Materials Today Bio 8 (2020) 100085

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Materials Today Bio

journal homepage: www.journals.elsevier.com/materials-today-bio

Micro/nanoscale magnetic robots for biomedical applications

M. Koleoso a, 1, X. Feng a, 1, Y. Xue a, Q. Li b, T. Munshi c, X. Chen a, *
a
School of Engineering, Institute for Bioengineering, The University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JL, UK
b
School of Engineering, Institute for Energy Systems, The University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JL, UK
c
School of Chemistry, University of Lincoln, Brayford Pool, Lincoln, Lincolnshire, LN6 7TS, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Magnetic small-scale robots are devices of great potential for the biomedical field because of the several benefits
Micro/nanorobots of this method of actuation. Recent work on the development of these devices has seen tremendous innovation
Magnetic actuation and refinement toward improved performance for potential clinical applications. This review briefly details recent
Biomedical applications
advancements in small-scale robots used for biomedical applications, covering their design, fabrication, appli-
Cargo delivery
Clinical availability
cations, and demonstration of ability, and identifies the gap in studies and the difficulties that have persisted in
the optimization of the use of these devices. In addition, alternative biomedical applications are also suggested
for some of the technologies that show potential for other functions. This study concludes that although the field
of small-scale robot research is highly innovative there is need for more concerted efforts to improve functionality
and reliability of these devices particularly in clinical applications. Finally, further suggestions are made toward
the achievement of commercialization for these devices.

1. Introduction whereas some others focus on strategies of actuation [13]. The main
focus of this review, however, will be on microscale and nanoscale robots
Microrobots and nanorobots are small-scale manipulatable devices at actuated using magnetic fields and the systematic summary and discus-
the micrometer and nanometer scale which have found uses in several sion of their actuation approaches and applications in biomedical field.
fields and have been noted to be of great interest in the biomedical field. The use of magnetic fields for manipulation is of advantage in biomedi-
The small size of these devices is of particular benefit in healthcare as it cine because of their minimal interaction with tissues below magnetic
allows for much less invasive procedures to be used in place of surgery field magnitudes of 3 Tesla (T) and the body's transparency to them [14].
and non-targeted chemical and radiation therapies [1]. This greatly eases Early applications of magnetic nanotechnology in biomedicine
diagnosis and detection of diseases and reduces risk of infection, com- mainly consisted of the use of magnetic nanoparticles (MNPs) whose
plications, side effects, and recovery time in patients [2–4]. They are also manipulation greatly relied on how magnetic materials respond to
widely used for other laboratory-based biomedical applications such as magnetic field gradients [15,16]. These applications include cell label-
genetic and tissue engineering, imaging, and investigations of biological ing, magnetic separation for lab analysis and synthesis, imaging, mag-
fluid properties [5–7]. Their size, however, also puts limitations on op- netic drug targeting, hyperthermia, and diagnosis among others [17–20].
tions for powering and manipulation, with onboard energy storage However, biomedical small-scale robots normally need to perform their
and/or conversion posing several obstacles in conceptualization. Several tasks in fluidic environments with low Reynolds numbers. Because of
reviews have been published, broadly explaining a range of methods to their relatively small size, they tend to face high drag forces and inertia
manipulate and actuate milli/micro/nanorobots, including the use of vacancy when operating in these environments. The use of magnetic
chemically powered motors, acoustic propulsion, and ultrasound energy gradients for propulsion in such environments may present low precision
[4,8,9], and their applications in drug delivery, precision surgery, control and jerky movements [21]. In view of this, more efficient actu-
sensing, and detoxification [10–12]. Some of these reviews cover very ating methodologies and propulsion efficacy than those typically
broad topics including milli/micro/nanorobots with different actuation observed when using magnetic field gradients for manipulation are
mechanisms with a brief review of each category and comparison, required.

* Corresponding author.
E-mail addresses: Michael.Chen@ed.ac.uk, xianfeng.chen@oxon.org (X. Chen).
1
These authors contributed equally.

https://doi.org/10.1016/j.mtbio.2020.100085
Received 29 August 2020; Received in revised form 21 October 2020; Accepted 25 October 2020
Available online 30 October 2020
2590-0064/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
M. Koleoso et al. Materials Today Bio 8 (2020) 100085

More recent developments involve the use of magnetic torque, lithography/direct laser writing/3D laser lithography), electron beams
rotating and oscillating magnetic fields, and other means to actuate (E-beam lithography), and X-ray (X-ray lithography) [29–32]. Other
nanorobots resulting in their propulsion and allowing for more accurate strategies used in establishing 3D structure include glancing angle
2D and 3D navigation of these devices [22]. A lot of the propulsion deposition (GLAD) which is based on physical vapor deposition,
methods of these devices have been adapted from nature, for example template-assisted electrodeposition, and use of a more advanced bio-
helical flagella found in some bacteria, tail-like flagella found in sperms, template technique [23,33–35]. Besides, the bodies of the magnetic ro-
and other designs that mimic motion of fish in water [23–26]. There have bots can also be made of soft materials with the use of soft smart
also been more imaginative designs such as surface walkers and materials recently seeing a rise [36,37]. This is due to their improved
two-armed swimmers [27,28]. functionality and better mimicry of organisms that inspire their designs
The field of biomedical magnetic micro/nanorobots is relatively new than their rigid counterparts.
and still in its highly innovative stage. As illustrated in Fig. 1, the number To allow for magnetic manipulation, the second step requires the
of papers published in this field over the past five years (2015–2019) is incorporation of magnetic components into the micro/nanorobots which
greater than the total number of publications in the field over the twenty- could be the partial or complete magnetic material coating of the robot
five years prior. This paper aims to investigate the current state of the art body, the connection of magnetic segments, and the use of magnetic
of biomedical magnetic nanorobots and microrobots, their propulsion micro/nanoparticles (detailed methods in Fig. 2). However, more and
mechanisms, fabrication methods, current applications, and the tech- more recently developed novel fabrication methods are in efforts to
nologies they use. The further incorporation of other technologies or simplify the manufacturing process or to fabricate robots with special
materials in designs for the purpose of improving biomedical function- structures. These methods will be discussed in more detail mainly in
alities and safety will also be systematically reviewed. There will be a Section 3.3.
brief comparison between microrobots and nanorobots, identifying
where they outperform each other in biomedicine. Finally, the challenges 2.1.2. Magnetic actuation mechanisms
faced in the use and implementation of these advancements in vivo will be The magnetic force (F) on a magnetic object with the magnetic dipole
looked at to identify areas for further research. moment (m) due to a magnetic field (B) is equal to (m
r)B. When the
magnetic field is homogeneous (gradient, r, is zero), the magnetic robot
2. Recent advancements of the design of magnetic small-scale will not experience gradient force and move along with the field but the
robots magnetic torque, τ ¼ m
B, can force the magnetic robot to align its dipole
moment with the applied magnetic field via rotation if they are not in the
2.1. Introduction to magnetically actuated micro/nanorobots same direction [41]. Thus, as illustrated in Fig. 3, magnetic fields utilized
for robots propulsion must be time-varying (for example, rotating,
2.1.1. General fabrication methods oscillating, and stepping magnetic fields) or inhomogeneous (field gra-
To manufacture a magnetically actuated micro/nanorobot, a mag- dients). These fields are normally generated from permanent magnet
netic component should be involved in the structure of micro/nano- systems, electromagnetic coil systems, or magnetic resonance imaging
robots. Thus, as summarized in Fig. 2, the general and most widely (MRI) machines. The different mechanisms of magnetic actuation will be
adopted fabrication technologies for magnetic small-scale robots often described in detail next.
contain two sections: micro/nanorobots fabrication and incorporation of
the magnetic component. 2.1.2.1. Interactions of time-varying magnetic fields with micro/nano-
The first step is establishing the basic structure of robots which can be robots. Time-varying magnetic fields actuate magnetic devices through
achieved through several routine nanolithography techniques that etch magnetic torque and often propel magnetic devices by inducing various
(write on) or polymerize photosensitive materials. Etching methods types of motion. Time-varying magnetic fields can be classified as
typically make use of UV light (photolithography), laser (two-photon rotating, oscillating, and stepping magnetic fields. Rotating magnetic
fields are one of the most commonly used time-varying fields. They are
often used to actuate helical robots, one of the most widely used designs
of microrobots or nanorobots whose actuation is achieved by the in-
duction of rolling, corkscrew, and spin-top motions [42–44]. It has been
found in the literature that the magnetic particle aggregates and some
other interesting structures can be manipulated by rotating magnetic
fields as well [45–50].
Oscillating magnetic fields normally center on flexible robots whose
developments will be the focus of section 2.2.1. Stepping magnetic fields
are a type of periodic magnetic field with ON/OFF phases. They can
induce the wave-like motion of the magnetic cilium on a robot resulting
in a power stroke to induce movement [51].

2.1.2.2. Interactions of magnetic field gradients with micro/nano-

robots. Older magnetic micro/nanorobot designs typically made use of
magnetic field gradients to manipulate magnetic micro/nanoparticles. As
touched upon earlier, the use of magnetic gradients for the propulsion of
micro/nanorobots presents some issues, especially if these devices are to
be used in vivo. The magnetic force due to the magnetic gradient expe-
rienced by a magnetic material varies directly with the volume of mag-
netic material present. This relationship poses a hurdle to the
Fig. 1. The publication trends in magnetic small-scale robots showing the cu- maintenance of the nanoscale size for some applications if magnetic
mulative number of publications from 1990 to 2019 (including 2019) and the gradients are to be used as the means of propulsion.
numbers of publications over five-year periods within this time range from the To acquire more precise control using field gradients, 3D field gra-
Web of Science. The key words used in the search were magnetic AND dients have been introduced. For example, Schuerle et al. [52] used eight
micro(nano)robots/machines/swimmers/propellers/motors.

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Fig. 2. General fabrication methods for magnetic micro/nanorobots contain two sections: micro/nanorobots fabrication and incorporation of magnetic components
[38–40]. (All images are used with permission).

stationary and independently controlled electromagnets to achieve the and imaging at a suitable frequency. Using this pulse sequence, a 2-mm
manipulation of magnetic micro/nanorobots moving in 3D space and chrome ball was steered through a complex vascular network phantom
proposed to use them in the single-cell manipulation and drug delivery. with velocities up to 74 mm/s while imaging at 27 Hz with a maximum
This manipulation system can generate field gradients up to 50 mT (5 gradient amplitude of 21 mT. Although this study was not conducted at
T/m) and allow high degree-of-freedom (5) motion control. Beyond the microscale or nanoscale, it acts as a proof of concept that magnetic
gradient-based pulling motion, the system can also manipulate the gradient magnitudes previously thought only capable of propulsion can
rocking motion and cork screw–like motion of microrobots when in carry out simultaneous imaging and propulsion and show great potential
combination with the rotating and stepping modes. for real-time image-guided navigation. By combining dynamic dipole
The existing MRI machines are promising tools for magnetic gradient field navigation (DFN-D) into clinical MRI, Shi et al. [54] produced a
pulling. The magnetic field gradients produced by MRI machines have piezoelectric actuation system which can manipulate microcarriers
been used to actuate devices with simple movement mechanisms moving in the vascular network. DFN-D can generate high field gradients
resulting in what is termed as magnetic resonance navigation [53]. This in MRI by distorting the uniform magnetic field in an MRI scanner using
could be of great use as if this method of actuation can be combined with precisely controlled ferromagnetic balls. The in vitro result showed that
MRI, it could provide a robust system for navigating devices through the magnetic microparticles can accurately follow the planned trajectory and
human body while in the bore of MRI machines. A major challenge faced go into the targeted branch at the bifurcation point under the navigation
in the achievement of this sort of navigation, however, is the difficulty of of this system.
simultaneously imaging and propelling devices as different pulse se- For more details of magnetic actuation mechanism, design, and
quences are required for both of those functions meaning that one operation, the readers are referred to several recently published reviews
function is usually favored over the other. Recently, Felfoul et al. [53] which have specifically introduced how magnetic fields (rotating, oscil-
attempted to show that this challenge can be overcome by working out an lating, and gradient) to actuate and control magnetic micro/nanorobots
optimal pulse sequence that allows for propulsion at a suitable velocity [55,56]. For example, in a very recent review, Yang and Zhang [57]

Fig. 3. Different magnetic fields for the actuation of different designs of magnetic micro/nanorobots.

