of the m-bots can be tion to a safe range in the organisms.
controlled with the external fields, avoiding the use of chem-
ical fuels.[255] Wang et al.[249] developed a magnetic/acoustic
hybrid fuel-free nanorobot composed of a segment of Au 4.7. Collective Behavior of m-Bots
nanorod and Ni-coated Pd helical structure (Figure 8e), which
can be actuated by either a magnetic or an ultrasonic field in The actuation and control of single m-bots using different
an on-demand manner (Figure 8f,g). More importantly, this energy sources have been extensively studied. However, in

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Figure 8. a) Schematic illustration of the catalytic and magnetic actuations of the hybrid Pt–Au–Agflex–Ni nanowire. b) SEM image shows the flexible
Pt–Au–Agflex–Ni nanowire motor. c) Motion of the hybrid nanowire motors i) without fuel and magnetic field, ii) with fuel, and iii) with magnetic field.
Reproduced with permission.[253] Copyright 2011, Wiley-VCH. d) Schematic illustration of the design of the magnetoacoustic hybrid microrobot and the two
types of actuation modes under acoustic and magnetic fields, respectively. Reproduced with permission.[112] Copyright 2017, American Chemical Society.
e) SEM image of a magnetoacoustic hybrid microrobot. Scale bar is 500 nm. The cycling motion processes shows the f) tracking lines and g) speed changes
between the magnetic propulsion, acoustic propulsion and without any fields. Reproduced with permission.[249] Copyright 2015, American Chemical Society.

practical applications, the single m-bot may be subject to its and dependent motion. In the independent motion mode of
limited capacity and unable to realize the expected objectives. the multiagents, the microagents are all independent without
The use of multiagents may become indispensable for the com- any restriction of origin from their neighbors. Their actua-
pletion of the designated tasks. The locomotion and control tion is, therefore, similar to that of the single m-bots. Inspired
of the multiagents have two modes, i.e., independent motion by the natural collective behavior indicated in Figure 10a,b,

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Figure 9. a) Schematic of a micro-bio-robot comprised of a motile sperm cell trapped inside a microtube. Reproduced with permission.[256] Copyright
2013, Wiley-VCH. b) Capture process of an immotile sperm by a magnetic helical microrobot controlled with external magnetic field to the oocyte for fer-
tilization. Reproduced with permission.[257] Copyright 2016, American Chemical Society. c) Coupling process shows a bull spermatozoon swarm trapped
inside a microtube. Reproduced with permission.[256] Copyright 2013, Wiley-VCH. d) Successive images show the i) sperm cell coupling, ii) transporta-
tion, iii) approaching the oocyte membrane, and iv) releasing processes. Reproduced with permission.[257] Copyright 2016, American Chemical Society.
e) Schematic of the transport and delivery of drug-loaded sperm by the hybrid microrobot to the tumor cells. SEM image of the microrobots. SEM
images show the sperm−HeLa cell fusion by the hit process. Reproduced with permission.[259] Copyright 2018, American Chemical Society.

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Figure 10. a) Collective behavior of fish and starling birds. Left image: Reproduced under the terms of a Creative Commons Attribution 4.0 International
License.[289a] Copyright 2016, The Authors, published by Springer Nature. Right image: Reproduced under the terms of a Creative Commons Attribution
4.0 International License.[289b] Copyright 2019, The Authors, published by Springer Nature. b) Light-propelled collective motion. The false color images
show the time dynamic evolution of the collective behavior of Janus particles belonging to diverse clusters under light radiation. Reproduced with per-
mission.[276] Copyright 2013, AAAS. c) US-propelled collective behavior. Schematic of the different motions of metal microrods under acoustic field and
dark field views of the typical chain structures and ring patterns formed by the microrods. Reproduced with permission.[169] Copyright 2012, American
Chemical Society. d–f) Magnetic field-propelled collective behavior. d) Reconfigurable swarm of magnetic particles with controlled particles swelling
and shrinking. e) Reversible elongation of ribbon-like swarming pattern. Reproduced with permission.[287] Copyright 2018, The Authors, published by
Springer Nature. Scale bar is 600 µm. f) Locomotion of magnetic particles in channel through swarming mode under magnetic field. Reproduced with
permission.[284a] Copyright 2018, SAGE. g) Hybrid energy input-propelled collective motion. Schematic and optical images show the collective motion
mode of clusters of superparamagnetic particles rolling along the wall of a channel under the magnetic field and acoustic field. The aggregation of
the particles is caused by the dipole–dipole interaction in the magnetic field and the migration of the particle clusters toward the wall is due to the
radiation force in the acoustic field. Reproduced under the terms of a Creative Commons Attribution 4.0 International License.[290] Copyright 2017, The
Authors, published by Springer Nature.

i.e., schooling of fish (Figure 10a) and swarming of starling The micro-/nanoagents inside the collective motion are all
birds (Figure 10a), the investigation of the collective behavior dependent and communicate with their neighbors, even with
and swarming motion of the m-bots have also been put on the inert micro-/nanoparticles inside the efficient region, in the
the agenda.[269,270] The collective behavior is strongly distance form of either attraction or repulsion. While the concentration
dependent. The short-range forces with either attraction or of the m-bots is low, more than one swarm pattern may be gen-
repulsion such as van der Waals attraction, electrostatic inter- erated because the short-range ­interactions between the active
action, steric repulsion all work during the swarming. Each particles may not strong enough to merge all the particles. The
unit generates a flow field that is experienced by the sur- collective motion and swarm formation of the m-bots allow the
rounding units and induces aligning interactions.[36,271–273] coordinated locomotion of dissimilar objects, making it easier

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Table 2. Comparison of and biomedical application scope of single m-bot, multiple m-bots, and swarming m-bots.

Pros Cons Biomedical application scope

Single m-bot 1) High precision control 1) Limited imaging contrast 1) Sensing
2) Applicable for 2D motion and 3D 2) Significant interference by Brownian 2) Diagnosis
motion motion for tiny robot 3) Guided nerve cell growth direction
4) Surgery
Independent actuation of 1) Large-area therapeutic effect; 1) Potential loss during locomotion in 1) Drug delivery toward broad region
multiple m-bots 2) Relatively high motion speed curved and branched channels 2) Gastrointestinal drug delivery
3) Effective motion mode for 2) Limited imaging contrast due to 3) Would healing
unbranched vessel the dispersion
Swarming of multiple m-bots 1) Reconfigurable and self-adaptable 1) Relatively low motion speed 1) Drug delivery toward specific site
motion through narrow channels 2) Motion along an interface 2) Targeted thrombolysis in 3D branched
and small cavities with low 3) Hard to move on a stepped surface vessel
agents’ loss
2) High imaging contrast due to the
aggregation effect and dynamic
motion
3) High precision control toward the
target

to transport and deliver cargoes to the designated regions. of the particles may attributed to the osmotic propulsion or
Table 2 summarized the pros and cons of the single m-bot, diffusiophoresis.
multiple m-bots, and swarming m-bots toward their biomedical The magnetic field-controlled swarming motion was recently
applications. reported.[271,283–286] The magnetite nanoparticles fabricated from
Light induced collective behavior has been extensively the solvothermal method can be assembled to a planar dynamic
studied.[274–276] Sen et al.[274] reported the light-driven collective cluster and disassembled to dispersed nanoparticles after the
behavior of the AgCl microparticles in aqueous solution under application of the rotational and dynamic magnetic fields,
UV radiation. The mechanism of the collective motion was respectively. The final particle concentration can be increased
attributed to diffusiophoresis. The UV radiation caused the dis- to ≈500% of the initial concentration for the assembly process
solution of AgCl to generate the protons and chloride ions.[275] and decreased to ≈20% of the initial concentration for the disas-
As a result, an electric field was generated in the solution sembly process. The assembled vortex swarm pattern can also
that acted both on the particles and on any nearby wall double realize the reversible merging and splitting process as shown
layer as the diffusivity of protons is much higher than that of in Figure 10.[283,284] The swarming motion can be also well
the chloride ions. The electrolyte gradient creates a pressure performed on uneven surfaces.[283b] The entity of swarm pat-
difference, which induces a flow of liquid from the region tern can be actuated to pass through the curved and branched
with high electrolyte concentration to the region with lower channels to the designated site with high precision with negli-
electrolyte concentration, describing the collective behavior. gible particle loss less than 10%, which is much more efficient
The study also offered a nonbiological model for the investi- than that of the conventional tumbling motion. Furthermore,
gation of the cell signaling and collective behavior. Similarly, they also extended the magnetic swarm behavior from 2D to
the 2D collective behavior of the Janus particles composed of 3D by introducing the dynamic bubbles for the purpose of
polymer microspheres with an antiferromagnetic hematite crosslinking and vertical axis stacking of the nanomotors.[271]
cube on one side is also demonstrated with the activation by Compared with the 2D swarming motions without bubbles,
light by Palacci et al.,[276] termed as living crystals. The osmoti- the integral rotation and translation was improved due to the
cally driven motion and steric hindrances caused the forma- dynamic dewetting and increased slip length caused by the con-
tion of dynamic living crystals. A thermally induced collective tinuously ejected tiny bubbles.
is also reported by Buttinoni et al.,[277] who presented an experi- Apart from the isotropic swarming clusters, anisotropic
mental study of a colloid suspension of Janus particles that are swarming clusters can be also formed. Zhang et al.[287] devel-
self-propelled by the heating (532 nm) of carbon-coated hemi- oped a reconfigurable ribbon-like swarming pattern with
spheres in a mixture of water and lutidine. In this system, a dynamic-equilibrium structure in fluid under a programmed
number of small dynamical clusters appear at low densities oscillating magnetic field. The reversible elongation with high
and one big cluster appears at high densities, which is ration- aspect ratio and controlled splitting and merging of subswarms
alized in terms of a dynamical instability because of the self- are realized. The authors also demonstrated that the ribbon-
trapping. Other photocatalytic and photosensitive m-bots are like dynamic swarming pattern can pass through a confined
also developed, such as SiO2–TiO2 micromotors,[278] Fe2O3 channel toward multiple targets with high access rates and
micromotors,[276,279] and TiO2-Pt micromotors.[247,280–282] For perform noncontact micromanipulation in the fluid. Apart
instance, Sen et al.[278] developed SiO2–TiO2 microparticles that from the planar swarming pattern, they further extended
can be reversibly assembled and disassembled under UV illu- the swarming behavior into 3D form by the introduction of
mination. The authors suggested that the TiO2 generated O2−, NIR light.[288a] To promote the biomedical applications of the
·OH, and H+ under the UV light and the collective behavior swarming m-bots, they have archived and systematically studied

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Table 3. Summary and comparison of bioimaging modalities for tracking the m-bots.

