Chemical Engineering & Processing: Process Intensification 141 (2019) 107530

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Chemical Engineering & Processing: Process Intensification

journal homepage: www.elsevier.com/locate/cep

Motion control of biohybrid microbots under low Reynolds number T

environment: Magnetotaxis
Wei Ming Nga, Xiau Jeong Tenga, Chen Guob, Chunzhao Liub, Siew Chun Lowa,
⁎
Derek Juinn Chieh Chana, Rohimah Mohamudc, JitKang Lima,d,
a
School of Chemical Engineering, Universiti Sains Malaysia, 14300 Nibong Tebal, Penang, Malaysia
b
State Key Laboratory of Biochemical Engineering & Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences,
Beijing 100190, People’s Republic of China
c
Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
d
Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Biohybrid microbots with small body size, have been integrated successfully into miniaturized system/process
Biohybrid microbot with confined geometry and/or closed environments. One such specific case is the construction of microbot,
Microswimmer composed of microswimmer with other functional nanomaterials that allow non-conventional taxis-based
Taxis-based motion control strategy to guide the motion of this micron-sized entity. This unique strategy has been receiving substantial
Magnetotaxis
considerations in tackling the challenges of miniaturization of on-board actuators and power sources for the
microrobotic systems as the microbot can swim effectively across huge distances and is capable of interacting
with its local environment. To achieve such goals, the migration pathways of these microbots are controlled by
regulating the actuation force of the microswimmers precisely in order to accomplish the microscale tasks. As a
result, various mechanical tasks and/or chemical processes can be initiated or carried out within a miniaturized
system. Here, we review the design, construction and control of biohybrid microbots that have been reported for
different applications. From the process intensification perspective, we discuss the possible applications and
associated challenges encountered in the development of the biohybrid microsystems for different types of taxis
based control strategies.

1. Introduction
Considerable interest has been demonstrated in the realization of
tiny mobile robots that can do convoluted works at microscopic length
scale. These tiny robots can move freely in the microscopic environ-
ment beyond the access of human and macroscale robot, and can ma-
nipulate and interact with micro- or nanoscale entities. The motivation
toward overcoming the limitations of human or macroscale robot sen-
sing, precision, and size for interaction with such tiny objects has led to
the emergence of microrobotics, or even nanorobotics, to extend our
interaction and exploration capabilities to submicron length scales [1].
The idea of micro- and nanorobotics was contemplated by Richard
Feynman in his 1959 talk “There’s Plenty of Room at the Bottom”
presented at the meeting of the American Physical Society, where the
possibility of manoeuvring things atom by atom to assemble the na-
noscale machine in the desired way was suggested [2]. Along this line
of thinking, the movie Fantastic Voyage captured the world’s imagina-
tion as it turned a scientific idea into a screenplay in 1966. This movie
was about the shrinking of a submarine into a microscopic scale and the
venture into human bloodstream to treat a life-threatening medical
condition [3]. Recent advances in the scale-down of mobile robots to
micrometer scale may help to realize Feynman’s idea and the vision of
Fantastic Voyage.
Microbots have their overall characteristic dimensions in the mi-
crometer range. This size range introduces remarkable new challenges
in the construction, actuation and power supply, which are not seen in
conventional macrorobotics [1]. The propulsion of these microbots is
challenging due to the fact that the physics for microscopic motion is
completely different from macroscopic motion. The underlying physics
is dictated by Reynolds number, a dimensionless quantity which is
defined as the ratio of inertial forces to the viscous forces. The funda-
mental differences between motion in microscale and macroscale were

⁎
Corresponding author at: School of Chemical Engineering, Engineering Campus, Universiti Sains Malaysia, Seri Ampangan, 14300 Nibong Tebal, Penang,
Malaysia.
E-mail address: chjitkangl@usm.my (J. Lim).

https://doi.org/10.1016/j.cep.2019.107530
Received 27 December 2018; Received in revised form 9 April 2019; Accepted 12 May 2019
Available online 15 May 2019
0255-2701/ © 2019 Published by Elsevier B.V.