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

elaborated actuation systems including systems with permanent magnets consistency in them. The three-link swimmer produced an average speed
(single and multiple magnets) and systems with electromagnets (paired of 14.44 μm/s or 0.93 body lengths per second. The findings of this paper
coils and distributed stationary or movable electromagnets). Beyond suggest that the challenge of the use of magnetic nanorobots in highly
research examples, another recent review paper detailed current com- viscous or low Re fluid environments, which are common in living or-
mercial magnetic actuation systems, such as Niobe, Genesis, ganisms can be overcome. However, this work did not attempt to
Aeon Phocus, MiniMag, OctoMag, and Catheter Guidance Control and investigate another challenge which is the use of such nanorobots within
Imaging systems [58]. Fig. 4 displays typical electromagnetic actuation living organisms, particularly areas very far from the skin surface [65].
(EMA) systems from studies discussed by our review. Using a similar method of propulsion to the three-link nanoswimmer
This section describes the fabrication of magnetic micro/nanorobots and inspired by the body and caudal fin (BCF) motion of fish in water, Li
and the actuation mechanisms. Next, we will systematically describe the et al. [26] adapted the link and hinge design to produce a nanoswimmer
recent advancement in micro/nanorobot propulsion, micro/nanorobots (Fig. 5b) called the nanofish. BCF motion is a result of wave propagation
design involving biological components such as bacteria, sperm, and along the bodies and tails of fish with their heads remaining relatively
integration of multiple functions in micro/nanorobots, as well as the inactive. Thus, the propulsion of this swimmer differs from that of the
biomedical applications of these wide ranges of micro/nanorobot three-link swimmer, in that, its body is magnetically actuated while the
systems. head and tail remain passive [68]. The fish-like nanoswimmer consists of
a gold head, two nickel body segments, and a gold tail all linked by
flexible, nanoporous silver hinges [26]. The swimmer produced its
2.2. Advancements in micro/nanorobot propulsion greatest speed of 30.9 μm/s at 11 Hz with speed decreasing at higher
frequencies and showed immediate changes in speed in response to fre-
2.2.1. Flexible swimmers quency adjustments. The nanofish's on-demand start–stop abilities were
Flexible swimmers are those that have flexible parts, usually joints or demonstrated by switching the actuating magnetic field off and on
tails allowing for deformations under the influence of a magnetic field. resulting in corresponding starting and stopping of its motion. It also
These devices are propelled because of an undulatory motion and are demonstrated the ability to go through on/off cycles with minimal speed
usually actuated by oscillating or rotating magnetic fields. There has been changes. To assess the effect of the lengths of components of this design,
a recent rise in the study of these swimmers due to their improved nanofish of different BCF-to–head length ratios were compared with
swimming efficiencies and speeds when compared with the already those of larger BCF-to-head ratios achieving higher speeds. The re-
extensively studied helical swimmers [23,61–64]. searchers compared the speeds attained by the nanofish to those attained
Jang et al. [65] investigated the locomotion of a magnetic three-link by other magnetically actuated swimmers at the time of publication and
nanoswimmer that produced undulatory motion under an oscillating found that it achieved the greatest dimensionless speed (0.6 body
magnetic field resulting from the superimposition of two sinusoidal length per revolution) [26].
magnetic fields on x and y axes (Fig. 5a). This design is adapted from Using the same fabrication technique, Li et al. [27] also produced a
findings in the work by Purcell [66] where a three-link two-hinge nanoswimmer inspired by human freestyle swimming motions as
swimmer produced the most efficient propulsion strategies at low Rey- opposed to motions found in other organisms as is typically seen. This
nold's numbers. This was the first to investigate external actuation of design researched a potentially more efficient propulsion method than
Purcell's three-link swimmer. The design of this device consists of Nickel others previously investigated, which possibly results from the kinematic
(Ni) links with flexible poly(allylamine hydrochloride) and poly(- optimization. This study demonstrates for the first time that an oscillating
styrenesulfonate) polymer hinges. The swimmers are made using a magnetic field can produce propulsion through motions other than
version of the fabrication technique from Mirkovic et al. [67]. The planar oscillation or undulation. This swimmer portrayed in Fig. 5c is
technique was modified by using polypyrrole to make the flexible tail and made up of a gold body and two magnetic nickel arms linked by flexible
the use of a deposition technique to produce the hinges which assured

Fig. 4. Electromagnetic actuation (EMA) sys-

tems. (a) A triaxial Helmholtz coil electromag-
netic system. Photo credit: Magdanz et al.⋅[25].
(b) The comprehensive system for external active
actuation and imaging of macrophage-based
microrobots. “The EMA system consisted of
three pairs of Helmholtz coils—one pair each on
the x-axis, y-axis, and z-axis—and two pairs of
Maxwell coils—one pair each on the x-axis and
y-axis. The role of the three pairs of Helmholtz
coils was to create a uniform magnetic flux, while
the purpose of the two pairs of Maxwell coils was
to induce a uniform gradient of magnetic flux in
the region of interest” [59]. (c) The integrated
eight-coil EMA and NIR system. In EMA system,
four coils in the upper side and four coils in the
down side [39]. (d) A commercial EMA system
(MFG-100-I, MagnebotiX, Switzerland).
Controlled locomotion along the trajectories of
capital letters “XMU” (Xiamen University) [60].
(All images used with permission). NIR,
near-infrared.

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Fig. 5. Hard flexible magnetic micro/nanorobots

and their magnetic actuation systems. (a) The
schematic of the three-link nanoswimmer with
undulation motion, subjected to a magnetic field
oscillation (2θ ¼ angular sweep of the magnetic
field, B⇀ ¼ magnetic field and τm ¼ magnetic
torque). A three-linked swimmer Ni (1.75 μm)–
PAH/PSS (1.5 μm)–Ni (1.75 μm)–PAH/PSS
(1.5 μm)–PPy (9 μm) [65]. (b) Artificial
nanofish. (i) The Schematic of a natural fish and
an artificial nanofish in BCF mode propulsion,
involving passing undulatory waves down the
entire length of the body. (ii) Magnetic propul-
sion of an artificial nanofish using a planar
oscillating magnetic field [26]. (c) The schematic
of two-arm nanoswimmers. Applying an oscil-
lating magnetic field on z-direction leads to
freestyle swimming of the nanorobot with two
nanoarms wobbling alternatively to generate
actuation in the x–y plane [27]. (All images are
used with permission). BCF, body and caudal fin;
PAH, poly(allylamine hydrochloride); PSS,
poly(styrenesulfonate).

silver hinges. The components of the swimmer are made by template ratio. This indicates that an increase in the tail length ratio widens the
electrodeposition into a 200 nm alumina membrane template. The range of frequencies for which the propulsion of the longer tail is
fabrication method allows for the creation of components of different dominant, allowing for more control of velocities in the direction of the
lengths which has an effect on the flexibility of the silver hinges. An long tail. There was no notable decrease in speed observed when
oscillating magnetic field resulting from two electromagnetic coils was compared with one tailed microrobots tested by the group.
used in the study. When compared with the three-link swimmer by Jang A cluster of microrobots could also be seen as a flexible swimmer
et al. [65] in which an undulatory movement was responsible for pro- because it is able to change its formation flexibly. A recent study dis-
pulsion, the freestyle nanoswimmer shows much greater speeds played that by inputting different magnetic fields programmatically the
(maximum speed of up to 12 body lengths per second vs. 0.93 body locomotion and formation of the magnetic microrobot swarm can be
lengths per second in the three-link swimmer). ideally controlled [70]. For example, microrobot swarms can form in the
Flexible swimmers also have the potential to perform back and forth liquid, chain, vortex, and ribbon shape when individual microrobot un-
movement. In theory, helical flagellar designs allow for back and forth dergoes oscillating, rolling, spinning, and tumbling motions, respec-
movement through changing the direction of spin of the helix. However, tively. This flexible formation change allows microrobot swarms to better
in one tailed planar flagellar microrobots, moving in the opposite di- address the complex biological environment, work in a confined envi-
rection requires a U-turn which may be difficult to achieve in narrow ronment and perform multiple tasks.
vessels. This limits their use for tasks that require back and forth motion Although most flexible swimmers that were examined in this review
in such biological environments. To address this issue, Khalil et al. [69] were developed to provide more efficient or robust means of navigation,
reported a bidirectional flagellated actuation without the U-turn trajec- the next flexible swimmer is of particular interest for drug targeting. Most
tory. This study looked into the change of direction on the same trajec- nanoscale drug transporters developed so far have depended on complex
tory of a microrobot that possesses two flagella of unequal length and the scientific methods to allow for drug loading. Gao et al. [71] presented a
effect of flagella lengths on reversal frequency (Fig. 6a). It proposes and cargo-towing nanoswimmer capable of transporting microspheres
attempts to verify a model that predicts velocity based on the tail length encapsulating drugs. The swimmer was made up of a magnetic nickel
ratio and magnetic field frequency and determines the reversal frequency head and a flexible silver tail. Drug-loaded microspheres are easily
of the different length ratios tested. Five tail ratios were tested in a attached to the nanoswimmers by means of magnetic attraction between
glycerine medium. Experimental results showed that the longer tail the swimmer's magnetized nickel head and the drug-loaded magnetic
provided the greater propulsive force at frequencies below the reversal polymer particles. Fabrication of the nanoswimmers involved the elec-
frequency and that the reversal frequency value increased with tail length trodeposition of the swimmers' materials into an alumina membrane

Fig. 6. Soft flexible magnetic micro/nanorobots.

(a) A soft-bodied two-tailed microrobot with a
magnetic head and two collinear, unequal, and
opposite tails fabricated using electrospinning. (i)
Magnetic particles are incorporated within the
head to provide magnetization (m) and direc-
tional control under the influence of a periodic
magnetic field (B) at frequency ω. (ii) Below
reversal frequency (ωr), the net propulsive force
enables the microrobot to swim using its long tail.
(iii) Above ωr, the short tail allows for swimming
along the opposite direction [69]. (b) Bovine
sperm cells are coated with rice grain–shaped
maghemite nanoparticles resulting in soft IRON-
Sperms [25]. (All images used with permission).
IRONSperm, iron oxide nanoparticles adhered to
part of the surface of the entire sperm cell.