Advantages Limitation Imaging probe

Fluorescent imaging Excellent planar resolution (≈100 nm); Shallow imaging depth (≈2 mm); poor biocompatibility M-bots decorated with fluorescent dyes
high sensitivity and biodegradability and nanoparticles
MRI Nonionizing radiation; high soft tissue High cost; long imaging time Magnetic m-bots
contrast
US imaging Noninvasive; portable; low-cost; Limited penetration/sensitivity; low signal noise ratio; M-bots generating microbubbles
safe; fast low resolution; interfered by bone
Radionuclide imaging High sensitivity; fast imaging time Low spatial resolution (≈1–2 mm); ionizing radiation Radioactive tracer functionalized m-bots
PACT High resolution; fast imaging time Limited penetration depth M-bots with high absorption of NIR

the active generation and magnetic actuation of microrobotic location with vision-based control. Moreover, the additional
swarms in various biofluids under the real-time tracking by motion of the m-bots may also enhance the imaging contrast
clinical imaging tools such as US imaging.[288b] because of the dynamic behavior in contrast with the static
The input of hybrid energies into a cluster of particles m-bots. Enormous advances in biomedical imaging[39,40] have
can cause a more diversified motion behavior. As showed in made the visualization of movable micro- and nanorobots a
Figure 10g, Nelson et al.[290] combined the magnetic field with novel tool for targeting specific locations with high precision
the acoustic field and applied to the particles system with and accomplishing certain medical tasks in a minimally inva-
boundaries to mimic the vasculature environment. They found sive fashion.
that the superparamagnetic particles that assembled to form
multiple clusters inside the vasculature exhibited rolling motion
along the wall of the vessel. From the combination of the mul- 5.1. Fluorescent Imaging
tiple external energies, this new motion behavior may overcome
the limitations encountered by single-energy actuation and Fluorescent imaging is an efficient imaging technique that is
shows its potential in targeted therapeutics. Li et al.[291] proposed widely used both in vitro and in vivo. Compared with other
another hybrid energy-driven collective behavior of nanomo- imaging techniques, fluorescent imaging has the advantages that
tors. The light and ultrasound fields were applied to control the it applies only nonionizing radiation to the tissues and that the
aggregation and separation of the nanomotors with ease. probe materials are relatively inexpensive. Various fluorescent
The motion of the swarming m-bots can be easily impacted probes like semiconductor quantum dots (QDs), fluorescent
by the fluidic environment, such as viscosity, mobility of the metal organic frameworks and organic dyes have been developed
liquid, boundary effect, and other impurities. Further investi- to label the cells at specific areas and peculiar biomolecules.[292–294]
gations about this field may require the development of highly Fluorescent imaging has also been miniaturized and integrated
responsive m-bots with rational structural and componential in catheterization and endoscopy systems for enabling minimally
design for overcoming the potential motion inhibition in real invasive inspection of deep tissue.[295] Owing to these advantages
biological systems. of fluorescent imaging, the i­ntegration of the actuation and con-
trol of m-bots with fluorescent imaging simplifies the localization
and next-step actuation of the m-bots and broadens the bioappli-
5. Localization of m-Bots cation to active bioimaging and diagnosis. To date, several fluores-
cent m-bots have been reported to achieve the fluorescence-based
Localization of m-bots is essential for their practical applica- tracking of m-bots with precisely targeted imaging under the vis-
tions. The location of the m-bots and the target inside the prac- ible locomotion using external fields. Based on the raw materials
tical application system is crucial for the next-step navigation used for imaging, the fluorescent m-bots can be classified into
of the m-bots. For in vitro applications such as sensing, the autofluorescence- material based microrobots, dye-based micro-
m-bots are generally localized readily with an optical micro- robots, and quantum dot-based microrobots.
scope and as a feedback, the location information also provides In nature, part of the biological organisms possesses
the manipulator with the next step to control the m-bots. If intrinsic fluorescence properties in the range from UV-visible
the m-bots are applied for in vivo applications such as tumor light to the near-IR light.[296] The autofluorescence of these
therapy and thrombus ablation, optical microscopy is unsuit- organisms originates from complicated molecules that serve as
able, and other imaging techniques should be explored to endogenous fluorophores. If autofluorescent organisms are
visualize the m-bots across the tissue. Newer imaging tech- used as the template to prepare m-bots, the as-prepared devices
niques including fluorescent imaging (FI), magnetic reso- may inherit the fluorescent property and facilitate the tracking
nance imaging (MRI), ultrasonic (US) imaging, computed of the devices even in real-time mode. The SU-8 photoresist is a
tomography (CT), positron emission tomography (PET), single- fluorescent material that shows its emission near the blue and
photon emission computed tomography (SPECT), and photoa- green light region. Steager et al.[119] fabricated autofluorescent
coustic computed imaging (PACT) have been tried for m-bot and biocompatible magnetic microrobots by printing using a
localization (Table 3). The synergy of imaging and motion con- mixture of the photoresist and iron oxide NPs. The autofluores-
trol makes it possible for targeted delivery/therapy in a destined cent microrobots could be actuated with an external magnetic

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Figure 11. a) Schematic of the surface functionalization process of the artificial bacterial flagellum microswimmers with NIR-797 dyes. b) SEM images
show the integral and enlarged views of the artificial bacterial flagellum microswimmers and the optical image shows the magnetic property of the
microswimmers. c) Schematic of the in vivo experiment conducted under the magnetic coil system, and the image of an anesthetized mouse inside
the coils. The red spot is the fluorescent signal generated by the injected artificial bacterial flagellum microswimmers. d) Successive images show the
in vivo tracking of the motion of artificial bacterial flagellum microswimmers. a–d) Reproduced with permission.[44] Copyright 2015, Wiley-VCH. e) TEM
images show the magnetotactic bacteria and the magnetosomes inside the bacteria. Reproduced with permission.[304] Copyright 2008, American
Chemical Society. f) The left microscope images show the bacteria after targeting to the interstitial area of tumor. The SEM image at the right side is a
magnetotactic bacteria with a chain of two flagella with the superposed distortion of the spatial magnetic field distribution. The MRI image shows the
magnetotactic bacteria swarm motion along the predesigned trajectory in microchannels. The MRI contrast of the magnetotactic bacteria with various
concentrations. Reproduced with permission.[305] Copyright 2009, SAGE. g) The upper image illustrated the folding and unfolding processes of the
microgripper controlled by temperature variation. The middle and lower images show the successive snapshots of the gripper during manipulation
and transportation of a beads captured by US and microscope imaging techniques, respectively. Reproduced with permission.[319] Copyright 2017, IEEE.

field and tracked in a dark field, demonstrating the potential of integrated with a fluorescent microscope, in the subcutaneous
fluorescence-based real-time tracking of the microswimmers. tissue and intraperitoneal cavity of nude mice.
Another example used natural autofluorescent organisms as Apart from autofluorescence, organic dyes are also widely
the template. Zhang et al.[64] developed a biohybrid helical mag- used as contrast agents for the imaging of biomolecules, cells,
netic microrobot by using Spirulina as the template to coat iron and organisms due to their easy availability and small molecule
oxide NPs via a dip-coating procedure. The resultant biohybrid size, which lower the risk of possible steric hindrance that may
helical magnetic microrobots show autofluorescence that interfere with biomolecule function.[297] Due to its ability for easy
could emit red light under the green light illumination. The conjugation that aids anchoring, organic dyes are applied with
authors demonstrated in vivo the real-time tracking and diag- m-bots for imaging. Servant et al.[44] proposed an artificial bacte-
nostic sensing under the guidance of an external magnetic field rial flagellum microswimmer modified with near-infrared probes