W.M. Ng, et al.
discussed by Edward Mills Purcell in his famous lecture “Life at low
Reynolds number” in 1977 [4]. As the microbots must be able to move
(or swim) across the microscopic, their motions are characterized by
low Re number, which are dominated by the viscous forces [5]. Inspired
by nature, the swimming strategies used by the microorganisms have
been utilized to create artificial microbot via biomimetic approach
[6–11].
Associated to this advancement is another challenge about the
steering system for the artificial microbots because the mechanical
power are required to actuate the imitated flagella or cilia for driving
these artificial microbots [12]. Due to the complexity of nature’s mo-
lecular motor units, artificial molecular motors have not yet been re-
produced to drive either biological or synthetic flagella though there
are considerable advances in the field of molecular machinery [12,13].
To overcome this shortcoming, alternative external driven forces such
as chemical potential gradient [14], magnetic field [15–18], ultrasonic
waves [19–22], or light [23,24], are used to move the microbot. Im-
plementation of such strategies allow the omission of an on-board
controllable propulsion platform for a miniaturization system which
significantly increases the usage of microbot for process intensification
purpose. For example, a microbot consisted of an artificial, helical
flagellum attached to a magnetic “head” was created previously [10].
The flagellum rotated when placed in an oscillating magnetic field and
enabled the microbot to propel through liquid at a speed of 1–2 μm/s
[10]. By combining the right magnetic substrate with the right target of
bacteria, such as B. subtilis, can open up a new domain for intensified
bioprocesses [25]. On the other hand, chemical fuels in the liquid
medium are also used to power the microbot. Similar to biological cells,
fuel-driven microbots convert chemical energy into mechanical energy.
However, they require a continuous supply of fuel components in their
respective medium and could produce toxic byproducts [26]. The bio-
compatibility of the fuel components and byproducts would be a major
problem if the microbot is considered for biomedical application. In this
regard, the implementation of external force field in steering the motion
of microbot is well aligned with the concept of process intensification
by providing a cleaner and safer alternative.
Biohybrid approach offers a promising solution for miniaturization
leading to greater process intensification. By integrating the S. mar-
cescens into a microfluidic channel fabricated from poly-
dimethylsiloxane, Kim and Breuer managed to form a bacterial carpet
which is capable of pumping fluid through the microchannel for several
hours at speeds as high as 25 μm/s [27]. Moreover, through the in-
tegration of motile biological cell as the skeleton of a functional mi-
crobot (see Fig. 1), this approach enables the use of highly motile
biological cells to explore the low Re number environment. The bio-
logical cells can harvest chemical energy from the surroundings and
show a high efficiency in conversion of chemical energy into mechan-
ical work to power the molecular motor proteins that serve as actuators,
provided that the sufficient nutrient can be found in the working en-
vironment [12,28,29]. In addition, biological cells have the ability to
functionally accommodate and thrive in complex in vivo environment,
and the capability of self-repair and self-assembly upon interaction with
2
Chemical Engineering & Processing: Process Intensification 141 (2019) 107530
their surroundings preventing wear-and-tear scenario [12,28]. They
possess intrinsic, highly sophisticated sensing and actuation mechan-
isms, which are artificially inimitable in any microrobotic system [30].
By integrating them into the microbot, their superior actuation and
sensing capabilities can be served as the basis for the development of
taxis-based motion control scheme to manipulate the microbot to per-
form their desired works within a miniaturized system. Taking cargo
delivery as an example, by combining E. coli and superparamagnetic
iron oxide nanoparticles (SPIONs) allows the fabrication of a biohybrid
microswimmer which can be used to deliver an anticancer drug dox-
orubicin (DOX) to specific regions locally [31]. Given the facts that this
E. coli-SPIONs biohybrid microswimmer can move through a highly
confined geometry, with a channel width of 3 μm, making it an ideal
candidate to be used for chemical reaction control in microfluidic
system [32]. Apart from that, biohybrid method provides a versatile
and attractive approach for potential applications in scale down sys-
tems such as biomedical applications, lab-on-a-chip devices and en-
vironmental monitoring.