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

followed by the dissolution of the membrane in NaOH to release the involve a swimming type of motion. This method opens up new prospects
swimmers. A set of triaxial Helmholtz coils were used to generate a in the field of micro/nanorobot propulsion, especially in confined spaces
rotating magnetic field for the actuation of the swimmer. Under the in- and complex geometries. Because of this device's robust navigational
fluence of a rotating magnetic field, the nickel head rotated causing the ability and its efficiency in changing speed, the developers of this device
silver tail to deform in such a way as to produce a whipping motion envision it being applied to a wide range of uses from nanomanipulation
resulting in the propulsion of the swimmer. The swimmer was used to to precise medical treatment. The actuation and operation of this device
transport spheres of sizes of 500 nm to 2.5 μm with the researchers noting is further discussed in section 3.1.4.
that the particle size affected the speeds achieved by the swimmer. An
interesting observation was the increase in speed when the swimmer 2.3. Propulsion designs incorporating biological and synthetic components
carried particles of 1.25 μm compared with when it bore no load.
Although the load of magnetic drug–containing particles increases Nature is a rich database which often inspires the ideas of scientists
viscous drag, it also sets up a rotating field because of spinning motion of and can provide solutions to scientific challenges. There have been plenty
these particles and, consequently, affects the propulsion speed of the of micro/nanorobot designs adapted from nature with research showing
nanoswimmer. Therefore, when the size of drug particles is approxi- promising results for their applications in the biomedical area, for
mately 1.25 μm, the speed of the nanoswimmer actually increased. example, the adaptation of bacterial flagella [76]. Because of such find-
However, further increase of the size of drug particles will lead to ings, researchers attempted to preserve the original function of biological
reduction of the speed of the nanoswimmer. components and include them in their robot designs.
A concern for this design is how effective it will be in the treatment of Ali et al. [77] created a self-assembled magnetic nanorobot consisting
tumors as nanowires are not likely to be readily taken up by cancer cells. of bacterial flagella attached to a superparamagnetic particle for actua-
There are also concerns about premature drug release; therefore, the tion and steering under a rotating magnetic field. To make the robots,
researchers hope to investigate stronger attachment methods as well as flagella were obtained from Salmonella typhimurium, depolymerized into
stimuli responsive and specific release of the drug carrying nanoparticles. the constituent protein flagellin and then polymerized into flagella
In addition, the means of propulsion needs to be verified as operable in fragments of roughly equal length (200 nm) (Fig. 7a). The fragments
flow environments similar to those found in many body fluid systems. were biotinylated using a method described by Asakura et al. [80] and
Asakura and Iino [81], and the superparamagnetic particles of radii
2.2.2. Helical swimmers 40–400 nm were coated with streptavidin and placed in solution
Helical- or screw-type microrobots and nanorobots are widely studied along with biotinylated flagella and agitated resulting in the attachment
because of their proven propulsion abilities. However, many robots have of flagella to particles [80,81]. To imitate environmental stimuli that
been limited by their inability to be propelled in gels and other complex results in conformational change, the swimmers were submerged in
media such as the extracellular matrix (ECM). To further increase their aqueous solutions containing organic solvents resulting in rapid confor-
use for biomedical applications, Schamel et al. [72] produced a mational change, similar to actual bacteria. The use of these robots has
400-nm-long and 70-nm-diameter magnetic nanohelix capable of navi- the potential to overcome several limitations faced in in vivo biomedical
gation through complex viscoelastic media. The nanohelix consists of a applications of magnetic nanorobots. Flagella that change conformation
SiO2 helix coated with a 40-nm-layer of nickel (for magnetic actuation by in response to environmental stimuli would be beneficial in navigating
a rotating magnetic field) produced by the GLAD method [73]. Because the heterogeneous fluids which may present a physical barrier to robot
of their small size (the smallest produced nanohelix at the time of pub- navigation. Another benefit of this design is the simplicity of its fabri-
lication), they have an advantage over their larger counterparts when cation process compared with several others that use complicated
moving through gels as they are similar in size to meshes in the gels. methods such as electrodeposition. Its fabrication method allows for easy
Although no movement of the nanohelix was observed in water because batch production of robots of different flagella and particle sizes.
of Brownian motion, the dimensionless velocities achieved in gels were Beyond serving as a source of inspiration for sophisticated structures,
greater than the greatest of those achieved by microhelices in Newtonian incorporating natural organisms into micro/nanorobots entails many
fluid. The step-out frequency of the nanohelix was much higher than that functional advantages, such as selective cytotoxicity, hydrophobicity/
of other micropropellers it was compared with, indicating a wider range hydrophilicity, fracture resistance, facile uptake of therapeutic agents,
of speed control of the nanohelices. This nanohelix shows potential in autofluorescence, renewability, and biodegradability. Incorporating
navigating complex fluid systems such as the ECM and, because of its these interesting functionalities in magnetic robot fabrication could
small size, potential in being taken up by cells. Hence, further research expand their biological applications.
can be done toward the determination of intracellular applications of Yan et al. [78] discovered that Spirulina platensis, a helical microalgae
such a nanorobot while also optimizing its design to prevent negative subspecies, exhibits intrinsic fluorescence, selective cytotoxicity to can-
interactions with organelles and other cell components. In the study by cer cells and natural degradability. Attaching Fe3O4 nanoparticles on
Pal et al. [74], the irreversible trajectory was observed when they S. platensis surface via a dip-coating method results in magnetic micro-
manipulated a helical nanorobot in a HeLa cell, which could be due to the robots under the general name magnetized Spirulina (MSP) which can be
influence of intracellular creeping flow and the reorganization of the propelled by a rotating magnetic field provided by a tri-axial Helmholtz
intracellular matter. The study confirmed that the exquisite control of coil system and can perform in vivo imaging-guided therapy with an
250 nm nanorobots in cells is possible using rotating magnetic fields emission peak at around 650 nm (Fig. 7b). The microrobots were injected
generated by a triaxial Helmholtz coil, despite the crowded intracellular in the intraperitoneal cavity of nude mice to test their in vivo fluorescent
environment. imaging abilities. The results showed that MSP can stably emit fluores-
cent signals in mice for about 15 h.
2.2.3. Surface walkers Recently, Yan et al. [82] updated their MSP microrobots and applied
A more unique method of propulsion more recently being used in them in controlled drug delivery. Apart from aforementioned beneficial
micro/nanorobots propulsion is surface walking. A recent example of a features, Spirulina cells have large pores for slime secretion allowing for
magnetically actuated microsurface walker is the Janus microdimer the uptake of large molecules. Thus, in this study, they used the dehy-
surface walker, consisting of two Ni/SiO2 Janus spheres joined magnet- dration and rehydration of spirulina for molecular loading. The spirulina
ically [75]. Under the influence of a planar oscillating magnetic field and microrobots were successfully navigated through a fluidic channel
near a surface, the spheres roll over each other in an asymmetric fashion modeled after the intestinal tract containing intestinal fluids demon-
that results in the net displacement. This is different from both propul- strating precise control capabilities. The loaded molecules were released
sion methods discussed in Section 2.2.1, 2.2.2 earlier as it does not because of two mechanisms, namely concentration gradients and

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Fig. 7. Micro/nanorobots involving biological components. (a) The diagram of flagella repolymerization [77]. (b) Magnetized Spirulina. (i) The schematic of the
dip-coating process of S. platensis in a suspension of Fe3O4 NPs. (ii) FESEM (top) and fluorescence images (bottom) of MSP-24 h, MCR-24 h, and MTS-24 h samples
[78]. (c) Assembly of DNA origami micromachine systems. (i) The ssDNA connecting two structures (polymerization strands) were designed with a U-shaped motif,
where half have a higher affinity to attach to one side of the interface whereas the other half have higher affinity to the other side of the interface. (ii) Stiff microlevers
are assembled by attaching 56 helix nanobricks end-to-end using polymerization strands. AFM and TEM images show microlevers. The scale bar is 1 μm. (iii) The
nanorotor is assembled by attaching a nanoplatform to a nanobrick via a single ssDNA overhang. AFM and TEM images show the nanorotor construct. The scale bar is
50 nm. (iv) Stiff microlevers are formed off the arm of the nanorotor using polymerization stands to connect the nano-arm to microlevers. AFM and TEM images show
the assembled microrotor. The scale bar is 100 nm. (v) A single nanobrick is attached initially to the top and bottom of the nano-hinge using two separate sets of
polymerization strands for top (green-blue) and bottom (red-blue). AFM and TEM images show the hinge with top and bottom nanobricks attached. The scale bar is 50
nm. (vi) Stiff microlevers are formed off the initial nanobricks by attaching top nanorods (green) and bottom nanorods (red) using two separate sets of polymerization
staples for the top (green) and the bottom (red). The zoomed out image of AFM and TEM images show a polymerized nano-hinge (Scale bars are 500 nm, left and
right). The zoomed-in image of the nano-hinge from in the AFM image (The scale bar is 50 nm, middle) [79]. (All images are used with permission). FESEM, Fiel-
d-emission Scanning Electron Microscopy; AFM, Atomic Force Microscopy; TEM, Transmission Electron Microscopy.

spirulina degradation, with more molecules released the longer the liposome and releasing the drug when exposed to NIR. Further work is
residence time. The release of molecules from these transporters can be desired to refine this design by conducting tests in animals involving the
controlled by adjusting magnetite thickness with thicker coatings extraction of macrophages from different organs and identifying the best
showing a slower rate of molecule release. This method of control, to use for investigations with a final goal of being able to implement this
however, requires a good knowledge of the amount of time it would take treatment method in humans with cancer [59].
to navigate to targets which will be difficult in a system as complex as the DNA origami structures have gained a lot of attention in the nano-
gastrointestinal system. External stimuli could be investigated as an technology field because of their potential to be used as building blocks
alternative means of controlling molecule release. for nanoscale machinery [85,86]. Lauback et al. [79] presented a set of
Another significant advantage of biological components is their microdevices assembled from nanoscale DNA origami structures, actu-
biocompatibility, with particular regard to components originating from ated by magnetic fields with subsecond response times. The first device is
within organisms, for example, various immune cells, DNA, sperms, and a nanorotor, capable of continuous rotational motion, and the second
plasma cells. device is a nano-hinge capable of limited relative rotational motion
A good example is the macrophage, an immune cell which may also (angle of about 120 between the 2 arms). The actuation of these struc-
have tumor targeting properties making it beneficial for chemothera- tures is due to the magnetic torque experienced by the magnetic micro-
peutic purposes as they could allow for better targeted drug transport, sphere when a rotating magnetic field is applied. The arms used in these
potentially reducing the effect of such therapy on healthy tissues and structures consist of bricks as in Fig. 7c formed from multiple DNA double
cells. In the work by Han et al. [59], a hybrid-targeting method based on helices. The rotor was able to execute 120 complete continuous rotations,
magnetic actuation and the propensity of macrophages to gather around and both structures are able to hold different conformations with preci-
solid tumors is proposed for more efficient targeting. This microrobot sion of about 8 . The study mainly explored the magnetic actuation of
consists of poly-lactic-co-glycolic-acid (PLGA) spheres containing mag- DNA origami structures; hence, no testing for biomedical applications
netic and chemotherapeutic nanoparticles which are taken up by was done, although it was suggested that these structures could be used
phagocytotic macrophages. The microrobots are actuated using a in the field of protein engineering for enzyme control and other appli-
gradient magnetic field generated by three Helmholtz coils and Maxwell cations. A major benefit of these structures is the low cost of making the
coils and their motion controlled by adjusting coils' currents. The control system which can be assembled from cheap electromagnets,
microrobots brought into the vicinity of tumor spheroids were found to increasing this design's potential for commercial availability.
infiltrate into them because of macrophage recruitment. This microrobot Sperms are naturally adapted to swim in the female reproductive
design was further modified using liposomes in place of PLGA for MNPs environment, and a study found that sperms can display a high uptake of
and drug containment as well as near-infrared (NIR) radiation stimulated doxorubicin hydrochloride (DOX-HCl) (a hydrophilic anticancer drug)
enhanced drug release [83]. Similarly, the robots were made by phago- because DOX-HCl exhibits high-binding affinity to DNA (nucleus) [87].
cytosis of liposomes containing MNPs and taxol (anticancer drug) pre- Based on this, to design a drug-loading microrobot for targeted cancer
pared by thin-film hydration [84]. NIR radiation enhanced the drug treatment, Magdanz et al. [25] adopted bovine sperm cells (length of
release rate because of the temperature sensitivity of one of the lipo- ~60 μm) as the temple to fabricate soft magnetic microrobots via a
somes’ components causing a phase transition, effectively melting the simple electrostatic-based method (Fig.6b). Because of opposite surface