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NIR-797 (Figure 11a,b). While the artificial bacterial flagellum 5.2. MRI
microswimmers were injected into the intraperitoneal cavity of
a 4-week-old Balb/C mouse, an obvious fluorescent signal was For m-bots guided by the magnetic field, MRI is a very efficient
detected in the abdominal cavity that was consistent with the tool to localize the magnetic m-bots both in vitro and in vivo
location of the artificial bacterial flagellum microswimmers with high contrast.[303] Imaging of m-bots with MRI possesses
(Figure 11c). When the microswimmers were actuated toward several advantages over other imaging techniques, especially
the lower part of the mouse body, the red and yellow s­ignals CT. First, MRI does not expose biological systems to ionizing
moved simultaneously, which was captured by the fluorescent radiation. Second, MRI can achieve 3D section imaging without
microscope in real-time (Figure 11d). The results demonstrated reconstruction. Third, MRI also gives better imaging contrast
the effectiveness of in vivo targeted imaging under the guidance for soft tissues such as bladder when compared with other
of an external magnetic field in realizing the whole-body fluores- techniques, and higher imaging resolution than CT. Basically,
cence imaging with the usage of long-wavelength dyes. two types of imaging modes are applied for MRI, namely, d
Quantum dots, which are ultrasmall size nanomaterials in longitudinal relaxation (T1-recovery) and transverse relaxation
the range of 1–10 nm, have been used for imaging in the form (T2-recovery). The T1 contrast agents generate bright contrast
of pure QDs and complexes that integrate QDs with different and T2 contrast agents generate dark contrast, respectively.
nanomaterials/nanoparticles including m-bots. QDs exhibit Commonly, superparamagnetic nanoparticles which are widely
remarkable optical properties such as high quantum yields, used for the construction of magnetic m-bots is applied as T2
broad absorption range, narrow and size-adjustable emission, contrast agents. The contrast can be enhanced with the increase
and good resistance to photobleaching.[298,299] Jurado-Sánchez in the concentration of the contrast agents and the magnitude
et al.[56] developed for the first time a kind of microtube fixed of magnetization (applied external magnetic field). As a type of
with CdTe QDs via a layer-by-layer self-assembly process which external field actuated m-bots, magnetic m-bots can be powered
coupled the optical properties of QDs and autonomous motion either by the magnetic field itself or powered by other means
of the microrobots. Moreover, the change in fluorescence was but steered by the magnetic field as illustrated in section on
monitored for evaluating the capability of detection of the actuation. To date, both natural and artificial magnetic m-bots
toxic organic and inorganic agents. However, QDs generally have been reported for visualization with MRI. Magnetotactic
exhibit severe cytotoxicity and the functionalization process of bacteria can align their body with an external magnetic field.
QDs on m-bots may easily cause the quenching of the fluores- The chain of magnetosomes inside the body of magnetotactic
cence, which limit the in vivo bioapplication of the QD-based bacteria, as shown in Figure 11e, causes them to arrange their
m-bots. To overcome the cytotoxicity, carbon quantum dots, body in an orderly fashion along the external magnetic field.[304]
which are QDs with good optical properties and biocompat- Martel et al.[305–308] systematically studied the motion behavior
ibility, have been developed for bioimaging applications.[300] of the magnetotactic bacteria and found that they navigate
Jurado-Sánchez et al.[301] loaded graphene quantum dots into through the microvasculature for directed chemotherapy under
the Janus microrobots to obtain the fluorescence microscope MRI. The authors established a medical interventional system
trackable micromachines under a dark field, which could be that used MRI as an imaging technique for feeding back loca-
applied for the detection of bacteria endotoxins. tional information to the controller, which takes responsibility
As demonstrated by the above-mentioned three types of fluo- for the real-time navigation of the magnetotactic bacteria and
rescent m-bots, the fluorescence imaging-based m-bots have the artificial m-bots along preplanned paths in blood vessels to
the advantages of high sensitivity, high selectivity, and diverse conduct targeted delivery tasks (Figure 11f). They also showed
features. But commonly, they possess the limitation of the that the MRI platform can be applied for the tracking of
low penetration of biological tissues that renders them unsuit- polar magnetotactic bacterial robots to load cargo.[309,310] They
able for deep-tissue imaging. Different fluorescent m-bots ­suggested that steerable magnetotactic bacteria may be applied
have their own limitations. In autofluorescence-material based for the treatment of cancer and thrombosis by using MRI as
­microrobots, the autofluorescence phenomenon is ubiquitous an imaging technique. Apart from natural magnetotactic bac-
in biological systems that may interfere with microrobot signals teria, the artificial magnetic m-bots were also visualized under
and thus restrict the in vivo applications of the microrobots. MRI with magnetic propulsion.[64,311] Zhang et al.[64] prepared
Moreover, the autofluorescence material-based microrobots have biohybrid magnetite helical microrobots that can not only be
a nontunable emission range, which is commonly blue or green localized by the fluorescence imaging, but also inspected with
emission. The short wavelength of the emitted light makes the MRI in vivo. The dual mode imaging of biohybrid microrobots
microrobots unsuitable for application in deep tissue imaging. broadened the application range of the specific environment for
As for the dye-based microrobots, most of the dyes are toxic to in vivo imaging-guided therapy.
the biological systems and may cause side effects. Moreover,
dyes like fluorescein, cyanine, and rhodamine, have limited
application in long-term imaging and multicolor detection.[302] 5.3. US Imaging
For QD-based microrobots, the limitation include the complex
functionalization process of m-bots with QDs, and the cytotox- US imaging is an imaging technique for the tracking of the
icity of QDs for in vivo applications. Future research regarding micro-nanorobots. Compared with other imaging techniques,
these m-bots may focus on long-wavelength fluorescent probes US imaging has the advantages of real-time control of m-bots
for deep-tissue imaging and development of biocompatible/bio- with instantaneous image feedback, no adverse health effects,
degradable fluorescent m-bots for in vivo applications. low cost of diagnosis, no requirement of contrast agents, and

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high imaging depth of ≈10 cm for human tissue. In the case using commercially available medical imaging platforms,
of other clinical imaging techniques, such as CT and MRI, making clinical microrobots foreseeable in the near future.
contrast agents in the micromolar to millimolar range may be RI has two main limitations: despite many safety regulations
required for the detection of the target position, which may in place, exposure to ionizing radiation due to the X-ray and
cause the potential side effects to the biological system. These radionuclides is inevitable. The optimal dosage that balances
advantages of US imaging have attracted extensive interest for imaging performance with patient safety must necessarily be
its potential in tracking m-bots. determined.[321] Research on the propulsion of m-bots with
Sanchez et al.[312] reported self-propelled microjets controlled RI-based tracking is in its infancy and has a long way to go.
by an ultrasound system in which the navigation of the microjets Apart from the above-mentioned imaging techniques, other
is affected by the continuous ejection of O2 bubbles originating kinds of imaging tools, such as PACT[322] and clinical optical
from a catalytic reaction on the inner platinum surface in the coherence tomography (OCT),[345] are also integrated for the in
presence of H2O2. The direction of motion of the microjets was vivo tracking of the m-bots. Gao et al.[322] developed a kind of
determined by the magnetic field and the motion paths of the m-bot capsules that can be tracked in real-time fashion by PACT
microjets were recorded by tracing the position of the microbub- in the GI tract of mouse with high-resolution and fast imaging
bles generated by the microjets via microscope and US imaging. speed. Due to the limited penetration depth of NIR, the PACT
The trajectories of the microjet recorded by these two imaging may be a good candidate for the localization and tracking of
modes all indicate that the microjet can locomote in a relatively m-bots inside the tissue and organs with a depth less than ≈7 cm.
precise manner following the preprogramed closed-loop trajecto- For in vitro use of m-bots, as well as for nonbiomedical appli-
ries. By comparison, the location accuracy of US imaging feed- cations, the actuation of m-bots using the optical microscopic
back is somewhat lower than that of microscopic imaging. tracking for simultaneous feedback is an affordable option.
Apart from the self-propelled microrobots, which are generally However, the optical microscope cannot penetrate the tissue to
tracked by the indirect imaging of the microbubbles,[312,313] some track the bots when applied to in vivo situations. Thus, other
other studies demonstrated the US imaging of microrobots actu- medical and clinical imaging techniques suitable for in vivo
ated by the magnetic field without any bubbles, such as the works inspections must, therefore, be used. Although studies on the
conducted by Khalil et al.,[314] Peng et al.,[315] and Zhang et al.[316–318] imaging of the micro-nanorobots have progressed significantly,
Moreover, Scheggi et al.[319] prepared soft miniaturized unteth- the field is still in its infancy. Compared with the other aspects
ered grippers which respond to the temperature to perform the of m-bot research, i.e., design, functionalization and actuation,
grasping and releasing with the 2D flat shape and 3D folded researchers may need to focus more on this aspect due to its
shape, respectively. The miniaturized grippers were fabricated decisive role in realizing in vivo applications of the technology.
from materials that contained 3% Fe2O3 to endow the grippers In vitro applications of micro-/nanorobots is well-documented,
with magnetic properties. The gripper was navigated with US and deeper study of the microrobot imaging will promote the
imaging, providing the feedback along both the step path and development of in vivo applications.
sinusoidal path (Figure 11g). The soft miniaturized gripper was
proved to possess the ability to grasp the bead (500 µm) and
transport it along the designed path to the destination. 6. Biomedical Applications of m-Bots
5.4. Radionuclide Imaging Although a large number micro-/nanomachines have been
proposed in the past two decades and their applications in
Radionuclide imaging (RI) is another imaging technique that various surroundings explored, the in vivo use of such devices
can be applied for deep tissue inspection and imaging. The had not received extensive attention until recent years. Exten-
imaging by RI can be whole-body imaging, which shows an sive research in this area is slowly bridging the gap between
obviously larger scan range than other imaging techniques. It research and actual in vivo application of these machines. The
also has the advantage of high sensitivity.[320] The RI commonly micro-/nanomachine applied for in vivo applications include
includes γ-scintigraphy, PET, and SPECT. RI usually requires the micro-/nanomachines applied in actual in vivo environ-
the introduction of exogenous agents such as radionuclides. In ments as well as those under study in in vitro environments
SPECT, the γ ray is emitted directly, while the γ ray generation and show promise for in vivo applications. Based on the above
is indirect for PET. The resulting γ ray can penetrate biological discussions regarding the design, functionalization, actuation,
tissues and be tracked in the real-time mode using imaging. The and localization of the micro-/nanomachines, in vivo applica-
actuation of m-bots by using RI inspection to obtain the feed- tions, such as diagnostics, cell isolation, guided cell growth,
back was proposed based on the encapsulation of positron or targeted delivery, and thrombus ablation, can be addressed
gamma emitters. Recently, Vilela et al.[67] applied the PET-CT to by combining these aspects ingenuously (Figure 12). Current
track 124I-functionalized bubble-propelled microtubes that were micro/nano robotic systems toward in vivo applications are
fabricated by the template-directed electrodeposition method fol- mainly adopted in the organs/tissues indicated in Figure 12.
lowed by the metal evaporation process. The radiolabeling pro-
cess of the 124I microrobots through chemisorption on the gold
surface is crucial for imaging using PET-CT, which broadenes 6.1. Diagnosis, Isolation, and Guided Cell Growth
the application of such microrobots from in vitro to in vivo. The
authors used linear phantoms to demonstrate location tracking M-bots can be applied for DNA/RNA sensing, isolation and
of the microtubes by applying PET combined with X-ray CT. detection of biomacromolecules, and isolation of cells and bac-
The study involved the investigation of direct tracking of m-bots teria from biological samples. Therein, the functionalization of

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Figure 12. Available biomedical application of m-bots. Insets: Drug delivery: Reproduced with permission.[81] Copyright 2016, American Chemical
Society. Cell delivery: Reproduced with permission.[116] Copyright 2018, AAAS. Micro-surgery: Reproduced with permission.[257] Copyright 2016, American
Chemical Society. Diagnosis: Reproduced with permission.[334] Copyright 2016, American Chemical Society. Guided cell growth: Reproduced with
permission.[336] Copyright 2012, Springer Nature. Thrombolysis: Reproduced with permission.[385] Copyright 2014, American Chemical Society. Wound
healing: Reproduced under the terms of the Creative Commons CC-BY license.[360] Copyright 2016, The Authors, published by Wiley-VCH.