In recent years, with the advancement in science and technology,
significant research efforts have been devoted to the development of
different control strategies for the manipulation of these biohybrid
microbot across the low Re number environment. This short review is
intended to address the recent progress made in the magnetotaxis
control of the biohybrid microbot using the magnetic field. We briefly
mention some other control strategies implemented for the motion
control of the microbots in Section 1. We then discuss the reason why
the magnetic field pursues significant interests from the researchers by
offering an attractive means to be used for the motion control strategy
over the others in Section 2. For more comprehensive reviews on the
fundamentals of biohybrid microbots and their motion control strate-
gies, the reader is referred to previous publications [12,28] as we focus
our review on magnetotactic motion control. In Section 3, we review
the design and fabrication of the magnetotactic biohybrid microbots
and how the magnetic control has been implemented in these micro-
robotic systems. Finally, we highlight the potential challenges and the
future outlook of these magnetic biohybrid microrobotic systems de-
veloped for different applications.
2. Motion control of biohybrid microbot
The biohybrid microbots exploit the motility of the swimming mi-
croorganism as the propulsion mechanism in low Re number environ-
ment. The control of the actuation force of the microswimmer has be-
come a crucial factor in determining the performance of the biohybrid
microbots. Various control strategies are being developed to manipulate
the microbots effectively to achieve autonomous propulsion for mi-
croscale application, especially in targeted cargo transport and delivery
system. Due to the intrinsic and versatile sensing ability of the biolo-
gical cell, cell-based control method utilizes the cell’s sensory and be-
havioral response to environmental stimuli, or commonly known as
“taxis” [33]. Different species of biological cells exhibit different types
of taxis behaviors such as chemotaxis [34–38], magnetotaxis [39,40],
Fig. 1. A schematic diagram showing the for-
mation of a magnetic microbot by artificially
attaching a magnetic bead onto micro-
swimmer. By using this strategy, a microbot
with its motion controlled by an externally
applied magnetic field can be constructed with
any combination of microswimmer and mag-
netic bead. Such strategy is the basis of biohy-
brid microbot’s construction and is not only
limited for magnetotactic control.
W.M. Ng, et al.
Table 1
Self-swimming and guided-swimming speed of different type of micro-
swimmers.
Mode of control Types of Self-swimming Guided-
microswimmers speed, um/s swimming
speed, um/s
Chemotaxis Bacteria: E. coli ˜21 28 – 36
Algae: C. reinhardtii < 100 100 – 130
Phototaxis Bacteria: R. rubrum N.A. ˜ 53
Algae: C. reinhardtii 140 150
Electrotaxis Bacteria: E. coli 19 11.5 – 27.3
Algae: Volvox algae ˜100 – 400 400 – 800
Magnetotaxis Bacteria: M. 40 – 80 300 (max)
gryphiswaldense
Algae: C. reinhardtii 95.9 ˜700 (max)
phototaxis [41,42], and electrotaxis [43]. However, the basis of all taxis
is that the microswimmer demonstrates a guided and directional
movement toward or away from the stimulus gradient. In addition, it is
also possible for the taxis guided-swimming speed to exceed the self-
swimming speed of the microswimmer (see Table 1). Nevertheless, it
should be emphasized here that it is not necessary for the guided-
swimming speed to be larger than the self-swimming speed of the mi-
croswimmer for its effective use as an integral part of the miniaturized
system.
2.1. Chemotactic control
The most common form of taxis based control method is chemo-
tactic steering, the movement of the cell in response to a chemical cue.
Chemotaxis is fundamentally important for all motile microorganisms
to find nutrient supply by swimming toward the food source.
Chemoattractants and chemorepellents are used to induce the chemo-
tactic behavior of the cell which result in a directed motion toward and
away from a concentration gradient, respectively [28]. In regards to
chemoattractants, an increase in speed and directionality of motion
were reported in the studies of chemotactic response of S. marcescens
toward L-theorine [51], L-aspartate [34], and L-serine [35] whilst S.
typhimurium toward L-aspartic acid [36]. Another special form of che-
motaxis, known as pH-taxis, can also be exploited to realize robust drift
control of multiple S. marcescens-propelled microbots [38]. These mi-
crobots showed a motion bias when they moved from unfavourable pH
(acidic or basic) to favourable pH (neutral) at higher swimming speed,
and hence, exhibited a stronger tactic motion [38]. By taking advantage
of such motion controlling scheme, Kim and Breuer have successfully
used E. coli to enhance the mixing of dextran molecules in a micro-
fluidic channel at bi-directional manner [52]. Using L-aspartic acid as
chemoeffector (see Fig. 2), they have successfully increase the diffusion
coefficient of dextran from 8.81 ± 1.25 μm2/s to 41.8 ± 1.25 μm2/s,
improving the mixing rate by a factor of four (almost linear increment
from the baseline with no bacteria chemotaxis). A push-and-pull con-
figuration can also be developed by simultaneous use of chemoat-
tractant and chemorepellent, which will give a much dramatic mixing
outcome.