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

zeta potentials, iron oxide nanoparticles adhered to part of the surface of as vessels, resulting in great promise in microvascular thrombolysis and
entire sperm cells (IRONsperms), which ensures magnetically actuated ultraminimal invasive surgery.
helical flagellar propulsion while flexibility. Their results displayed that
the moving speed of IRONsperms can exceed 6.8  4.1 μm/s under a 2.4. Multifunctionality in magnetic micro/nanorobots
rotating magnetic field actuation with a frequency of 8 Hz. After cocul-
ture of IRONsperms and DOX-HCl for about 1 h, IRONsperms showed 2.4.1. Hybrid actuation
good cargo-encapsulating ability with 4.3  0.2 pg of DOX-HCl per Several recent designs of small-scale robots consist of various func-
IRONsperm. tional materials that let the magnetic robots respond to more than one
Often when operating in vivo, small-scale robots are attacked by the type of external stimuli (e.g. light, ultrasound, and temperature),
body's immune system or bound to biological molecules. Although sub- resulting in hybrid actuation and multifunctionality. As concluded in a
stantial research has been done into the development of more biocom- recent review, magnetically and optically actuated microrobots have
patible microrobots and nanorobots, most have a focus on reducing different pros and cons in material, locomotion performance, or
cytotoxicity and negative effects which these devices have on biological biocompatibility [94]. Magnetic microrobots are more promising for
systems, but little has been accomplished in research on the reduction of applications in deep tissue because of better locomotion and navigation
interactions that are detrimental to the performance of these devices. and optical microrobots are softer and more suitable working in trans-
Because of this, Li et al. [88] developed a helical nanoswimmer coated parent environments or used for biotechnology and lab- /organ-o-
with the plasma membrane of human platelets to allow for hindrance-- n-a-chip. Therefore, naturally, the combination of these two actuations
free propulsion by avoiding biofouling. Human platelets have many may potentially combine their advantages. Similarly, the combination of
functions in the blood, for example, immune evasion, pathogen in- other actuation will be beneficial as well.
teractions, and subendothelium adhesion [89,90]. These also give the Low-frequency ultrasound waves have the potential ability to aid in
nanoswimmer-added functionality due to the ability to specifically bind guiding the movement of magnetic robots because of their deep pene-
certain substances. The fabrication of these swimmers involves electro- tration in vivo. Khalil et al. [95] developed a magnetic helical microrobot
chemical deposition of palladium into a template followed by dissolution used for the mechanical disruption of blood clots, which was actuated by
of the template in methylene chloride to release the swimmers. The rotating magnetic fields and tracked by an ultrasound system. The ul-
swimmers are then coated in nickel (for magnetic actuation) and gold by trasonic field they produced has a maximum penetration depth of 16 cm
electron beam evaporation. A negative charge is induced on the gold and can locate the microrobots via their ultrasound feedback and guide
surface by incubating the coated swimmers with 3-mercaptopropionic microrobots toward blood clots. After arriving at the blood clot area, the
acid. After incubation with plasma membrane vesicles, the protein rotating magnetic fields induce a rotary motion in the helical microrobots
coating is adsorbed onto the gold surface. The protein-coated swimmers at ω ¼ 35 Hz to rub against and tear the fibrin network of the clot. At body
displayed much greater propulsion speeds than uncoated swimmers temperature, using this rotary frequency, these microrobots have a blood
when tested in plasma, serum, and whole blood exemplifying their clot cleaning rate of 0.482  0.23 mm3/min. Combining acoustic
enhanced performance in biological media. The swimmers further actuation with rotational magnetic actuation, Ahmed et al. [46] reported
demonstrated their abilities by maintaining propulsion speeds after in- a special propulsive mechanism which can let magnetic spheroidal ag-
cubation with blood indicating little or no biofouling. During experi- gregates perform a rolling motion along vessel walls. Acoustic fields of
mentation, it was also noted that some toxins and pathogens selectively appropriate frequencies can force magnetic aggregates to migrate to the
bound to the surface of the swimmer as they would to platelets, diverting vascular boundary (Fig. 8a). This close-to-wall propulsive mechanism
the pathogens away from healthy cells [90]. The swimmer was able to could eliminate the thrombosis caused by the shear-induced platelet
bind to up to 15 bacteria at a time indicating its potential to be used as a activation resulting from the rolling motion of microrobots.
means of pathogen diversion from healthy cells. The study envisions The sperm-templated soft magnetic microbots described in Section
further development of this design leading to it becoming a new standard 2.3 were also one example of hybrid actuation [25]. The localization of
method of pathogen isolation and diversion. IRONsperms was achieved by ultrasound waves because the coated iron
Beyond directly employing natural biological components to fabri- oxide particles enhance the acoustic impedance of IRONsperms. The
cate micro/nanorobots, it is also common to create such systems to study displayed that only a 20-MHz ultrasound wave can visualize a
simulate the nature. For instance, a behavior which has been adapted single IRONsperm in vitro.
from nature recently is the swarming behavior observed in some insects, Chen et al. [96] reported a magnetically actuated helical piezoelectric
birds, and fish. The ribbon-like paramagnetic nanoparticle swarm by Yu microrobot made up of a polyvinylidene fluoride-co-trifluoroethylene
et al. [91] consists of paramagnetic nanoparticles reconfigured into mi- (P(VDF-TrFE)) matrix encasing MNPs applied in targeted cell delivery.
crostructures termed microswarms using oscillating magnetic fields. This This microrobot is used to ultrasonically stimulate cell differentiation for
design is advantageous because of its ability to elongate reversibly and neural networks repair. The piezoelectric microrobots are loaded with
greatly increase its aspect ratio, split into subswarms, and navigate neuron-like cells which differentiate because of the electrical polariza-
multiple channels simultaneously and other abilities. The ability of the tion of the piezoelectric body when exposed to acoustic waves (Fig. 8b,
microswarms to maintain stability when encountering obstacles was i-ii). These microrobots are manipulated by a rotating magnetic field
demonstrated by navigating the device to approach solid boundaries of causing them to swim in a programmed corkscrew motion to the targeted
different geometries including circular, planar, and sharp-angled area. The fabrication of the microrobots involves mixing CoFe2O4 MNPs
boundaries. After these tests, the microswarms maintained their shape into a piezoelectric polymer solution ensuring even distribution of the
and only lost a few nanoparticles. The microswarms also demonstrated particles. A copper wire of the desired helical diameter is coated in the
its non-contact ability to manipulate other microstructures by arranging mixture, and a moving laser is used to cut the coating into the desired
randomly distributed polystyrene microbeads into a straight line. The helical shape and pitch. The microswimmer is then released from the
envisioned biomedical applications of this device include targeted de- copper wire by selective etching. As the machine is intended to work in
livery and micromanipulation. the brain, the suitability of the robot for working in the environment of
Another example is an artificial soft magnetic cilia carpet fabricated the ECM (of typical viscosity around 200 mPas) was assessed by testing it
by Gu et al. [92] which can vividly mimic the walking of the millipede. in silicon oil with a viscosity of 340 mPas. One swimmer, optimized in
Xie et al. [93] designed a spheroidal soft hydrogel microrobot embedded terms of the pitch angle, length, and etch ratio achieved a top speed of
with a chain of aligned iron oxide nanoparticles inside which can pre- 0.5 mm/s at a magnetic field frequency of 5 Hz in silicon oil. The
cisely mimic the flexible motion of magnetotactic bacteria. This soft swimmer was able to move in three dimensions, however, only until a
microrobot is capable of working in confined biomicroenvironment such frequency of 1.8 Hz. To test the swimmers' ability to induce cell

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Fig. 8. Micro/nanorobots with hybrid

actuations. (a) Rolling motion in acous-
tic and magnetic fields. The aggregate
migrates toward the channel wall
because of the radiation force of an
acoustic field [46]. (b) (i) Schematic
illustration: ultrasound (US) stimulation
of the piezoelectric microswimmer in-
duces neuronal differentiation of PC12
cells. (ii) An SEM image showing
differentiated PC12 cells on the inner
surface of a helical swimmer after US
stimulation [96]. (c) NIR laser induced
photothermal therapy and PA image
tracking ability in a plastic tube [60].
(All images are used with permission).
SEM, Scanning Electron Microscopy;
NIR, near-infrared.

differentiation, the swimmers were put under acoustic stimulation with Chen et al. [102], the same group that produced piezoelectric
cell differentiation clearly observed after 7 days. microrobots (in Section 2.4.1), used the same polymer (P(VDF-TrFE))
Polydopamine (PDA) as a functional coating has attracted much along with magnetostrictive iron–gallium (FeGa) alloys as the functional
attention in the biomedical field over the last decade because of its materials to manufacture a nanoscale wire-shaped magnetic robot. The
versatile characteristics. These characteristics include the ability to combination of these materials in the robot allows for the spontaneous
adhere to almost all materials, strong NIR absorption, biodegradability, electric polarization of P(VDF-TrFE) resulting from its strain which is
and excellent water solubility [97–99]. Xie et al. [60] used PDA to coat termed the piezoelectric effect. Thus, these materials enable both tar-
MSP microrobots designed by Yan et al. [78] to give them more func- geted drug delivery and release under only magnetic field stimulation.
tions. This coating allowed for the photothermal therapy and photo- Fabrication of these nanorobots first involves the formation of
acoustic imaging of the MSP microrobots as PDA can generate P(VDF-TrFE) nanotubes using a template-based wetting method. This is
photothermal effects and strong photoacoustic signals under NIR laser followed by electrodeposition of the FeGa alloy into the tubes. PDA is
irradiation (Fig. 8c). In this study, the corkscrew magnetic actuation was then adsorbed onto the surface of the produced nanotubes to allow for
provided by a commercial system (MFG-100-I, MagnebotiX, Switzerland) drug binding. Under the influence of an alternating magnetic field, the
(Fig. 4). magnetostrictive core deforms producing strain which triggers a piezo-
When the body of a soft micro/nanorobot consists of thermores- electric response in the shell, redistributing the charges on its surface.
ponsive hydrogels, for example, the microrobot designed by Iacovacci This results in the breaking of the bonds between the PDA and the drugs
et al. [100], MNPs inside the microrobot can not only actuate the loco- resulting in their release (Fig. 9a). This nanorobot is unique in that it is
motion, but also induce the shape transformation (tubular to planar) of rigid and can execute 3D motion via an unsymmetrical rotary motion,
robots under the magnetic field. This morphological change can be used which traces out a cone shape when it is actuated using a cone-shaped
forcontrolled drug delivery and release. Another work by Go et al. [101] rotational magnetic field. Under a rotating magnetic field, it moves via a
presented a similar magnetically actuated microrobot that can fold and tumbling motion. The drug-release method presented here was verified
unfold in response to temperature changes. The microrobot is made up of by navigating the robot to cancer cells and triggering the magnetoelectric
layers of polyethyleneglycol diacrylate loaded with MNPs for magnetic effect which resulted in a 40% drop in the viability of the cancer cells. It
actuation and N-isopropylacrylamide (NIPAM) which is sensitive to was also observed that there was negligible drug release under direct
temperature. Upon heating, NIPAM releases water and shrinks. Coupling current (DC) fields used for navigation.
this shrinking to a stable structure results in the folding of the microrobot Recently, this group also produced a similar piezoelectric wire-sha-
into a spherical cage-like structure. The folding and unfolding properties ped nanorobot named ‘nanoeel’, this time, removing the alloy core
allow for this microrobot to pick up, transport, and release therapeutic resulting in a soft polymeric body [103]. This soft piezoelectric ‘nanoeel’
agents. Magnetic actuation was done by an EMA system consisting of is still capable of magnetic actuation and controlled release of drugs, and
three Helmholtz coils for propulsion and two Maxwell coils for naviga- magnetic fields worked as the single external power source as well. The
tion. The device was successfully navigated toward a microbead con- nanoeel consists of a nickel head for magnetic actuation and a flexible
taining therapeutic agents, positioned near it, and heated to induce piezoelectric P(VDF-TrFE) tail linked by a polypyrrole nanowire. Fabri-
folding resulting in the entrapment of the microbead. The device used the cation was done using the coaxial lithography technique, involving the
rolling motion to deliver the microbead to the desired site and was then deposition of the constituent materials of the nanoeels into an anodized
cooled allowing for the release of the microbead. One device could aluminum oxide membrane template [104]. The drugs were functional-
transport up to five microbeads at a time, and the delivered microbeads ized on to the surface of the nanoeels by subsequently dispersing the
demonstrated their therapeutic effect by severely changing the nanoeels in solutions of Tris-HCl, dopamine, and RhB (drug). Under
morphology of cancer cells that were cultured with for 24 h. Moving alternating magnetic fields, the flexure of the soft P(VDF-TrFE) tail was
forward, this design could be adapted at nanoscale to allow for wider use. induced resulting in a change in its electric polarization leading to
desorption of drugs loaded on the surface of the tail (Fig. 9b). Results
2.4.2. Uses of magnetic field to induce local non-magnetic effects showed that about 90% of the drugs were released under the induced
Although hybrid stimuli are often used to achieve multifunctionality, piezoelectric effect, compared with a negligible amount without piezo-
the interactions of diverse magnetic fields with different materials can electric stimulation. The therapeutic effect of this design was also
also produce different responses such as deformation in magnetostrictive improved under piezoelectric stimulation with 35% of cancer cells killed
materials and imaging in some other materials. This implies that micro/ under stimulation compared with 10% without. Betal et al. [105]
nanorobot multifunctionality under one type of the external stimulus designed a magnetoelectric nanorobot which also utilizes the piezo-
(magnetic field) can be achieved. electric effect and is capable of the targeting, permeation, and transport