m-bots is crucial for diagnostics, isolation, and biosensing applica- potential for applications such as the isolation and removal of dif-
tions.[225,323–327] Based on the donor–receptor interactions, m-bots ferent biological threats for detoxification.
can capture, transport, and release biomacromolecules and cells Sensing and diagnosis may also be conducted using the
for isolation purposes.[328–332] Concanavalin A lectin shows strong micro-/nanomotors. As is known, miRNA is an important
coupling effect with polysaccharides. As mentioned earlier, micro- biomarker that can be used for diagnosis and therapy. The
robots equipped with concanavalin A lectin bioreceptors were abnormal expression of miRNA is an indicator of many con-
efficient in the selective recognition and isolation of E. coli owing ditions, which makes the detection of the intracellular miRNA
to the polysaccharides on the cell surface.[126] Boronic acid shows important in clinical diagnosis. For instance, miRNA-21 is
strong interactions with monosaccharides. In a similar approach, found to be overexpressed in 80% of the tumor tissues. Zhang
Wang et al.[134] also proposed a boronic acid-functionalized micro- and Wang et al.[334] developed a nanomotor-based strategy that
robot that can selectively recognize and bond with the monosac- can be efficiently applied to intracellular biosensing and detec-
charide on the yeast cell, therefore performing the transportation tion of the miRNA-21, which is expressed in intact cancer
of the yeast cells in media. Another example of donor–receptor cells at the single cell level (Figure 13a). The nanomotor was
interactions is between the anti-carcinoembryonic antigen mono- composed of a gold nanorod that wrapped the DNA (ssDNA)/
clonal antibody (mAb) and the carcinoembryonic antigen (CEA). graphene-oxide (GO) (Figure 13b), which shows a quenched
CEA is an antigen that is overexpressed in ≈95% of colorectal, gas- fluorescence signal due to the π–π interaction between GO and
tric, and pancreatic cancers. Zhang and Wang et al.[57] developed a dye-labeled ssDNA. Under an ultrasound field, the ssDNA@
an in vitro strategy for the isolation of cancer cells by selective GO-coated gold nanowires can be actuated to penetrate intact
binding and transportation of the cancer cells on the ­mAb-grafted cancer cells (Figure 13c). The internalized nanomotor in cancer
microrobots. They[333] also proposed ultrasound-actuated nanoro- cell showed an intracellular “OFF–ON” fluorescence switching
bots composed of gold nanowires cloaked with a hybrid of red because of the replacement of the dye-ssDNA by miRNA-21
blood cell membranes and platelet membranes. The intrinsic as schematically illustrated in Figure 13a. The authors applied
functional proteins on the hybrid membranes endow the nanoro- cancer cell lines, i.e., MCF-7 and HeLa cells, to demonstrate the
bots with some attractive biological capabilities, such as adhesion intracellular detection of the miRNA-21 at the single-cell level.
and anchoring to Staphylococcus aureus bacteria, and neutraliza- Previous findings[335] indicate that the level of expression in
tion of α-toxins. The ultrasound-­actuated nanorobots moved like MCF-7 cells is much higher than that in the HeLa cells. The
naturally occurring motile cells and showed nonadhesive prop- authors then propelled the ssDNA@GO-modified AuNWs
erty with respect to blood vessels. These bots exhibited significant with US field under incubation (10 min) and found that the

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Figure 13. Diagnosis and sensing. a) Schematic illustration of the intracellular detection of the miRNA by the US-actuated functional nanomotors
from the OFF-ON switching of the fluorescence of the cells. b) SEM image shows the GO modified Au nanomotor. c) Time-lapse images show the
internalization process of a nanomotor (interval is 4 s). d) Optical and fluorescent images give the detection results of the miRNA-21 in the MCF-7 and
HeLa cell lines. The scale bars in c) and d) are 10 µm. Reproduced with permission.[334] Copyright 2015, American Chemical Society.

fluorescence intensity of the MCF-7 cells is 44 times higher radio transmitter, and antenna have been developed and
than that of the HeLa cells (Figure 13d), thus verifying the reli- commercialized by several companies.[339] These tetherless
ability of their strategy for the detection of miRNA among dif- capsular devices have sizes in the centimeter range and may
ferent type of cells. Such micromotor-based sensing indicates not be applicable for small vessels and channels in the body.
the potential for real-time monitoring of intracellular miRNA Moreover, most commercial capsules without any external
expression and cancer diagnosis. moving parts may only be applied for imaging and sensing,
Apart from the transportation and release of the cells, and mechanical operations can hardly be realized with them.
notable microrobot-guided cell growth was also achieved by
Berns.[336] The authors developed an optics-based system to
guide and control the direction of growth of the individual
nerve fibers using a light-actuated spinning microsphere. The
rotating micromotor created a localized microfluidic flow with
a shearing force of ≈0.17 pN that could control the direction of
growth of the nerve cells as shown in Figure 14. Another recent
finding shows that the delivered micromotors can also induce
the differentiation of the neural stem-like cell by converting
ultrasonic energy to an electrical signal in situ because of the
piezoelectric effect.[337] These micromotor-guided cell growth
and differentiation may show potential for in vivo regeneration
of axons to mediate brain and spinal cord repair.

6.2. Microscale Surgery

Minimally invasive surgery (MIS) is traditionally carried out

by inserting a tethered tool outside the body to the targeted
site in body, and it is commonly equipped with a light source,
tiny cameras, and mechanical devices for grasping, cutting,
and suturing.[338] However, navigation of the tethered tool to
the targeted area is difficult and as the tools are not collaps-
ible, they are not useful for tissues with small interspace. To Figure 14. Guided cell growth. The photon-driven micromotor rotating
tackle the disadvantages of tethered tools for MIS, wireless to facilitate guided nerve fiber growth. Reproduced with permission.[336]
capsules that include light sources, tiny cameras, batteries, Copyright 2012, Springer Nature.

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Figure 15. Minimally invasive surgery with microrobots in vessels. a) In vitro capture of the blood cells by self-folding microgrippers. Reproduced with
permission.[340] Copyright 2014, American Chemical Society. b) In vitro results show the thermally and biochemically triggered capture of cells mass
stained with neutral red in a tube (diameter is 1.5 mm). Reproduced with permission.[54] Copyright 2009, National Academy of Sciences. c) In vivo biopsy
of the bile duct by the microgrippers. Schematic of the porcine upper gastrointestinal track. Fluoroscopic image shows the endoscope entering the
pig body from mouth and arriving at the duodenum. Endoscopic images show the delivery of the microgrippers to porcine biliary orifice via a catheter
and their removal via a magnetic catheter tip. Optical image shows the removed microgrippers on the magnetic catheter tip. The tissue obtained by
microgrippers after staining with trypan blue. Reproduced with permission.[341] Copyright 2013, Wiley-VCH.

The well-developed field of remotely actuated micro-nanoma- MIS by magnetic microrobots may also be used in the treat-
chines filled the gap in the microscale world to achieve ment of eye disorders. Due to the transparency of the vitreous
mechanical motion and operations at the microscale for deep- body of the eyes, real-time localization of the microrobots in
tissue therapy. vivo can be addressed quite simply with an optical microscope.
Gracias et al.[340] developed tetherless cell microgrippers Nelson et al.[342–344] proposed an invasive, wirelessly steered and
composed of biocompatible and bioresorbable silicon mono­ powered microrobot for application in ocular medicine. These
xide and silicon dioxide that can be applied for grasping the microrobots are made of magnetic materials such as CoNi with
single cells. The tetherless grasping of the cell is realized by the a coating of Au and PPy (Figure 16c). These can be injected
release of the residual stress (Figure 15). Further, they[54] pro- without suture along with a hyaluronic acid solution into the
posed a tetherless, thermo-biochemically actuated microgripper eye and precisely steered with an external remote magnetic
with magnetic properties, which was fabricated by photolithog- field with five degrees of freedom (Figure 16a,b).[343] Figure 16d
raphy. The microgripper was sized in the range of hundreds of shows the injection process. The microrobots may be precisely
micrometers and navigated magnetically to areas in the body navigated to the areas in the eyes that traditional tools can
that were inaccessible to tethered or wireless-capsule devices. hardly reach. As shown in Figure 16e, the microrobots could
The thermo-responsive polymer hinges of the microrobots arrive at the posterior part of the vitreous cavity close to the
made them rigid at cold temperatures, keeping the star-fish retina for the surgery. However, long-term implantation of the
like tool flat and open, and when the temperature was raised microrobots may cause optic nerve inflammation and perma-
to body temperature, these polymer hinges softened and closed nent detachment of the retina (Figure 16f), depending on the
to grasp the tissue. After that, the in vivo MIS by the micro- implantation period of the microrobots. Histopathologic studies
grippers were also realized through a delivery process with a further confirmed the inflammation as showed in Figure 16g.
­catheter and camera for localization. As shows in Figure 15c, Most recently, Fischer et al.[345] developed a swarm of slippery
the authors[341] showed that the microgrippers could excise micropropellers (Figure 16h) that can be magnetically actuated
tissue samples from real organs and hard-to-reach regions in to penetrate the vitreous body (a tight macromolecular matrix)
a live pig. Up to 95% of microgrippers with the obtained tis- and reach the retina after the surface functionalization of the
sues could be retrieved with a magnetic catheter tip. Future micropropellers with a perfluorocarbon coating for reducing
research may focus on the complete recovery of the microgrip- drag (Figure 16i).
pers and elimination of the cytotoxicity of such micromachines. These results suggested that the microrobots are good can-
Moreover, the more efficient localization approaches may be didates for the new-generation MIS for the eye, and targeted
applied for the real-time guidance of microrobots to replace delivery and diagnostic techniques via implantation in the pos-
the catheter and camera-based imaging system that has limited terior part of the eye. However, microrobots may be unsuitable
imaging scope and resolution. for long-term implantation and should be removed after the