Even though sounds promising, the chemotactic control scheme is
not without drawbacks. As chemotactic control methods rely on the
cell’s short-range sensing capability for certain chemicals, the main is-
sues to be tackled would be the poor temporal and spatial resolution of
the local chemical gradients in the system. Unless there is enough flow
or mixing of the solution, the response time is often dependent on the
chemical diffusion rate [28]. This makes real time application of pro-
cess flow control extremely challenging. In addition, the needed che-
micals have to be introduced close to the microbots to allow a good
detection by the cell and reduce the response time and this requirement
makes chememotatic control a highly localized method. In addition to
all these limitations, the chemotactic directional control displays a high
Chemical Engineering & Processing: Process Intensification 141 (2019) 107530
degree of stochasticity though it does provide a net directional control
of the microbot’s motion [34,35,51]. This implies that the microbot
incessantly changes its heading direction and may not be moving in the
Ref desired direction at any given point in time [28]. However, the che-
mical control methods still offer a simple way to utilize the cell’s sen-
sory and behavioral response for the motion control of biohybrid mi-
crobot without the need of large, external control systems [28].
[44]
[45]
[46] 2.2. Phototactic control
[47]
[48]
Phototactic control methods can be used to drive biohybrid systems
[49]
[40]
consisted of microorganism with light-induced sensory responses such
as phototactic bacteria and algae. These phototactic microbes can show
[50] positive and negative phototaxis at different intensities of light, by
swimming toward and away from the light source, respectively. Thus,
by varying the light intensity, the modes of motion can be switched
among random swimming, positive or negative phototaxis. Examples of
phototactic steering control of microbot include microbot driven by C.
reinhardtii [42], S. macrescens [41,43], E. elegans [53] and T. pyriformis
[54] using light-emitting diodes (LEDs) and ultraviolet (UV) light.
Phototactic control method provides a rapid control of the microbot as
most phototactic cells give immediate response to optimal simulation in
less than a second [42]. LEDs, lasers and fiber optic cables can be in-
tegrated into microfluidic chamber to produce a more focused point
source of light for steering purpose [28]. Based upon phototactic con-
trol method, a biohybrid micromotors can be constructed by utilizing a
rotating unit (see Fig. 3) that can capture individual E. coli into an array
of microchambers so that the cells motion could applied torque into the
system [55]. Then the speed of individual micromotors can be in-
dependently tuned by adjusting their illumination with a spatial light
modulator. This strategy allows the micromotor to achieve a maximum
rotational speed up to 20 rpm with each cell capture is capable to power
the rotating unit to around 1.2 rpm. Thus it takes around 16 cells to get
the micromotor to rotate at its highest speed. From process in-
tensification perspective, this is a classic example showing how the
microbot can be used to power-up a micromachinery as an integral part
of a miniaturized system.
The major limitation of optical control is that light cannot penetrate
through all environments and it is restricted to certain orientation due
to the possible position of optical guide. The integration of light source
into microscale system becomes difficult especially for biomedical ap-
plication. It is still challenging to translate into actual biomedical ap-
plications due to the safety concerns of UV light which cause DNA and
protein damage to living organisms [56,57]. For small volume micro-
scale system, focused light can cause gradual localized heating of the
surrounding media, which may harm the cells [28,58].
2.3. Electrotactic control
Electric fields can be applied to steer microbot through electrotaxis
or electrophoresis. Electrotaxis, or galvanotaxis, is the directed move-
ment of a cell in response to an electric simulation whereas electro-
phoresis is the movement of charged particle under the influence of an
electric field [28,59]. Examples of microbes that respond to an electric
field are S. marcescens [43,60,61] and T. pyroformis [54]. One of the
drawbacks of electric field driven control is that this control method is
invasive. The electrolysis can lead to generation of bubble and heat in
the media, changes in pH, and formation of toxic gases and inorganic
ions from electrode corrosion as the electrodes are placed in the culture
medium or in direct contact with cells to produce the electric potentials
[28,61]. Moreover, the externally applied electric field might cause cell
lysis due to the electroporation of cell membrane [62]. The choice of
the electrode is limited because the electrodes used must minimise
these negative effects. Nevertheless, electric fields still would be one of
the favourable control methods because the electric field strength and
direction can be easily altered. In addition, it has been proven that the
3
W.M. Ng, et al.
possible to combine various electrokinetic phenomena in motion con-
trol [63].