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Fig. 9. Magnetic fields induced non-magnetic effects.

(a) FeGa@P(VDF-TrFE) core–shell nanowires. The
anticancer drug is loaded onto a PDA-treated
FeGa@P(VDF-TrFE) core–shell nanowire and then
released by applying an alternating magnetic field.
[102]. (b) A soft hybrid nanoeels with PDA and drugs,
followed by magnetically triggered drug release
[103]. (All images are used with permission). Dox,
doxorubicin; RhB, rhodamine-B; ME, magnetoelectric;
AC, alternating current; PDA, polydopamine; PTX,
paclitaxel; P(VDF-TrFE), polyvinylidene
fluoride-co-trifluoroethylene.

of living cells. This nanorobot consisted of a magnetostrictive CoFe2O4 areas. To permeate cells, the nanorobot was excited under a 50 Oe, 60 Hz
core and piezoelectric BaTiO3 shell and was controlled by alternating AC magnetic field. This induced magnetostriction in the core which when
current (AC) and DC magnetic fields. Under a DC magnetic field of 50 coupled with piezoelectric nature of the shell produces a negative pulse
Oe, the piezoelectric effect gave rise to negative and positive dipoles on strong enough to temporarily dislocate the phospholipid layer of the cell
the device's shell. The negative dipole repelled the negative cell mem- membrane when close to cells. This work has provided a novel means of
brane resulting in thrust generation which could be used to propel cells cell manipulation, combining multiple functionalities typically per-
until obstacles were encountered or the magnetic field was turned off. formed by different tools into a single device. This allows for minimally
For cell-targeting purposes, a 40 Oe, 30 Hz AC magnetic field caused the invasive cell therapy, cell engineering, and more. However, its current
nanorobot to produce low-intensity negative pulses just strong enough to fabrication methods are very complex and energy intensive; thus, this can
create a repulsive force. This resulted in the motion of the nanorobot and be investigated further to develop a more cost-effective manufacturing
subsequent avoidance of other negatively charged obstacles. This inter- technique leading to this device's commercial availability and use.
action also resulted in increased propulsion speeds in high–cell-density

Fig. 10. The biomedical applications of magnetic micro/nanorobots. MRI, magnetic resonance imaging.

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

3. The biomedical applications of magnetic micro/nanorobots micropropellers sized to efficiently propel and navigate through the
and the process toward clinical use matrix of the vitreous humor. These micropropellers were also given an
additional liquid layer coating allowing the device to overcome adhesive
3.1. In vivo and in vitro biomedical applications forces. These microhelices were made of SiO2–Ni using the GLAD tech-
nique. The researchers noted that because Ni is toxic, Fe can alternatively
The current biomedical applications of micro/nanorobots are sum- be used as the magnetic component with very similar performance to
marized in Fig. 10. They can be classified into two broad categories in improve biocompatibility. The micropropeller was able to navigate from
this review, in vivo and in vitro applications. As described in the previous the ercenter of the vitreous membrane to the retina in 30 min, about ten
content, some magnetic robots focus on one application, but some de- times as fast as passive diffusion of a similarly sized particle. The re-
vices can perform multiple functions. searchers, therefore, envision this device as a means of targeted delivery,
significantly reducing the amount of time it takes for certain therapies to
3.1.1. In vivo: cargo transport and enhanced therapy work and reducing the side effects caused by the non-specificity of pas-
One of the most significant functions of micro/nanorobots is trans- sive diffusion. The researchers proposed that this device's precision in
portation because of their precise active movement and relatively high targeted therapy could be improved with a controlled injection system
speed to the targeted areas compared with passive diffusion. As delivery and instantaneous feedback and navigation of the micropropeller
devices, they can achieve a number of diverse applications depending on through the vitreous humor.
their loaded cargos. For example, they can be used for cancer treatment The potential to use MRI machines for targeted therapy termed
when their cargos are anticancer drugs; they can deliver live cells for cell magnetic resonance targeting (MRT) has also been explored by research
therapy, deliver tissue plasminogen activator for thrombolytic purposes, groups. A study by Muthana et al. [114] detailed the successful naviga-
and deliver fluorescence agents for in vivo imaging [60,106-108]. tion of magnetic macrophages from the blood stream into tumor sites in
To transport cargos, Lee et al. [109] fabricated a microrobot with a mice using an MRI system operating at 300 mT. This enhances therapy by
capsule-like head. This capsule-like head can capture drug-loaded par- increasing the infiltration of the tumor by macrophages. The MRI system
ticles and suspended or adherent cells, then assemble with the cap to also allowed for the imaging of macrophage distribution after MRT
encapsulate cargos, and deliver them to the targeted area via a cork- alluding to the potential of real-time imaging for navigation purposes.
screwing motion under rotating magnetic fields. This microrobot The researchers envision this technology being used for targeting tumors
comprised a magnetic helical plunger produced by 3D laser lithography and other cell types such as mesenchymal stem cells.
and physical vapor deposition of Ni and Ti layers and a cap. To unload At present, most magnetic robots designed for in vivo applications
cargos, an opposite rotating field was provided to open the cap. The have only been verified on in vitro models (e.g. microfluidic system) or ex
maximum translational velocity of this helical microrobot was 850 μm vivo models, with only few of them passing to the animal tests [115–117].
s1 achieved under 10 mT at 65 Hz. Recently, this group used the same This may be due to the resource restrictions for large magnetic fields set
fabrication method to produce another similar helical microrobot in up, the difficulty in in vivo observation of the robots, and most robots’
which the capsule-like head was replaced by a needle-like structure that inability to deal with realistic medical environments of complex geom-
can stab the targeted tissue [110]. Thus, this type of magnetic microrobot etry filled with biological fluids. Notwithstanding, highly qualified in
can be fixed at lesion tissues preventing the flushing away of the vitro proof-of-concept studies are solid foundations for progressing to in
microrobots by body fluids without the magnetic actuation assistance. vivo verification. Table 1 lists the current publications that contain in vivo
This enables the long-term release of drugs from microrobots for efficient tests. It can be seen that although these robot models have been tested on
therapy. animals, they were mainly subcutaneously injected into the diseased
Apart from the targeted delivery of therapeutic agents to the tumor areas or intraperitoneal cavity for imaging experiments.
areas and their controlled release (Many studies on this have been dis-
cussed in previous sections), magnetic microrobots can also facilitate the 3.1.2. In vivo: surgery
deep interstitial penetration of these agents in solid tumors to maximize Magnetically manipulated micro/nanorobots have promising appli-
their therapeutic efficiency. Tumor tissues normally have high interstitial cation in minimally invasive surgery because magnetic fields have nat-
pressure which will prevent the diffusive transport of drugs that are ural ability to penetrate thick biological tissues. In a new study, Vysko
cil
released from robots [111]. Schuerle et al. [112] studied two magnetic et al. [40] reported the possibility of magnetic microrobots performing
microrobots which used two different strategies to induce the localized microsurgery in cancer cells. They fabricated a rod-shape ‘walking’
convective flow for enhancing tissue penetration of nanoparticles. One is Au/Ag/Ni microrobotic scalpel via sequential electrodeposition of these
the helical-like artificial bacterial flagellum (ABF), and the other one is three elements into commercial polycarbonate membrane holes after an
the natural magnetotactic bacteria (MTB) with two chains of magnetic H2O2 etching step to partially remove the middle Ag segment (Fig. 11).
crystals inside. Under the actuation of a 3D uniform rotating magnetic The length of microrobots is about 6 μm and 600 nm in diameter. Because
field consisting of eight electromagnets, the ABF will disrupt laminar of the magnetic asymmetry of microrobots (one Ni end) and the bent Ag
flow via their rotational forward motion, which can force nanoparticles part, the microrobot can transversally move and enter in human osteo-
to move toward the vascular wall and penetrate into the adjacent tissues. sarcoma (U-2 OS) cells under a weak transversal rotating magnetic field
In contrast, dense swarms of MTB can generate volumetric convective (5 Hz at 3 mT). They estimated that under this magnetic field conditions
flow via their circular motions under the same magnetic field. Combining the microrobots are capable of generating force up to 100 pN. As a result,
their tumor-homing properties, they were observed to penetrate tumor they observed that the microrobotic scalpel can move in the cytoplasm,
ECM and induce convection, further increasing the penetration of extract a small cellular fragment, and then remove it outside the cell.
nanoparticles in tumor. As surgical operation requires various tools to grasp and remove
Intravitreal microrobots and nanorobots have been envisioned to be diseased tissues, the minimally invasive surgery also needs miniaturized
of great use in ocular therapies and procedures. This is partly due to the tools for precise surgery. Thus, the demand for developing precisely
relative ease of visualization of such devices in the eye compared with controlled small-scale tweezers or grippers is increasing [119–122].
other parts of the body, but also due to the challenges faced in the use of Barbot et al. [123] fabricated a magnetic sheet by curing the mixture of
topical and other therapies currently used in ophthalmology. Two major polydimethylsiloxane (PDMS) and iron powder, and then the sheet was
challenges faced in the use of intravitreal microrobots or nanorobots are cut into rectangular microrobots (2 mm-3mm-200μm) which enabled
the difficulty of propelling through the vitreous humor because of floating on a fiber for wet transfer. Two of these microrobots with
adhesion and its tight matrix which prevents penetration. Considering different preferred magnetization directions (different iron line di-
this, Wu et al. [113] presented magnetically actuated helical rections) can form a gripper and grasp the item between them under the

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Table 1
Publications including in vivo experiments of magnetic micro/nanorobots.
Shape of Type of magnetic Applications In vivo models Administration methods Reference
robots fields

Helical Rotating Imaging Mice Intraperitoneal injection 2017 [78]

Rod Rotating Targeted thrombolysis Distal middle cerebral artery occlusion Internal carotid artery 2018
mouse model injection [108]
Porous Gradient Cell delivery/release Yolks of zebrafish embryos/mice Injection/subcutaneous 2018
spheroid injection [115]
Helical Rotating Imaging/photothermal Antibacterial Mice Subcutaneous injection 2020 [60]
Therapy
Helical Gradient Cancer imaging Radio-Photodynamic Mice Intravenous injection 2020
Therapy [118]