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Figure 16. Minimally invasive ocular surgery with microrobots. a) Magnetic actuation system with eight electromagnets for wireless magnetic micro-
robot control (OctoMag). The lab rabbit was placed at the center of the OctoMag. b) Schematic of the injection and removal of the magnetic microrobot
(with a magnetic field applied for orientation of the microrobot). a,b) Reproduced with permission.[344] Copyright 2013, Association for Research in
Vision and Ophthalmology; c) SEM images show the magnetic cylindrical CoNi microrobot. d) Successive images show the injection of microrobots
into the eye at the center of the vitreous cavity. e) Images show the rabbit eye after one day of microrobot injection. The left one shows the microrobot
at the center of the vitreous and the right one shows the microrobot at the posterior area of the vitreous cavity next to the retina. f) Images show
the eye i) one day before microrobot injection, ii) 14 days after microrobot injection with optic neuritis, and iii) 28 days after microrobot injection with
the complete detachment of the retina. g) Images show the histopathologic changes in eyes after microrobot injection. i) Image shows the hemisected
eye with a microrobot in the vitreous. ii) complete detachment of the retina. iii) Image shows the vitreous traction band labelled with black arrow and
the retinal fold labelled with red arrow. iv) Image shows foreign matter (may be PPy origin from the microrobot) placed in a multinucleated giant cell
labeled with black arrow. c–g) Reproduced with permission.[342] Copyright 2017, Wiley-VCH. h) Schematic of the targeted delivery process of slippery
micropropellers with magnetic field. i) Fluorescent images of the retina and the center of vitreous cavity after magnetic actuation of the mixture of the
micropropellers (labeled with red fluorescence) and passive particles (labeled with green fluorescence). h,i) Reproduced with permission.[345] Copyright
2018, AAAS.

treatment in a timely manner as tissues in the eye are typically such as controlled release rate, high loading capacity, and
more sensitive than the surrounding ones. rapid kidney removal.[355–361] However, nanoparticle-based drug
delivery commonly relies on the circulatory system, and lack
6.3. Targeted Therapy proper drug-targeting and barrier-penetration ability for highly
localized therapeutic drug delivery. Sometimes, the passive par-
During the past decades, micro- and nanoparticle-based drug ticles require functionalization to increase the targeting ability.
delivery systems have been extensively explored.[346–354] In this respect, active matter and m-bots that can be actuated
­­Micro- and nanoparticles shows a lot of merits in drug delivery autonomously or be propelled by external fields, have unique

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Figure 17. Peroral drug delivery. a) Schematic of micromotor toxoids for oral vaccination. b) Optical images of the gastrointestinal tract of male mice
6 h after the administration of static microparticles or motor toxoids by oral gavage. a,b) Reproduced with permission.[371] Copyright 2019, American
Chemical Society. c) Optical image shows the disk-shaped micromotor pills for oral administration. The pill composed of pill matrix and the encapsu-
lated Mg/TiO2/PLGA micromotors. Right image shows the dissolution and propulsion of the released Mg-based micromotors of a pill in gastric fluid.
d) Schematic of the in vivo actuation of a micromotor pill. Bright-field, fluorescent, and merged images shows the mouse stomachs after oral gavage
of DI water, fluorescent silica pills, free fluorescent Mg-based micromotors, and fluorescent Mg-based micromotor pills at 4 h. Scale bar is 5 mm.
c,d) Reproduced with permission.[373] Copyright 2018, American Chemical Society.

advantages in directed/targeted drug delivery from single cell autonomous propulsion in intestinal fluid and the enteric
delivery to local tissue/organ delivery.[362–367] Targeted therapy polymer coating protects the microrobots from being dissolved
by m-bots have been achieved for various diseased region via in the acidic environment of the stomach until the microrobots
either the peroral route (for gastrointestinal tract) or intrave- reach the intestines which have a nonacidic environment. The
nous injection (via circulatory system) route.[368–370] proposed microrobots can achieve desired biodistribution and
enhanced retention in the gastrointestinal tract for site-specific
delivery. Based on this strategy, the active delivery of antigens
6.3.1. Drug Delivery for Gastrointestinal Disease for oral vaccination may be realized as schematically illus-
trated in Figure 17a.[371] When the micromotor toxoid was orally
Mg- and Zn-based m-bots are the most promising among all administered to mice, the micromotors entered the stomach
the m-bots for drug delivery in the peroral route. Guan et al.[55] and the enteric coating prevented the degradation of the motors
proposed Mg/Pt-PNIPAM Janus microrobots for the efficient in the low pH environment. Improved retention and uptake of
uptake, transport, and temperature-controlled release of drugs. antigenic material occurred within the intestinal tract, as demon-
The targeting is achieved by the autonomous motion of the strated in Figure 17b. Wang et al.[372] also reported Mg-based
microrobots and on-demand release is realized by the ther- microrobots that can autonomously and temporally neutralize
moresponsive PNIPAM hydrogel layers. Wang et al.[81] devel- gastric acids via the self-propulsion of Mg Janus particles in the
oped an enteric microrobot consisting of a magnesium core gastric fluid by depleting the protons. The drugs loaded within
and an outer enteric polymer coating. The Mg core allows the surface of the pH-responsive polymer layers are, therefore,

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autonomously released due to the local pH change caused by core–shell nanorobots that were actuated by enzyme catalysis
Mg neutralization. The in vivo experiment showed that the for the active transport and delivery of the drugs to the sites
stomach of the mice treated with Mg microrobots (5 mg) pos- of interest. Compared with the passive counterparts, a four-fold
sessed evenly distributed fluorescence intensity generated from increase in drug release is achieved by the nanorobots after 6 h
the drugs loaded over the entire stomach, demonstrating the of treatment. The authors found that the active DOX-loaded
microrobots could actively adjust to the stomach environment nanorobots shows enhanced effect on HeLa cells compared to
and dissolve the pH-sensitive polymer for drug release. As for passive carriers due to the improved drug release kinetics and
inert PS microparticles, the fluorescence intensity was as low ammonia production generated from the catalytic decomposi-
as the DI water control group because the PS microparticles tion of urea. A similar strategy is also promoted to treat bladder
could not change the stomach pH and trigger the dissolution cancer.[381] The high urea concentration in the bladder acts
of the pH-responsive polymer for drug release. They[373] further as the fuel for the autonomous actuation of the nanomotors.
processed the active Mg-based micromotors into micromotor Compared with most self-propelled m-bots, the new m-bots
pills that contained the encapsulated micromotors in the that employ enzymes as catalysts open up tremendous applica-
pill matrix with other inactive excipients and disintegration- tion potential for in vivo situations.
aiding additives from a pharmaceutical strategy (Figure 17c).
The in vivo study indicated that the micromotor pill platform
effectively protected and carried the active micromotors to the 6.3.3. Targeted Cell Delivery
stomach. After the micromotors with the loaded cargo were
released from the pill matrix, the micromotors could propel Targeted delivery of various cells was also realized by the microro-
efficiently in the gastric fluid and release the drugs in a con- bots.[67,74,383,384] Choi et al.[111] demonstrated the targeted delivery
centrated manner. Figure 17d indicated that the florescent of the cells using the 3D direct laser writing technique. The cage-
Mg/TiO2/PLGA/chitosan micromotor pill exhibited the most like microrobots were coated with Ni and Ti layers to endow
intense signal compared with the DI water, fluorescent silica them with magnetic and biocompatible properties (Figure 18a).
pill, and free fluorescent Mg/TiO2/PLGA/chitosan micromotor After being cultured in 3D with the HEK 293 cells, they found
groups as the micromotor pill enhanced the transportation, that the cells readily adhered, migrated, and proliferated over the
dynamic release, and improved retention of the micromotors scaffold of the 3D microrobots (Figure 18b). The microrobots
in the mouse stomach. These results indicated that the com- loaded with cells can be propelled using an external magnetic
bination of traditional pills and the active micromotors offered field gradient. The proposed microrobots can be applied for the
an appealing route for in vivo motor-based drug delivery appli- targeted micromanipulation of the cells for in vivo applications.
cations. Mg and Zn based microrobots[374] show good potential Sun et al.[116] proposed another biocompatible burr-like micro-
for serving as active drug delivery carriers due to their biode- robot that can load the cells on the 3D framework via 3D cell
gradable nature that generates harmless by-products and does culture (Figure 18c) and release them at the desired site with
not require the separation of the microrobots after the delivery ease (Figure 18d). The in vivo release of stem cells by this kind of
process. Further, they[375] fabricated in vivo therapeutic micro- microrobots has been also verified from subcutaneous injection
robots for active drug delivery for the treatment of a gastric at the dorsum of nude mice with the tracking by FI (Figure 18e).
bacterial infection in a mouse model by setting clarithromycin
as the model antibiotic for the simulated Helicobacter pylori
infection. Compared with passive drug carriers, effective 6.4. Thrombus Ablation
antibiotic delivery was demonstrated by the actuation of the
drug-loaded Mg-based microrobots in the gastric media with sig- Obstruction of blood vessels due to blood clots is one of the
nificant reduction of the bacteria burden in the mouse stomach. leading causes of death in the world.[382,385] Thrombosis
may appear at diverse sites and depending on the site of the
thrombus, it may lead to ischemic stroke, coronary infarction,
6.3.2. Drug Delivery toward Cancer Therapy pulmonary embolism, and so on. Two strategies are developed
for thrombus ablation, namely thrombectomy and thrombol-
Targeted therapy of tumor is a topic that has attracted exten- ysis. Thrombectomy involves using a catheter to remove the
sive research attention.[47,376–382] Pané et al.[382] developed thrombus mechanically through the blood vessel. However, it
FeGa@P(VDF-TrFE) core–shell magnetoelectric nanowires has many contraindications and the catheter may not reach the
that can be propelled for targeted drug delivery by using dif- vessels with small diameter.
ferent magnetic fields. The P(VDF-TrFE) nanotubes are pre- Thrombolysis is another strategy for removing blood clots by
pared by melt-wetting of the AAO template, followed by the drug-induced lysis. Tissue plasminogen activator (tPA) is one of
electrodeposition of FeGa to generate the FeGa@P(VDF-TrFE) the drugs for thrombolysis that has been approved by US Food
core–shell nanowires. After surface functionalization with and Drug Administration (FDA). It can catalyze the transfor-
polydopamine, the nanowires can be loaded with the anti- mation of plasminogen to plasmin and the generated plasmin
cancer drug paclitaxel. The loaded drug can be released for on- can break up the thrombus via binding with the fibrin on the
demand killing of cancer cells after alternating magnetic fields blood cells. Commonly, thrombolysis is performed by an intra-
are applied to cause the magnetoelectric effect. Intensive drug venous injection and the dose of the tPA should be controlled
release may also be realized by the actuated m-bots. Sánchez to less than 0.9 mg kg−1 due to potential side effects such as
et al.[376] developed urease-modified mesoporous silica-based internal hemorrhage. The rapid and efficient delivery of tPA