2.4. Magnetotactic control
One of the major benefits of using magnetic fields to control the
biohybrid microbot is that the magnetic fields can be generated re-
motely and can penetrate most environments. The use of phototactic
control has limitations as light cannot penetrate all environments,
hence it is not applicable in many environments. The phototactic and
chemotactic control require the intrinsic sensing ability of light and
chemical of the microorganisms [28]. Although magnetotactic control
also requires the presence of magnetosomes in the cell body, the
magnetotactic behavior still can be created easily and artificially via
synthetic attachment of magnetic objects to the microbot [12,64]. For
application where a high directional control accuracy is required,
Fig. 3. Phototactic steering control of microbot. (a) Bright-field microscopy image showing 36 rotating micromotors. (b,c) Array of 16 rotors with clear visible of
fluorescence cell bodies with high occupancy fraction within the microchambers. (d,e) Magnified view on one rotor in (b,c) with the cell bodies as ellipsoidal shape
appeared as dashed line in (e). The scale bar is 20 μm for (a,b,c) and 5 μm for (d,e). Image is adapted from G. Vizsnyiczai et al. work published in Nat. Comm. [55].
4
Chemical Engineering & Processing: Process Intensification 141 (2019) 107530
Fig. 2. A schematic drawing showing the mi-
crochannel and sample diffusion profiles of
dextran as they flow within the microchannel:
(a) baseline control (no E. coli), (b) just E. coli
but no chemoeffector (chemotaxis is not hap-
pening), (c) E. coli in the center stream and the
chemoattractant in the right stream, and, (d) E.
coli in the center stream and chemorepellent in
the right stream. Copyright 2007 American
Chemical Society. Adapted with permission
from Ref. [52].
magnetotactic control is more preferable than chemotactic control as
magnetotactic control offers a deterministic directional control over the
stochastic chemotactic control. Furthermore, the magnetic control
method is less invasive than electric control because the electrodes for
electric control are needed to be in contact or close contact with cells or
culture media. This arrangement would be leading to the generation of
unnecessary electro-osmosis current around the electrode that cause
perturbation flow to the motion control strategy [65]. The main dis-
advantage of magnetic control is the generation of heat through re-
sistive heating when high magnetic field strength is produced by elec-
tromagnet. Such condition will lead to the increase in the workspace
temperature, which may alter the cell behavior or affect their viability
[28]. To mitigate the heating effect, a permanent magnet can be used to
generate large magnetic field, however, it only allows the adjustment of
the magnetic field by physically manipulating the magnet position.
W.M. Ng, et al.
3. Magnetotactic control of biohybrid microbot
Magnetotaxis has been proven as a versatile approach for motion
control of microbot because magnetic fields can be applied in many
forms such as gradient, oscillating, rotating or combinations thereof, at
different frequencies [66]. Magnetic forces and torques can be applied
independently onto a magnetic microbot using the magnetic field and
its spatial gradient respectively, giving to a wide range of microbot
design and actuation opportunities [1]. Magnetic fields and magnetic
field gradients can be remotely generated with magnetic coils or per-
manent magnets outside the workspace.
Assuming that there is no electric current flowing in the workspace,
→
the magnetic force Fmag exerted on a microbot with magnetic moment → μ of 200 μm/s [75,76], this work is further extended to the design of a
→ fully operational robotic platform. Here, the main goal is on the de-
in a magnetic field B is given by [1]
→ →
Fmag = (→
μ ∙∇) B (1)
and the magnetic torque →
τmag is given by
→ →
τmag = →
μ ×B (2)
These equations form the underlying principles for the magneto-
tactic control of the microbot under the magnetic fields. The magnetic
torque generated from a homogenous magnetic field, acts to align a
magnetic moment with the direction of the applied field (see Fig. 4). On
the other hand, the magnetic force is created from the spatial gradient
of the magnetic field, and operates on a magnetic moment in a less-
intuitive manner [1]. It is possible to provide independent magnetic
torques or forces, or even a combination of both, depending on the
design of the magnetic field system. For the construction of microbot is
concerned, the magnetotaxis of biohybrid microbot can be either nat-
ural or artificial (see Fig. 1 for the pictorial illustration of an artificial
microbot).