Fig. 11. Microrobotic scalpels. a) Surface microrobotic scalpels fabrication by sequential electrodeposition of Au, Ag, and Ni into polycarbonate membrane holes and
b) Au/Ag/Ni surface microrobotic scalpels motion in a transversal rotating magnetic field and c) its application for cancer cell microsurgery [40]. (All images are used
with permission). PVA, polyvinyl alcohol.

control of a permanent magnet. The microgripper can generate the cardiovascular system.
average force of 0.5 N, its transfer precision is within 5 μm, and the
orientation error is lower than 0.4 . 3.1.3. Rheology and biosensing
Vascular diseases have been identified as a disease that is becoming Rheology, the study of flow is of great importance in several fields,
more widespread nowadays because of recent prevalent lifestyles. The particularly in the biological/biomedical field where there can be strik-
invasiveness and side effects of current treatment methods have led re- ing differences in fluid properties depending on length scale of investi-
searchers to search for alternatives. Previous studies have shown the gation. Jeong et al. [6] presented a chiral helical plasmonic
potential of magnetic microrobots capable of drilling through thrombi as nanostructure, made of gold and iron which can work as a mechanical
a possible treatment for thrombosis; however, most of these designs have sensor, allowing for the study of flow in complex fluid systems under
only been tested in 2D environments where the effects of gravity do not circular dichroism spectroscopy. Under the influence of a rotating mag-
need to be taken into account. To evaluate the potential of using this netic field, nanostructures are actuated resulting in a regulated optical
design in 3D space, which better emulates the human cardiovascular response allowing for a nanorheological study. Synthesis of these nano-
system, Lee et al. [124] developed and tested a magnetic drilling actuator helices involved the use of block copolymer micelle nanolithography
(MDA) capable of 3D navigation. This device consists of a 3D printed drill (BCML) [59]. The nanohelices formed from this are then coated in gold
made of MicroFine, an acrylonitrile butadiene styrene–like material with and iron using physical vapor GLAD. The ability of these nanohelices was
a neodymium alloy insert for magnetic manipulation. The MDA is actu- demonstrated in their determination of the viscosity of a fluid with and
ated using an EMA system (Octomag, Aeon Scientific GmbH, without microparticles used to model cells and other components that
Switzerland), consisting of eight hemispherically configured electro- influence the viscosity of fluids on the macroscale. Results displayed that
magnetic coils with different currents flowing through them. Three there was no significant change in viscosities measured by the nano-
different designs with two, three, and four spirals were tested in a helices. This is due to their nanosize and ability to distinguish the fluid
vascular network mimicking fluidic channels to determine which was from solid particles. When viscosities of the same two fluids were
best for optimal drilling and propulsion. The MDA was able to accurately determined using the KriegerDougherty model, the viscosity of the
navigate and drill through an artificial thrombosis made of gelatine and fluid with microparticles was determined to be ten times that of the fluid
porcine blood to mimic soft jelly-like thrombi. As the MDA is remotely without [125]. This design showed great potential in biomedical appli-
controlled and capable of robust 3D navigation, it can simply change cations such as in the determination of blood plasma viscosity for diag-
direction to drill through thrombi multiple times if the need should arise. nosis purposes. However, during experimentation, it was noted that
The researchers suggest that this device can be visualized using X-ray or protein coronas formed around the helices, affecting their dynamics.
CT scans and intravascular ultrasound. Although the MDA is not at the Further investigations can be carried out toward the use or development
microscale, this research presents a crucial step toward the use of of materials that repel these proteins ensuring the preservation of
microscale devices similar to the MDA in the complicated network of the nanohelix dynamics.

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

The flexible motion of magnetic micro/nanorobots also allows them intelligence (AI) planner. The AI planner can intelligently construct a
to be effective biosensors for diagnosis. The propulsion of microrobots collision-free path for microrobots and give corresponding input signals
can accelerate the transport of analytes toward bioreceptors and achieve to the magnetic field generator which then outputs programmable
fast and sensitive sensing even for ultrasmall sample volume. After sur- rotating fields to help microrobots to surmount obstacles. In the study,
face functionalization, micro/nanorobots have abilities to sense DNA, this system was also programmed to recognize cancer cells and guide
proteins, and cancer cells [126]. Recently, Molinero- Fernandez et al. microvesicles to them. A similar vision-back controlled system can be
[127] developed a magnetic micromotor to rapidly detect C-reactive found in the recent study of Zarrouk et al. [130], where they added two
protein in preterm infants’ plasma for neonatal sepsis diagnosis. The microscopes to the vision section with a camera to observe magnetic
tubular micromotors comprise a graphene oxide outer layer for immo- microrobots in different scales.
bilizing antibody, an intermediate Ni magnetic layer, and a PtNPs cata-
lytic inner layer. Although the movement of the micromotor is from the 3.2. Biocompatibility and biodegradability of magnetic micro/nanorobots
bubble propulsion of PtNPs catalytic layer fueled by H2O2, the magnetic for clinical availability
layer is used to stop the flow operation, guide motion, and collect sam-
ples. Using a similar propulsion mechanism, Amouzadeh Tabrizi et al. Although magnetic actuation is biocompatible depending on the
[128] produced a MnO2-PEI/Ni/Au nanomotor modified with aptamer strength of the magnetic field used, the biocompatibility and biode-
KH1C12, which can specifically sense human promyelocytic leukemia gradability of magnetically actuated micro/nanorobots themselves and
cells (HL-60 cancer cells) in the human serum sample. MnO2 can also the threat from the immune system (robots clearance before they execute
generate oxygen bubbles using 1% H2O2 as a fuel. Ni nanoparticles in the tasks) are still limitations in their in vivo use.
nanomotor are used to magnetically guide its oxygen-propelled move- To obtain magnetic actuation properties, robots always need to be
ment and isolate nanomotors. This nanomotor shows good sensitivity to coated or connected to magnetic materials, e.g. nickel, cobalt, and iron
HL-60 cancer cells and has a low limit of sensing of 250 cells/mL. (e.g. NdFeB, Fe3O4 and FePt micro/nanoparticles). The biocompatibility
of magnetic micro/nanoparticles is yet to be thoroughly assessed, but as
3.1.4. In vitro devices with advanced control systems has been mentioned in other studies nickel, for example, can be cytotoxic
Motivated by a desire to gain a better understanding of mechanobi- and its accumulation in the body could potentially lead to negative side
ology for improved tissue engineering, Jing et al. [129] developed a effects [9,131]. To shield cytotoxic layers, titanium, as a known
micromachine with microforce sensing and regulating abilities. This biocompatible material, has been used to cover them. In addition, as
enables the testing of forces on cells to understand the effects of them and discussed in section 2.3, the incorporation of biological components,
the cell's physical limits allowing for the development of better-informed especially objects originating from human beings, in the design of robots
cell manipulation processes. The machines' integrated actuation and can improve their biocompatibilities and reduce the cytotoxicity by
testing system also offer a less cluttered alternative to previous methods eliminating biofouling effects. The recent rise of soft robots also serves a
of investigating mechanobiology. The device is made up of compliant similar purpose. Despite the fact that many biocompatible micro/-
PDMS for sensing purposes, a silicone frame for mechanical strength and nanorobots have been developed and investigated to induce only mini-
nickel body for magnetic actuation. The robot is capable of translational mal side effects in healthy tissue, there are still several refinements to be
motion with speeds of 2 mm/s achieved under 10 mT. Under weaker made before these are ready to be used in humans. One concern is the risk
magnetic fields, the robot exhibits rotational motion without locomotion. of the permanent retention of these devices in bodies. Current strategies
An advanced control system has been developed for this microrobot for preventing retention include producing biodegradable robots and
allowing for automated operation. When directing a microobject to a developing retrieval methods for non-biodegradable components. For
target, the control system tells the robot to either carry out a push or example, several magnetic micro/nanorobots are made out of biode-
realign motion based on visual feedback to the control system and gradable materials such as PLGA, hydrogel, chitosan, and microalgae
computations by the implemented algorithm. These two motions are [78,132–135]. A microrobot proposed by Kim et al. [39] is biodegrad-
applied as needed until the navigation task is completed allowing for able and allows for both controlled drug release and retrieval of poten-
robust, automated microobject direction. The control system also allows tially harmful MNPs after magnetic actuation is completed. The
for regulation of the force applied in moving microobjects. A maximum microrobot is made up of a gelatine/poly vinyl alcohol hydrogel con-
force threshold is set before operation, and when this set threshold is taining MNPs and doxorubicin and is actuated by NIR radiation as well as
reached the robot stops applying force to the microobject. This ability magnetism (Fig. 12a). The microrobots can be navigated toward desired
was tested at 6, 10, and 12 μN with results showing that the robot applied targets by magnetic actuation, and upon exposure to NIR radiation the
about 2 μN more than the threshold force. This was due to a lag between hydrogels decompose releasing the MNPs and cancer drugs. A magnetic
the sensor and the control system and the low resolution of the sensor field is applied during the radiation step to prevent the uptake of MNPs.
(1.5 μN). This system presents an integrated and automated method for The released MNPs are brought together using a rotational magnetic field
mechanobiological research on cells allowing for investigations into how and subsequently retrieved using a rotating magnetic field gradient
different magnitudes of force affect cell development at different stages. (Fig. 12a,i-iv). The robot's abilities were verified in vitro by its successful
However, currently, the smallest size of microobject it can interact with is navigation through a Y-channel from an arbitrary start point to a target
10 μm; therefore, it would need to be downsized to interact with smaller area followed by the aggregation and retrieval of MNPs. This is a big step
microobjects such as red blood cells. Size is also an issue for maneuvering forward in making magnetically actuated drug carriers safer for use in
in tight spaces as this requires the robot to constantly realign itself which vivo; however, because of the large size of these microrobots (100–250
makes such operations take longer. Finally, although the researchers μm), it is unable to operate in several blood vessels which limits its
have identified ways to overcome the current challenges faced with the practical use. While the manufacture of similar, but smaller, robots is not
control system, there is still room to improve responsivity and force necessarily an impossible task, the reduction in magnetic volume
resolution of the system. resulting from the smaller size would make magnetic actuation via field
Seeking to improve the abilities of microrobots in navigation, Li et al. gradients more difficult so alternative means of actuation could be
[75] set up a smart rotating magnetic fields system which can adjust the investigated for this purpose.
direction of motion of Janus sphere microvehicles to allow for autono- Hydrogels are a very promising material for biomedical applications
mous navigation in complex and dynamically changing biological envi- because of their biodegradability and biocompatibility [132]. However,
ronments. This is achieved by connecting the field generator with a most hydrogel microrobots previously reported were propelled by means
charge-coupled device (CCD) camera which provides real-time visual of magnetic field gradients, limiting their use in the human body because
feedback of microrobots and the unknown environment to an artificial of the magnetic field strengths required to reach certain areas and

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Fig. 12. Several hydrogel-based magnetic small-

scale robots. (a) Structure of hydrogel micro-
robots, consisting of gelatin/polyvinyl alcohol
(gelatin/PVA) hydrogel, poly(lactic-co-glycolic
acid)–doxorubicin (PLGA–DOX) drug nano-
particles and magnetic nan,oparticles (MNPs).
Concept of the treatment process using hydrogel
microrobots, where (i) the hydrogel microrobot
moves to a target lesion using magnetic field, (ii)
the hydrogel microrobot is decomposed by near-
infra red (NIR) irradiation, (iii) remaining MNPs
are retrieved by magnetic field, and (iv) cancer
cells are treated by the PLGA–DOX drug particles
[39]. (b) (i) Biodegradation of the hydrogel
microswimmers by the mmp-2 enzyme. (ii) DIC
images of a degrading microswimmer array in the
presence of 4 μg mL–1 enzyme. Degradation
starts with the rapid swell of the microswimmers
followed by the collapse of the entire network
[1–136]. (c) Fabrication process of biodegradable
soft helical microswimmers for targeted cell
therapies [134]. (All images are used with
permission). (For interpretation of the references
to color in this figure legend, the reader is
referred to the Web version of this article.) DIC,
Differential interference contrast; MMP2, matrix
metalloproteinase 2.