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Figure 18. Targeted cell delivery. a) Schematic and optical images show the translational and rotational motion of the microrobots. b) SEM and fluo-
rescent images show the microrobot loaded with cells. a,b) Reproduced with permission.[111] Copyright 2013, Wiley-VCH. c) Cell culture process on the
burr-like microrobots. SEM images shows the burr-like microrobot cultured with MSCs for 12 h. d) In vitro cell release process of the burr-like micro-
robot in a microfluidic chip. e) Fluorescence images show the in vivo cell release experiments on nude mice. The upper images show the left dorsum
of mice injected with microrobots carrying HeLa GFP+ cells. The lower images show the right dorsum of mice injected with microrobots carrying no
cells. The section of HeLa tumor contains the injected microrobots. c–e) Reproduced with permission.[116] Copyright 2018, AAAS.

by the carriers after the onset of thrombosis is crucial for the inside the blood clot with the assistance of thrombolytic agents.
treatment. In recent years, due to the rapid development of the Sitti et al.[386] verified and conducted the experiments on the in
field of m-bots, researchers have promoted the utilization of the vitro model and found that mechanical rubbing with the helical
m-bots in the efficient removal of the thrombus.[132,385–391] robots showed a removal rate approximately three times larger
The macroscale helical robots with lengths in the centim- than that of chemical lysis with streptokinase. Moreover, the
eter range were applied to drill holes by mechanical rubbing removal process can be tracked with ultrasound guidance.[387]

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Figure 19. Thrombus ablation. a) Schematic of the nanorobot-enhanced thrombolysis process with free tPA under an external rotating magnetic field.
b) Fabrication process of Nickel nanorods. c) Optical images show the in vitro experiment of the thrombolysis process with dye (D), nanorobots (R),
tPA (T), and nanorobots + tPA (R+T) at different time points. d) Optical images show the in vivo experiment of the enhanced thrombolysis by the
nanomotors in a mice embolism model. a–d) Reproduced with permission.[385] Copyright 2014, American Chemical Society. e) Schematic of photo-
thermal therapy of the thrombus. f) SEM image of Janus polymeric motors after template removal and EDS mapping of the Janus polymeric motors
before template removal. Scale bar is 2 µm. g) Schematic of the modification process of Janus polymeric motors with erythrocyte membrane by the
vesicle fusion method. h) Successive CLSM images show the variation of fluorescent thrombus in the presence of membrane-cloaked Janus polymeric
motors under NIR (760 nm) irradiation. Scale bar is 20 µm. e–h) Reproduced with permission.[389] Copyright 2018, American Chemical Society.

Zhao et al.[385] developed active nickel nanorods to extent. Also, the m-bots can form a thrombin-inhibiting coating
directly guide and enhance the tPA-mediated thrombolysis that is capable of preventing the regeneration of the thrombus.
(Figure 19a,b). The results demonstrated that nanorobots can
be used for enhancing tPA thrombolysis speed using magnetic- 6.5. Wound Healing
field generated hydrodynamic convection (Figure 19c). Efficiency
of thrombolysis is also verified by the in vivo experiment on a A wound is an injury to the body that may originate from
mouse (Figure 19d). Engelhard and co-workers[388] applied a various external forces such as accidents, violence, or surgery,
rotating permanent magnet to rotate and translate of iron oxide and may be in the form of abrasions, lacerations, punctures,
NPs inside the vessel so that the drugs can be directed to the avulsions, or animal bites. It usually involves the breakage of
thrombus site with a stagnant flow. Hest et al.[389] constructed the organ skin and may cause possible damage to the under-
erythrocyte membrane-cloaked Janus polymeric microrobots lying tissues. Most of the people experience an open wound at
(Figure 19f,g) which were actuated by near-infrared (NIR) laser some point in their life. Proper treatment of wounds is crucial
illumination for thrombus ablation (Figure 19e). These biode- since ­inappropriate treatment increases the chances of bacterial
gradable and biocompatible microrobots can generate a local infection. Minor wounds can be treated by oneself at home
thermal gradient under NIR irradiation because of the asym- while large or deep wounds are better handled by a doctor.
metric distribution of Au on the surface of the microrobots, Wound healing can be typically classified into four successive
causing “on/off” controlled motion of the microrobots by the self- stages, namely, the hemostasis phase, inflammation phase,
thermophoresis effect generated by the control of the irradiation ­proliferation phase, and remodeling phase. Open wounds are
source. Therapeutic microrobots showed excellent performance conventionally closed and healed using skin glue, medical
in thrombolysis photothermal therapy (Figure 19h). Compared sutures, laser welding etc. However, these strategies are either
with the traditional methods that involve intravenous injection invasive or require a long time for rehabilitation after treatment,
of tPA, the nanorobot-guided therapy may require smaller doses and thus, affect the daily activities of the patient. Nanoparticles,
of the drug due to the locally accelerated flow effect.[392] Accord- nano scaffolds, and other biomaterials have also been devel-
ingly, the potential side effects of tPA may be reduced to some oped to perform topical drug delivery for wound healing.[393–395]

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Figure 20. Active motor-based wound healing. a) Schematic of the propulsion of micromotors in water by release of CO2 and accompanying cargo
delivery process. b) Schematic of clotting and occlusion of flowing blood plasma ex vivo in vertical and horizontal directions. c) Relationship between
the clotting occlusion time and the flow rate in a vertical orientation. d) Left graph shows the bleeding times of mice after tails were amputated. Right
graph shows the volume of blood loss of mice after the livers were punctured and subsequently treated. e) Fluorescent images show the histological
sections of liver treated with propelled and nonpropelled thrombin. Right graph shows the dose of the CaCO3 delivered to punctured liver sites. Repro-
duced with permission.[359] Copyright 2015, AAAS.

However, passive delivery of therapeutics into damaged deep techniques are minimally invasive and do not introduce new
tissue during bleeding remains a challenge due to the out- trauma like traditional stitches.[358]
ward flow of the blood. The development of the m-bots offers Kastrup et al.[359] proposed self-propelled micromotors made
a brand-new strategy for an enhanced healing effect despite of carbonate and tranexamic acid (Figure 20a) that can navigate
the outward blood flow. Treatment of wounds with the micro-/ through aqueous solutions with a maximum speed of 1.5 cm s−1
nanomotors results in reduced clotting velocity of the blood and due to the release of CO2 and can move against the blood flow.
accelerated wound healing rate compared with the conventional Three animal models, namely, mouse liver, mouse tail, and pig
treatment methods. Moreover, the nanomotor-based healing femoral artery, have been used to verify the enhanced delivery

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of the coagulation enzyme and staunching of severe hemor- ferromagnetic particles via remote and nonintrusive magnetic
rhage (Figure 20b,c). When the micromotors were loaded field control combined with a radio-frequency alternating
with thrombin, they could penetrate deeply into the wound magnetic field. The advantage of this strategy is that the ini-
(Figure 20c), shorten the bleeding time, and reduce blood loss tial particle dose could be maintained at a low level to reduce
efficiently (Figure 20d). The system shows far-reaching appli- the toxicity to the surrounding cells/tissue. The local particle
cations for the delivery of therapeutics, and may potentially be concentration could be tuned within a wide range under a
applied for postpartum hemorrhage, which is one of the main magnetic field. The shrinking of the particle swarm pattern
risks for maternal mortality in childbirth. He et al.[360] further would induce a higher localized temperature rise after the
developed magnetic field- and NIR- actuated Janus micromo- alternating magnetic field treatment whereas the swelling of
tors with high controllability for restoration and hemostasis of the particle swarm pattern would induce a lower temperature
wound by laser beam irradiation. Local temperature rose in the rise (Figure 21b). Also, the locomotion of the particles swarm
wound melted the collagen fiber and temperature reduction led pattern could be easily controlled for targeted energy delivery
to the formation of a collagen film that closed the open wound. of certain location. The magnetic particle swarm offered a new
Micromotor assisted welding of wounds was verified on beef means for achieving enhanced the localized treatment of the
liver, beef meat, and chicken meat and showed in the improved, tumor with a relatively low initial particle dose.
laser-controlled halting of bleeding. Wang et al.[401] investigated the ultrasonic propelled axial pro-
Active micromotor-based halting of hemorrhage is signifi- pulsion and spinning of the Au rod inside the living HeLa cells
cant in the case of severe and massive trauma, such as the without chemical fuels. The cells can be properly aligned under
postpartum hemorrhage and combat wounds. The patient is at the ultrasonic field with a cluster of Au rods (Figure 21c), and
risk for hypovolemic shock and may die due to the exsanguina- the internalized Au rods showed active motion in the cells. The
tion. Fast-acting active delivery of the hemostatic agent by the authors suggested that the ultrasonic propulsion of nanomo-
micro-/nanomotors locally to the deep, difficult-to-reach wound tors may offer a new tool for stimulating the living cell by
increases the possibility of saving the patient’s life. mechanical excitation and intracellular organelle manipulation.