inability to properly navigate in flow systems. A helical hydrogel-based (controlled drug release) and specific diagnostic tasks. In addition, taking
microrobot actuated by a rotating magnetic field by Lee et al. [137] advantage of the GelMa hydrogel, Dong et al. [134] fabricated helical
proposes a new design for hydrogel robots that overcomes magnetic field microrobots with 100 μm long via direct laser writing. After incorpo-
gradient related challenges. Its hydrogel construction also enables rating with magnetoelectric nanoparticles (CoFe2O4 core/BiFeO3 shell),
NIR-stimulated drug release. The microrobot is fabricated by simply the microrobots can swim to the target lesion even with a low magnitude
pumping the MNP containing hydrogel into an aqueous solution of cal- rotating magnetic field (a few millitesla). They can then be used as
cium chloride using a syringe, causing chemical polymerization resulting electrostimulators to activate the differentiation of neuronal cells under
in its spring-like shape. The resulting spring is then exposed to UV light an alternating magnetic field (Fig. 12c). More importantly, the results
for photopolymerization. The microrobot was heated in deionized water showed that when these hydrogel microrobots fulfilled their therapeutic
resulting in water loss, shrinkage, and creation of space for DOX to be task, they can be completely degraded in 7 days by the enzymes in the
loaded. The microrobot was actuated by a rotating magnetic field and ECM secreted by human neuroblastoma cells.
was successfully navigated through a vascular phantom with speed Although there are many strategies to lower the toxicity of magnetic
increasing with field frequency until step out frequency of 2 Hz. When micro/nanorobots to human bodies, the in vivo environment also poses
cultured with Hep3B cancer cells for 24 h, cell viabilities of 51.9% dangers to micro/nanorobots. For example, as discussed earlier (section
without stimulation and 19.5% with NIR stimulation were recorded. 2.3), the immune system is a critical obstacle for the in vivo application of
However, a significant challenge this design faces is its size (800 μm micro/nanorobots. The microrobot will be recognized as an intruder by
diameter) which limits its use. Research can be done into the develop- macrophages which then induce a series of immune responses to elimi-
ment of a smaller version of this microrobot to be used as an intravenous nate it. Despite the fact that biological objects (e.g. plasma cells’ mem-
drug carrier. brane coating) can provide help to micro/nanorobots in immune evasion,
In regard to lowering the size of microrobots, recent studies discov- better understanding the interaction principles between the immune
ered a photocurable, gelatin–methacryloyl (GelMA)-based hydrogel, system and robots is essential for the safe design and clinical trans-
which can be fabricated into much smaller biodegradable microrobots. formation of microrobots. Yasa et al. [138] recently proposed an opinion
Ceylan et al. [136] mixed GelMA with MNPs and used two-photon that for any medical small-scale robot design its immunogenicity is
microprinting to produce a double helical magnetic hydrogel-based equally important with locomotion performance. In the study, they chose
microrobot with length only of 20 μm. Importantly, the study further a magnetically driven helix and fully rigid microswimmer as the model
displayed the GelMA hydrogel contains specific cleavage sites for matrix and systematically investigated the influence of its surface morphology
metalloproteinase 2 (MMP-2) enzyme which is highly expressed in tumor (same length, diameter, and volume but in three different turn numbers,
ECM (Fig. 12b). Thus, this hydrogel microrobot can perform MMP-2 2, 5 and 10, respectively), size and surface chemistry (with or without
triggered degradation toward the tumor-targeted drug delivery PEG) on the immune response. The results showed that all these factors

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

have an impact on both locomotion and immunogenicity of microrobots nanoscale diameter. To produce the microswimmers, the single chains
but with complex entanglement. Specifically, they observed that the were further magnetized for a few minutes which caused them to
initial contact between the microrobots and the macrophage is through aggregate into microswimmers of microscale diameter. Both structures
random physical encounter when macrophage probes the environment are flexible and deform in motion because of hydrodynamics, and when
by using its filopodia. Then the macrophage will flatten over the actuated by a rotating magnetic field they form chiral shapes that pro-
microrobot surface to complete phagocytosis with favorable orientation. duce propulsion during rotation. During testing, it was observed that the
Thus, one confirmed principle about morphology-dependent phagocy- nanoswimmer moved in a jerky fashion because of Brownian motion. The
tosis is that an increase in the number of turns of a helical microrobot (i.e. effects of Brownian motion were much less severe in the microswimmer
higher surface area and surface area rate of change) is beneficial to slow which produced much smoother movements, and moved at a speed of
down the phagocytosis process because macrophages need to use more 3.6655 μm/s, than the nanoswimmer's 0.4912 μm/s at the same magnetic
energy to flatten over higher turn numbers. Consequently, the two-turns field frequency of 10 Hz. This design could potentially be combined with
microrobot was the fastest to be engulfed even though it has the highest drug-carrying nanoparticles and an efficient means of ensuring disas-
swimming speed. However, for the parameter of size, its impact on sembly to produce nanorobots that release the drug bearing nano-
phagocytosis is indeterminate, which is cross-influenced by surface particles upon disassembly.
morphology of microrobots, such as the depth of helical grooves. The Alapan et al. [48] reported a fabrication mechanism that can flexibly
influence of surface chemistry on the immunogenicity of microrobots is produce specified and complex structures for microrobots. They took
the same as the results reported by many studies for nanomedicines [139, advantage of shape-encoded dielectrophoretic interactions to achieve
140]. If the surface chemistry shows high resistivity to macromolecules dynamic self-assembly of mobile microrobots comprising diverse mod-
corona formation, microrobots could gain more invisibility to macro- ules and reconfigurable locomotion modes. As illustrated in Fig. 13a, a
phages. It should be noted that some sites of our body are series of microrobots consisting of magnetic ‘microwheels’ and 3D
immune-privileged, e.g. the eye and the central nervous system. Thus, non-magnetic body were assembled and actuated by vertically and hor-
when robots work in these areas, the locomotion performance can be the izontally rotating magnetic fields. Because most materials are electrically
primary consideration in design. polarizable, and the electric field gradient around each module can be
precisely controlled by modifying its 3D shape; this fabrication technique
3.3. Unique fabrication techniques to facilitate commercialization enabled flexibility and programmability in design for robots performing
complex tasks in medicine.
This section covers novel fabrication techniques and the designs they Ali et al. [142] proposed a hollow magnetic silica nanoswimmer
have produced. A lot of these simplify the production of very similar fabricated using bacterial flagella as a biotemplate aimed at reducing
already produced designs allowing for cheaper, quicker, and bulk costs of manufacture, enabling large-scale production of magnetic
manufacture of small-scale robots moving them toward commercial nanoswimmers. Because of the ability of bacterial flagella to morph into
availability while others cover new techniques used to produce new different conformations, these were used as templates to produce artifi-
designs to address challenges previously identified in other studies. cial flagella of different forms for different functions. The transcription of
Work by Kim et al. [132] presented a new method of rapidly making silica on the flagella was done by mixing a solution of the depolymerized
drug carrying microrobots that allows for their mass production and flagella with an aqueous solution containing (3-aminopropyl)triethox-
simpler drug encapsulation as it does not require light exposure for ysilane and placing the mixture in an ice bath. Tetraethyl orthosilicate
polymerization. These microrobots were made up of PLGA, iron nano- was then added to the mixture forming silica on the surface of the
particles, and the drug to be carried. The fabrication process involved depolymerized flagella. Because of flagella's propensity to conform into
carving out desired shapes from polyvinyl alcohol sheets using laser the s-circular shape during standard templating conditions, researchers
micromachining to make templates for microrobots. These templates used their knowledge of pH-induced conformation change to maintain
were then dipped into a solution of PLGA, MNPs, and the drug to be desired flagella geometry during templating. The nanotubes formed were
carried for about 5 s, then removed, and dried. The templates were coated with a nickel film approximately 10% of the thickness of the
removed by decomposing them in aqueous solution. This fabrication nanotubes by evaporation onto the dried tubes. The nanotubes were then
technique allows for easy tuning of robot characteristics such as MNP and magnetized and washed which depolymerizes flagella resulting in its
drug concentration by simply altering their concentrations in solution release from nanotubes. The speed of these swimmers increased with
and shape alteration for different purposes. The researchers also noted frequency with no step-out behavior observed in the tested frequency
that they could potentially be used as building blocks for 3D assemblies. range. From extrapolation of experimental results, it was found that at
The drug release rate and speed in these robots can be controlled by the frequency of rotation of bacterial flagella swimmers would swim at
varying iron content, with robots containing less iron moving faster 22 μm/s, similar to actual bacteria's 25 μm/s. The fabrication technique
under magnetic gradient and degrading slower, resulting in slower drug presented in this work allows for mass production and for several geo-
release. The robots were successfully manipulated by the EMA system metric parameters to be adjusted by adjusting pH, initial concentrations,
and showed quick responses to directional changes. In addition, this and nickel layer thickness. The use of silica also presents potential for
method has the potential to be applied in the rotating magnetic fields biomedical applications due to factors such as their biocompatibility and
with the fabrication of different shapes of robots. Cancer treatment porosity, allowing for high specific surface areas. Their specific surface
abilities were demonstrated by culturing the microrobots with cancer areas open them up to use as excellent drug carriers because of increased
cells for two days resulting in a cell survival rate of about 20%. The capacity for bearing therapeutic agents.
biodegradability and ease of manufacture of these microrobots are of Having noted issues with stem cell transplantation such as premature
great benefit to advancements in targeted drug therapy. differentiation before reaching targets, low stem cell retention, and cell
Cheang and Kim [141] proposed self-assembling microbots and death and noting of these are all due to transportation in uncontrolled
nanorobots made from MNPs. The self-assembly method of fabrication environments, Yasa et al. [21] presented a 3D printed microrobot which
allows for cheaper, simpler, and quicker production of nanoswimmers incorporates a recapitulated stem cell niche to overcome these issues.
and microswimmers than methods typically used such as electrodeposi- This robot consists of a double helical shell encapsulating a niche-like
tion, 3D printing, laser etching, and others. This fabrication first involved scaffolding, providing a controlled environment for the transportation
the dilution of 50–100 nm iron oxide magnetic particles in deionized of stem cells while also preconditioning them to differentiate into desired
water to a concentration of 0.1 mg/mL. The nanoparticles were then cell lineages (Fig. 13b). The microrobots were fabricated using a high--
magnetized for a few seconds under a 5.06 mT magnetic field to produce resolution 3D printer allowing for precise replication of cell niche con-
single chains which served as the nanoswimmers as they retained a ditions required by the stem cell, down to the micron level. The shell was

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

Fig. 13. (a) Shape-encoded assembly of

magnetic microactuators to a non-magnetic
body fabricated with direct laser writing.
(i–ii) A 3D microcar body with four-wheel
pockets is designed to generate site-
selective attractive DEP forces toward the
wheel pockets. Color bar: normalized electric
field strength (E/E0)2. (iii) Directed assembly
of the magnetic microactuators into the
wheel pockets is realized on-demand using
DEP. (iv) The microcar translates under a
vertically rotating magnetic field and is
steered by changing the rotation axis of the
magnetic field. (v) The microrotor body and
magnetic microbeads are coupled together
with DEP and rotate when a horizontally
rotating magnetic field in the x–y plane is
applied. Scale bars, 25 μm [48]. (b)
Patterning biological and physical aspects of
a stem cell niche in a microrobotic cell
transporter (MCT). (i) The stepwise strategy
of microrobotic transporter fabrication and
(ii) illustration of fine-tuned biochemical,
biophysical, and cell-to-cell interactions be-
tween cells and their niche [21]. (All images
are used with permission). DEP,
dielectrophoretic.

made from a polymer, trimethylolpropane ethoxylate triacrylate indicated that the use of smart materials has greatly increased the
(TMPETA), containing MNPs, and enabling propulsion via a corkscrew functionality of these devices and allowed for on-demand execution of
motion when exposed to a rotating magnetic field. TMPETA is known for tasks.
its biocompatibility, and the use of cytotoxic metal coating for magnetic This review of the literature enabled a comparison of the microrobots
actuation was avoided by using MNPs incorporated into the polymer, and nanorobots which clearly indicated areas or applications for which
further enhancing biocompatibility. The cell niche was made from either is more capable or has significant advantages. For example, complex
gelatin, hyaluronan, and fibronectin and was constructed using a machinery and automation is certainly easier to implement in microrobots
femtosecond laser. This fabrication method allows biological signals as they have the size advantage that allows for more components to be
from the target tissue to be incorporated into the cell niche, enabling incorporated into a single device. That being said, nanorobots are quickly
faster differentiation into target cell types. The resulting microrobot catching up in terms of complexity of designs and extra components being
performed better than its niche free counterparts in terms of cell reten- integrated into them. This suggests that this may soon no longer be a
tion and viability and swam at an average speed of 11.14  0.46 μm/s. benefit of microrobots over nanorobots. The size of microrobots further
Despite addressing several issues identified in the use of stem cell proves useful in propulsion and direction, as Brownian motion has a far
transporters, this microrobot is still limited by not being biodegradable less significant effect on larger objects allowing for smooth operation and
and its inability to swim in non-Newtonian fluids which are found in easy steering as opposed to jerky movements that may be observed in
several biological environments. Further studies can be done to address nanorobots. However, their size also poses limitations in their use in vivo as
these issues and to gain an understanding of how these microtransporters even some larger nanorobots risk being trapped in the smallest vasculature
and the stem cells inside them interact with tissue they may come in of animals that they are usually tested on [143]. The nanorobots size has
contact with during delivery to further advance these toward use in vivo. allowed them to propel through complex viscoelastic media, far out-
performing the microrobot in all viscoelastic media despite producing
4. Discussion: advantages, limitations, and challenges of micro/ negligible propulsion in water [72]. With the recently developed cell
nanorobots permeation and penetration methods, researchers are able to manipulate
living cells with less risk of cell damage or death; researchers even envision
This paper aimed to investigate the current state of the art of magnetic one day operating nanorobots intracellularly [144]. All in all, although, in
nanorobots and microrobots in biomedicine suggests other biomedical some cases, one scale of devices may have advantages over the other, they
applications for these devices and identify areas that would benefit from both occupy very important and usually different niches when it comes to
further research. This study revealed that the field of biomedical small- biomedical applications; thus the field would benefit from continued
scale robots has experienced rapid advancements in the past few years, research into both of them.
with successive incorporation of more complex technologies in their The biomedical applications of micro/nanorobots are mainly divided
designs and a stronger focus on functionality and safety. It is also into in vivo and in vitro uses. Undoubtedly, drug targeting and

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M. Koleoso et al. Materials Today Bio 8 (2020) 100085

regenerative medicine fields stand to gain the most from these ad- overcoming this limitation. In terms of characterization, an important
vancements with targeted triggered drug release and cell differentiation gap in research is how these devices will behave in flow conditions. This
greatly enhancing the efficiency of such procedures. Small-scale robots must be understood if these are to operate in the vascular network. The
are also becoming less hazardous for in vivo use with the development of characterization of propulsion, however, is probably the most standard-
biodegradable devices and the incorporation of MNPs into device ized of research fields in small-scale robot development, with many
structure rather than making devices from or coating with cytotoxic studies reporting velocities in terms of International System of Units’
magnetic materials. units as well as dimensionless units, for example, the body length per
The various difficulties in the use of these devices generally and revolution unit. Perhaps other fields should also look into the develop-
particularly in vivo persist despite many recent studies to identify ways of ment of dimensionless and standard characterization methods and
overcoming them. Relatedly, one of the major gaps in research identified parameters.
in this study and which has received a lot of attention recently is the Micromachines have seen further development toward being able to
biocompatibility and biodegradability of the microrobot and nanorobot carry out very ambitious functions despite the limitations they face in
devices. The few empirical studies on this issue indicated that these de- terms of remote powering and control. Some micromachines have
vices have the potentials to harm body cells and tissues. The use of advanced control schemes integrated into their control platforms to
biodegradable materials, substances, and organisms along with MNPs in enable automation or complex remote control. Although their potential
safe concentrations in the production of these devices is a big step to- for use within the body is limited because of their dependence on visual
ward tackling this issue. However, this solution poses another problem, feedback, their development greatly enhances the study of cell behavior
which is that of MNPs accumulation in the body after biodegradation. in vitro and has enabled new means of cell manipulation. A review of the
Different means of retrieving MNPs and even whole devices are being state of the art of small-scale robots carried out in 2017 indicated that at
considered in research. For example, Kim et al. [39] have attempted to the time micromachines could only accomplish simple mechanical tasks.
use the rotational magnetic field gradient to aggregate and retrieve re- Examples of these tasks include gripping, drilling, and scraping [13].
sidual MNPs after degradation of hydrogel microrobot in vitro. The same However, recent design developments such as the ability for a microrobot
group recently applied hydrogel microrobots for drug delivery to the eye to regulate the force it applies to cells are indications of more successful
followed by MNPs retrieval [145]. In addition, Iacovacci et al. [146] research in the attempt to design micromachines that will accomplish
developed an intravascular magnetic catheter, allowing to collect up to more complex tasks.
94% of the unused iron oxide nanoparticles from blood stream. However, With some designs having been extensively studied in terms of
this type of research is still at its infancy period, and there is undeniably a effective propulsion and modifications that expand functionality, there
need for further studies that will attempt to determine what happens if has also been a rise in research toward the refinement of their fabrication
said devices are used multiple times in one individual resulting in processes with a focus on ensuring consistency, reproducibility, and
accumulation of MNP's beyond safe concentrations. Ran et al. [147] re- large-scale production. These fabrication techniques demonstrate that
ported that if the concentration of Fe3O4 MNPs (~70 nm) beyond 25 commercialization may indeed be a valid prospect of these designs. Batch
μg/mL in vitro and 12 mg/kg in vivo they will cause significant damage or manufacture processes improve ease of scalability and allow for testing
apoptosis of erythrocytes. Recently, Malhotra et al. [148] published a on multiple devices to improve reliability of experimental results. It also
review paper which summarized the studies in exploring the toxicity of opens researchers up to research into the potential applications of mul-
various MNPs both in vitro and in vivo, but they found that when using tiple units of the same device, further expanding the research field. In
different study models (from different publications) even similar MNPs contrast to the methods that allow for large-scale production, fabrication
can cause different toxicities. This is because besides properties of MNPs, methods such as that used in the making of the artificial stem cell niche
the toxicity of MNPs may also depend on cell lines, organisms, immu- indicate that research is also going into the development of extremely
nogenicity, breakdown, and elimination from the body. More efforts and precise methods of fabrication that enable the tuning of the finest details
studies are needed in this field to build a reliable database for the safe and reproduction of intricate biological systems.
usage of MNPs in clinical in the future. However, for the clinical transformation of micro/nanorobots,
Research that could investigate the development of coatings that will there are many concerns proposed by previous reviews, for example,
allow for drug loading and other biomedical multifunctionality could be robot localization in body, communication, ease of fabrication, and
conducted to evaluate the value of modifying the gold components on the undesired immunological reactions [8,10–12,149]. Biomedical
likes of the free style and fish-like nanoswimmers. For example, they micro/nanorobots have been expected to perform their work in every
could be modified as with the protein-coated helical swimmers to allow corner of the human body in clinic. Apart from precise control, precise
for similar functionality such as pathogen diversion. In view of the po- real-time tracking of a single robot inside body could be the urgent
tential for cytotoxicity of nickel which is commonly used in flexible challenge at the present especially for those operating in deep tissue
swimmer designs, these devices could be further modified by reducing areas. Pane et al. [150] detailed various imaging technologies which
the amount of nickel in them or using researching less cytotoxic nickel have been used to monitor biomedical micro/nanorobots in vivo,
alternatives. including MRI, X-ray imaging, ultrasound imaging, and fluorescence
Propulsion is probably the most matured aspect of research and imaging. In those imaging methods, magnetic field and X-ray have
development in the field of small-scale robots, with helical swimmers large imaging depth (full body), and magnetic micro/nanorobots could
actuated with rotating magnetic fields being a standard for propulsion in provide intrinsic MRI during therapy if their magnetic components
low Re situations, as is the case for several biomedical applications. More comprise MRI contrast agents, e.g. superparamagnetic nanoparticles
recent research which examined oscillating magnetic fields and undu- [58]. However, these two imaging technologies are limited by
latory motion indicates that these features may be the future of propul- spatiotemporal resolution, and the actuating and imaging magnetic
sion for magnetically actuated robots because of their high speeds. fields for magnetic robots should be separated. In contrast, ultrasound
Although it appears that despite this recognition, there have not been and fluorescence can provide high spatial resolution and real-time
many proposed biomedical applications for them. imaging, but penetration depths are relatively low [151]. Thus, it is
Another indication is that there is ongoing research to address the still a challenge currently to real-time track the position and state of
heterogeneity of fluid in biological systems and the difficulty of navi- these tiny robots in the deep tissue with microscale or nanoscale res-
gating them. With the numerous studies on the possibility of producing olution. Future studies should consider the improvement of the im-
devices that change conformation in response to environmental stimuli aging depth together with the high resolution, such as the
such as temperature and pH and those that can propel themselves in development of multimodal imaging [152,153]. Recently, some
complex viscoelastic environments, this field is on the way toward studies reported that the cooperation of photoacoustic imaging

17
M. Koleoso et al. Materials Today Bio 8 (2020) 100085

technology to micro/nanorobots can achieve high imaging resolution continue to show their potential for use in biomedical applications.
in relatively deep tissues (e.g. 2 cm in Wei's study [154]) and real-time Studies of this nature can help to point out trends in research and
tracking in vivo [60,154–156]. In addition, Iacovacci et al. [100] re- identify areas that may benefit from collaborative research aimed at
ported the successful tracking of a single magnetic microrobot with a overcoming the current challenges of these devices, particularly in
diameter of 100 μm in ex vivo mouse abdomen via single-photon their use for clinical applications.
emission computed tomography (SPECT) imaging. Techne-
tium-99m–based radioactive compounds were encapsulated in the Declaration of competing interest
microrobot structure as contrast agents. The study can clearly observe
the shape change of the single microrobot, and the SPECT imaging is The authors declare that they have no known competing financial
more efficient in distinguishing microrobots from the surrounding interests or personal relationships that could have appeared to influence
tissues. the work reported in this paper.
A major finding of this study which corroborates the findings of Soto
and Chrostowski [157] is that most research in this field focuses on Acknowledgement
tackling a single challenge which in itself may be a challenge facing the
commercial or widespread use of magnetic small-scale robots. It will be This work was supported by the Royal Society of Edinburgh and
essential to apply micro/nanorobots to practical and important applica- National Natural Science Foundation of China (RSE-NFSC) International
tions and address systematic challenges – a key to demonstrate the value Joint Project Grant (60633) and the Cancer Research UK (CRUK) Grant
of the field. It should be recognized that the importance of such research for cancer early diagnosis.
will be sensitizing stakeholders such as pharmaceutical companies to the
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