6.6. Biomedical Applications of Swarming m-Bots

7. Comprehensive Evaluation of State-of-the-Art In
The swarming behavior of the m-bots not only broadens the
Vivo Applications
scope of understanding related to self-assembly behavior in
natural living systems as introduced in Section 4.7, but also To date, in vivo applications of the micro-/nanomachines,
brings out the potential for applications such as the multiple such as microsurgery, drug delivery, cell delivery, thrombus
cargo manipulation,[273,396,397] antidiffusion by the swarming ablation, and wound healing have achieved preliminary suc-
m-bots,[287] enhanced delivery capability (Figure 21a),[398] recon- cess in animal models, such as different organs and tissues of
figurable adjustment of the energy delivery dose for enhanced mouse, rat, and pig, as listed in Tables 4 and 5. Among all the
magnetic hyperthermia (Figure 21b),[399,400] and cell alignment real in vivo applications, three kinds of propulsion modes are
(Figure 21c) and manipulation of intracellular organelles.[401] extremely popular and favored for the steering and actuation
The in vivo swarming behavior of biological and artificial m-bots of the micro-/nanomachines, i.e., magnetic field, bubbles, and
have been investigated and explored, and it has been verified light field. Studies on other modes of propulsion remain in the
that the collective motion behavior of micro-/nanoagents can stages of in vitro and ex vivo investigation. Among these three
commonly realize the enhanced delivery of drugs and energy. propulsion modes, magnetic field-based propulsion and bubble-
By combining the enrichment of MC-1 in the oxygen-depleted based propulsion are applicable for both superficial and deep
hypoxic regions of the tumor and magnetic field g ­ uidance, Martel tissues whereas the light field is applied only for superficial
et al.[398] examined the magnetoaerotactic and collective migration treatment like wound healing. As for the imaging of the in vivo
behavior of magnetotactic bacteria (MC-1) and applied this to the treatment procedures with micro-/nanomachines, researchers
transportation of drug-loaded nanoliposomes into the hypoxic have hitherto realized the localization of the tiny robots and the
regions of the tumor for cancer therapy. The peritumoral injection nidus using endoscopy, FI, and MRI. Different imaging tech-
of MC-1 into the tumor xenograft in mice showed that directional niques are usually used for different applications. Endoscopy is
magnetic fields can considerably enrich MC-1 in the central hypoxic applicable for the imaging of micro-/nanomachines in the in
region of the tumor as shown in Figure 21a. The MC-1 stained with vivo ducts. FI is a good candidate for the superficial localization
antirabbit FITC-labeled secondary antibodies exhibits a higher den- of tiny robots with high-resolution. MRI is a reliable localiza-
sity at 4 and 6 cm which is at the center of the tumor than at the tion technique for deep tissue imaging. The delivery strategies
boundary region. The surface of the MC-1 can be anchored with of micro-/nanomachines are commonly completed by catheter
several liposomes with drug loaded in them for targeting to the delivery from mouse, oral administration, IV injection, topical
tumor center with a directional magnetic field. The result indicated application and in situ injection. Most of the real applications
that the targeting ratio could reach up to 55% (Figure 21a) in the did not conduct any postclearance process after the treatment.
tumor with this kind of collective motion by magnetic field. The However, for the bubble-propelled micro-/nanomotors based on
work demonstrated the merit of the swarms of microorganisms Mg and CaCO3, the motors gradually dissolved in the stomach
with magnetoaerotactic behavior could efficiently boost the thera- and wound site with low cytotoxicity after treatment and no fur-
peutic index of various nanocarriers in tumor hypoxic regions. ther removal processes were required.
Zhang et al.[399] developed a new strategy to realize a tun- Other proposed applications for micro-/nanomachines,
able energy dosage by using a reconfigurable swarm of which show tremendous potential for in vivo applications, have

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Figure 21. Swarming m-bots toward in vivo applications. a) Optical image shows the magnetotactic directional control system. Peritumoral injection
of the MC-1 into the tumor xenograft in mice (the magnetic field direction was aligned to the tumor center). The distribution of MC-1 in tumor sections
at different distances from the injection site. The inset in the top right corner gives the SEM image of the MC-1 anchored with drug-loaded liposomes
(MC-1-LP) and the estimated amount ratios of the MC-1-LP in the tumor after the magnetic field guided targeting process of a cluster of MC-1-LP. Repro-
duced with permission.[398] Copyright 2016, Springer Nature. b) The motion of colloidal swarm for targeted and enhanced magnetic hyperthermia (the
green color in the fluorescent image represents the live cells, and the red color represents the dead cells). Reproduced with permission.[399] Copyright
2018, Wiley-VCH. c) The trajectory of a gold rod inside a HeLa cell. The optical images show that the gold rods can cause the rotation of HeLa cells to
which they bound at the acoustic nodal line. Reproduced with permission.[401] Copyright 2014, Wiley-VCH.

not successfully transferred the in vitro and ex vivo models to the all these propulsion modes, the magnetic field is still the most
corresponding in vivo cases, such as hyperthermia, micromotor popular one and US propulsion becomes relevant for in vitro
guided neural repair, infertility, and cancer diagnosis. Among and ex vivo applications. We foresee that the US propulsion

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Table 4. Summary of the in vitro and ex vivo applications of m-bots.

In vivo/ex vivo Material Geometry Propulsion Method Type of cells Proposed disease Delivery site Imaging Year Refs.
trials mode treatment method
Target interven- Magnetotactic Sphere with Magnetic Not mentioned None None None MRI 2009 305
tions in blood bacteria flagella
Guided cell growth Vaterite Sphere Light Not mentioned Nerve bras Neural reparation Outside cell BF 2012 336
3D cell culture Photoresist, Cuboid frame- Magnetic DLW Human embryonic Drug delivery Outside cell FI 2013 111
and Ni, Ti work structure Kidney 293 cells and cell delivery
transportation
Sperm delivery Photoresist, Microtube Magnetic Photolithog- Sperm infertility Outside cell BF 2013 256
Ti, Fe raphy and PVD
Sperm, photo- Helical flagella Magnetic DLW and PVD Sperm, oocyte infertility Inside cell BF 2015 257
resist, Ni, Ti
Cancer diagnosis GO, Au, DNA Wire US Template- MCF-7, HeLa Cancer diagnosis Inside cell FI 2016 334
directed elec-
trodeposition
and surface
grafting
Cargo delivery SU-8, PNIPAM- Starfish-like Magnetic Photolithog- None None None US 2017 319
AAC, Fe2O3 gripper raphy
Hyperthermia Fe3O4 Sphere Magnetic Solvothermal HepG2, HeLa Cancer therapy Outside cell FI 2018 399
and 3T3
Thrombus Erythrocyte Sphere Light LbL assembly Erythrocyte Vascular Outside cell FI 2018 389
ablation membrane, Au and sputter thrombosis
coating
Drug delivery Sperm, photo- Flagella with a Magnetic DLW Sperm, HeLa Cancer therapy Outside cell BF 2018 259
resist, Fe, Ti helmet
SiO2, Ni, per- Helical Magnetic Glancing angle Retina cell Ocular disease Porcine eye BF and optical 2018 345
fluorocarbon structure deposition (ex vivo) coherence
coating tomography

may be successfully applied for in vivo cases soon. Among all other kinds of novel imaging techniques should be studied
these propulsion modes, their prospect and significance may be for integration with the propulsion modes toward real in vivo
ranked according to the frequency of use in in vivo applications: localization. Third, most researchers are aware of the need to
magnetic field > light field > bubble > US field. The short effec- avoid cytotoxic materials for in vivo applications, such as the
tive actuation range of the magnetic propulsion system may be replacement of Ni with Fe3O4. However, the clearance of the
a considerable challenge for the translation of these methods m-bots is seldom evaluated in most cases according to the data
from the lab to human clinical cases because the attractive force in Tables 4 and 5, though several researchers have used biode-
between the magnetic m-bots and the magnetic field is inversely gradable materials that self-dissolved after use and magnetic
proportional to no less than the fourth power of the distance. As materials that can be retrieved using a magnetic catheter tip.
for the localization of the m-bots, the BF is the most frequently
applied imaging mode for in vitro and ex vivo trials, whereas for
actual in vivo trials, the FI is the most widely used localization 8. Conclusion and Outlook
technique. Besides BF, FI and US imaging are also developed
for the in vitro/ex vivo applications. Although considerable efforts have been made in the develop-
Based on the above discussions, we believe that m-bots ment of microrobotic platforms for the biomedical applications,
hold significant potential for broad development. First, sev- it is still a huge challenge to achieve realistic biomedical tasks
eral propulsion modes have not yet developed to the stage of in vivo due to several issues in the design, functionalization,
in vivo applications, such as electric field-propelled micro-/ actuation, and localization of m-bots, and the integration of
nano-machines. As for the implemented propulsion modes the actuation system and real-time imaging system with living
for in vivo applications, the targeting regions are limited to, in organisms for specific tasks and treatments.
turn from top to bottom of a mammal, the stomach, bile duct,
mouse liver, abdomen, back skin, intra-peritoneal cavity, gastro-
intestinal tract, and femoral artery. The feasibility of m-bots for 8.1. Design
the treatment of other organs and tissues of mammal with dif-
ferent pathologies have not yet been verified. Second, existing For an in vivo application, the usage of biocompatible/biode-
localization methods of the m-bots for the real in vivo appli- gradable materials is fundamental to the initial design and fab-
cations are mainly endoscopy, FI, MRI, PACT, OCT, etc. The rication process. Inevitably, some m-bots use toxic materials as

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Table 5. Summary of the in vivo applications of m-bots.

In vivo Material Geometry Propulsion Method Animal model Targeting site Delivery method Imaging Clearance Year Refs.
applications mode method
Microsurgery Cu, Ni, Cr, Starfish-like Magnetic Photolithog- Pig Bile duct Catheter from Endoscopic Remove with 2013 54
Si, polymer gripper raphy mouth imaging magnetic
catheter tip
Thrombus PS, Ni Rod-like Magnetic Oblique angle Mouse Femoral vessel Retro-orbital IV None Not 2014 385
ablation deposition injection mentioned
Delivery Photoresist, Ni, Helical Magnetic DLW and Mouse Intraperitoneal Injected in FI Not 2015 44
Ti, NIR-797 dye flagella surface cavity intraperitoneal mentioned
grafting cavity
Wound CaCO3, Organic Sphere Bubble Wet chemical Mouse and Mouse liver and Topical None Dissolved 2015 359
healing acid, propulsion method pig tail, pig femoral application
artery
SiO2, Fe3O4, Sphere Magnetic, LBL Mouse Back skin Topical None Not 2016 360
PEM, Au light application mentioned
Drug delivery Mg, Au, Tubular Bubble Template Mouse Gastrointestinal Oral administration Ex vivo Dissolved 2016 81
PEDOT propulsion method Tract imaging
enteric coating with FI
Magnetotactic Sphere with Magnetic Surface Mouse Abdomen Peritumoral None Not 2016 398
bacteria, LP flagellum grafting injection mentioned
Mg, TiO2, PLGA Janus sphere Bubble ALD Mouse Stomach Oral administration Ex vivo Dissolved 2018 373
propulsion imaging
with FI
Intraocular CoNi, Au, PPy Cylindrical Magnetic Electroless Rabbit Posterior segment Sutureless BF Not 2017 342
surgery structure deposition of eye injection mentioned
Delivery Spirulina Helical Magnetic Dip-coating Mouse and Intraperitoneal In situ injec- FI and MRI Not 2017 64
microalgae, rat cavity and tion and oral mentioned
Fe3O4 stomach administration
3D cell Photoresist, Burr-like Magnetic DLW Mouse Dorsum Subcutaneous FI Not 2018 116
delivery Ni, Ti framework injection mentioned
structure

the important components, which may limit their further appli- ligands, peptides, proteins, nucleic acids, lipids, polymers, and
cations in in vivo therapy. For instance, nickel is an efficient functional QDs through certain target groups have been per-
material that is usually applied for the fabrication of magnetic formed well. The surface wetting property is usually neglected
m-bots, in photolithography, direct laser writing, electrodepo- for the m-bots even though it has been widely considered in
sition techniques, etc. However, nickel is commonly deemed the design of ­macroscale robots for locomotion on the water
as a toxic material for cells and tissues that should be avoided surface and water/oil interfaces, as in the water strider.[402–405]
or at least encapsulated in biocompatible soft shells to prevent M-bots are always intrinsically hydrophilic and can be navigated
direct contact with cells for in vivo applications. To improve the in water-based media. The surface functionalization with special
biocompatibility, FePt and Fe3O4 with much lower cytotoxi­city wetting molecules[403–405] may offer brand-new applications for
may be applied for the in vivo applications. Besides, the design the m-bots for interface-based navigation that shows reduced
and fabrication of micro- and nanorobots are depending mainly resistance to the swimming. Fischer et al.[345] have given a good
on ≈20 elements, and most of them are the transition metals example that the drag force and adhesion can be well reduced
with a few of them from the Group IIA, IIIA, IVA, VA, and via hydrophobic coating during the navigation of m-bots inside
VIA elements of the periodic table. More than two-thirds of body.
the transition metals are excavated for use as core materials
of m-bots. The future directions of the design and fabrication
may shift to the use of other elements for the integration of 8.3. Actuation
multifunctionality.
In most cases, the actuation and steering of m-bots occur in
the 2D planar situation. However, for practical applications,
8.2. Functionalization the navigation of a m-bot inside a blood vessel is quite sophis-
ticated. To date, a few studies have been conducted to study the
With the development of the bioconjugate techniques, the motion of m-bots in 3D space with feedbacks of the 3D locali-
surface functionalization and labeling of the m-bots with zation.[265,406] The future investigation of the m-bots may pay

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significantly more attention to the locomotion of the m-bots in is often inconsistent with the real in vivo environment, which
the 3D form, especially for the 3D navigation of multiagents is much more complex and contains many biomolecules that
and the swarming of a cluster of m-bots. Second, several types may react with the injected m-bots and show unspecific affinity.
of m-bots still lack the directional steering required for targeted These unexpected phenomena may not only alter the motion
locomotion. Some external fields, such as the magnetic field forms and speed of the m-bots, but also result in failure of
and electric field, exhibit their unique merits in directional con- in vivo applications. Fischer et al.[408] have provided a good
trol. Therefore, combination of different motion mechanisms example for addressing this problem. Inspired by Helicobacter
will facilitate the mainstream application of the m-bots. Third, pylori, they functionalized helical microrobots with the enzyme
the external field, such as magnetic field, electric field, and urease that could locally raise the pH and consequently liquefy
ultrasound field, generally possesses an effective working dis- mucus to overcome the mucus barrier and actuate the microro-
tance for the propulsion of the m-bots. Currently, the in vivo bots. This case is only the tip of the iceberg, and biological bar-
actuation and control of the m-bots based on these external riers in the organism are ubiquitous. To realize the delivery of
fields work well as the animal models used are mainly that of the m-bots in vivo, this aspect may require broad and profound
small mammals like mice. However, m-bot-based therapy must investigation.
ultimately be used for human beings who are much larger than
the animals used as models. The external fields must have the
capability for propelling and controlling the m-bots at the deep 8.5.1. All-in-One Integration of Micro-/Nanomachines and Their
tissue level. Therefore, the scale-up of the therapy system based Functionalization, Actuation, Localization, and In Vivo Applications
on m-bots should be improved.
While impressive strides have been made in the development
of various kinds of m-bots, especially in design and actuation,
8.4. Localization among the five aspects showed in Figure 1, the achievement of
real biomedical applications may require further improvements
The current medical image techniques are generally suitable in several other aspects such as functionalization, biocompati-
for macroscale in vivo imaging as they have limited resolutions bility, localization, and systematization. To date, the harmoniza-
and imaging contrast. Therefore, the clinical imaging tools- tion of these aspects to realize the visualizable in vivo diagnosis
based localization of m-bot swarms may be affordable whereas and therapy with micro-/nanorobotic systems is extremely rare.
the in vivo localization of individual micro and nanoscale robots We foresee that the bioapplication of the m-bots should not be
for precise surgery is still challenging.[407] limited to the simplified platforms under manual operations
with poor integration of the actuation system and the localiza-
tion system. For the future investigation, efforts should be paid
8.5. Applications in the design of the automated platforms[409,410] that integrate
the multiple functions in complex biological systems and the
Although m-bots have been investigated extensively for various actuation and control of the m-bots become more functional-
applications from the microscale manipulation and transporta- ized and self-regulated. It is worth noting that, several specific
tion of objects to biomedical applications such as in vitro and in fields related to m-bots are still in the preliminary stages, such
vivo diagnosis, drug delivery, thrombus ablation, tissue repara- as the swarming and localization of m-bots and their applica-
tion, and regeneration, these application related to the m-bots tion to thrombus ablation. These fields may require the further
still lack of a “killer application” that can be only addressed by development before an integrated procedure can be developed
the m-bot technology. for translation from lab to clinic.
The critical challenge for the bioapplication of autonomous
and self-propelled m-bots is the use of nontoxic fuels. Although
a few enzyme-catalysis-propelled m-bots have been developed
Acknowledgements
based on nontoxic fuels such as urea, the field has a long way
to go. Other types of novel enzyme-catalysis-propelled m-bots The authors thank the comments and discussions with Prof. Z.G. Guo
should be explored for certain particular in vivo applications. from Lanzhou Institute of Chemical Physics, CAS, and discussion with
Prof. T.T. Xu from Shenzhen Institutes of Advanced Technology (SIAT),
Another solution is substitution of the toxic fuels with external
CAS. This work was partially supported by the Hong Kong RGC Joint
applied energies. Laboratory Funding Scheme (JLFS) with Project No. JLFS/E-402/18,
The influence of the navigation of m-bots caused by the the RGC Collaborative Research Fund (CRF) with Project No. C4063-
complex in vivo fluidic environment should be addressed. As 18GF, the projects funded by the Hong Kong ITC with Project Numbers
distinct from the macroscale objects in the fluidic environ-
­ MRP/036/18X and ITS/374/18FP, the projects from CUHK internal
ment, the motion in micro-/nanoscale is prominently weak- grants, and the support from SIAT-CUHK Joint Laboratory of Robotics
ened by the liquid viscosity and Brownian motion. In in vitro and Intelligent Systems. B.W. would like to thank the financial support
from the Impact Postdoctoral Fellowship Scheme from the Chinese
applications, the properties of the liquid environment such
­ University of Hong Kong.
as mobility, viscosity, and pH can be artificially controlled to
an optimized condition that is proper for the navigation and
steering of the m-bots. Extra surfactant may be added to reduce
the adhesion force between the surface and the m-bots to facili-
Conflict of Interest
tate navigation control. However, the ideal fluidic environment The authors declare no conflict of interest.

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Ben Wang obtained his Ph.D. degree at the Department of Biomedical Engineering, The Chinese
University of Hong Kong (CUHK), in Prof. Li Zhang’s group. Then, he worked as a postdoctoral
fellow at the same group in Department of Mechanical and Automation Engineering, sup-
ported by the Impact Postdoctoral Fellowship Scheme of CUHK. He joined Shenzhen University
in December 2019, as an assistant professor in the College of Chemistry and Environmental
Engineering. His current research interests are focused on surface functionalization, magnetic
nanoparticles, and soft robots for remote actuation and targeted delivery.

Kostas Kostarelos currently is Professor of Nanomedicine at the Faculty of Biology, Medicine &
Health and the National Graphene Institute (NGI) of the University of Manchester and is the
Severo Ochoa Distinguished Professor at the Catalan Institute of Nanoscience and Nanotechnology
(ICN2). He is a Fellow of the Royal Society of Chemistry (FRSC), Fellow of the Royal Society of
Medicine (FRSM), and Fellow of the Royal Society of Arts (FRSA) all in the United Kingdom. In 2010
he was awarded the Japanese Society for the Promotion of Science (JSPS) Professorial Fellowship
with the National Institute of Advanced Industrial Science and Technology (AIST) in Tsukuba, Japan.
His expertise lies with the biomedical and clinical translation of novel nanomaterials and nanotech-
nologies and leads nanomedicine labs in the UK and Spain.

Bradley J. Nelson has been the professor of Robotics and Intelligent Systems at ETH Zürich since
2002. Before moving to Europe, Prof. Nelson worked as an engineer at Honeywell and Motorola
and served as a United States Peace Corps Volunteer in Botswana, Africa. He has also been a
professor at the University of Minnesota and the University of Illinois at Chicago. He has over
30 years of experience in the field of robotics. He serves on the advisory boards of a number of
academic departments and research institutes across North America, Europe, and Asia.

Li Zhang received his Ph.D. degree from the University of Basel, Switzerland, in 2007. From 2007
to 2012, he was with the Institute of Robotics and Intelligent Systems, ETH Zürich, Switzerland, as
a postdoctoral fellow and then as a senior scientist. He is currently an associate professor in the
Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong,
and a director of SIAT(CAS)-CUHK Joint Laboratory of Robotics and Intelligent Systems. His main
research interests include micro-/nanorobotics for biomedical applications. He is an IEEE NTC
distinguished lecturer.

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