3.1. Natural magnetotactic microbot
In nature, there are a polyphyletic group of microorganism called
magnetotactic bacteria that orient along the Earth’s magnetic field lines
[67]. Magnetotactic bacteria (MTB) are unique flagellated prokaryotes
containing intracellular membrane-surrounded magnetosomes (see
Fig. 5a) [39]. These magnetosomes are naturally occurring nanocrystal
of either the magnetic iron oxide magnetite, Fe3O4 or, less commonly,
the magnetic iron sulphide greigite, Fe3S4, that are arranged as a fer-
romagnetic intracellular chains [68,69]. During magnetotaxis, the
chain of magnetosomes allow them to align and swim along the mag-
netic field line by rotating their flagella [67,70]. This unique and
genuine feature has made them to become an attractive microorganism
used in the biohybrid microbot. Since the chain of magnetosomes in the
MTB responds to the directional magnetic field as low as the geomag-
netic field, it offers a simple and energy cost-effective way for actuation
and application well compared to any artificial entities [71]. In fact,
just by using a chain of paramagnetic particles with diameter at around
1.4 μm with chain length at 15–20 μm, Biswal and Gast have managed
to induces secondary flows (from rotating particle chain) that enhance
the mixing by diffusion within a microfluidic channel [72].
Due to the magnetic property possessed by the MTB, the manip-
ulation of these MTB using microelectromagnets arrays has been
5
Chemical Engineering & Processing: Process Intensification 141 (2019) 107530
demonstrated [73,74]. However, Martel et al. was the first to propose
the manipulation and actuation of micro-objects with MTB using
magnetic field in 2006 [40]. By modifying the torque on a chain of
magnetosomes within the bacterium with a directional magnetic field
of 0.35 m T generated from a small programmed electrical current,
Magnetospirillum gryphiswaldense could propel 3 μm melamine resin
beads at an average velocity of 7.5 μm/s (see Fig. 5b). Here, a small
electrical energy would be required to manipulate and change the di-
rection of these MTB-based microbots as they can orient themselves and
swim along the geomagnetic field lines (0.05 m T) with the magnetic
moment of the MTB at 1 × 10−15 A m2 [40,73]. By switching to a fast
swimmer, Magnetococcus marinus strain MC-1, with an average velocity
velopment of hybrid nanorobots designed for targeting locations only
accessible through human microvasculature and the controlled ma-
nipulation of these bacterial nanorobots through calculations on the
magnetic controllability, swimming speeds and directions [75]. Later,
the same microbot was used for the detection and diagnosis of breast
tumor [77]. A tumor-therapeutic carrier, which was constructed by
attaching nanoliposome onto the surface of MC-1 via carbodiimide
cross-linking chemistry was developed based upon microbot concept
(see Fig. 5c) [78]. The swimming speed of the microbot recorded at
approximately 80 μm/s when ˜70 liposomes having a diameter of
170 nm were attached onto the surface. The cytotoxicity study con-
firmed the improvement in the biocompatibility of MTB after the li-
posomal attachments. In addition, the same system based upon MC-1
MTB could be used to transport drug-loaded nanoliposomes into hy-
poxic regions of the tumour through magneto-aerotaxis behaviour in-
vivo experiment in mice [79]. On the other hand, Ma et al. worked on
the magnetotactic control of a MTB-based microbot constructed by the
means of antigen-antibody interaction to improve the reliability of their
attachment method [39]. They deployed an immunoreaction to im-
prove the adsorption efficiency and bond strength between the Medi-
terranean magneto-ovoid bacteria strain MO-1 and 2 μm polystyrene
(PS) microbead. Consequently, the speed of the magnetotactic microbot
was increased to 21 μm/s (about 2.8 times than the velocity reported in
ref [40]) while transporting the microbead though the magnetic field
used was measured at 0.2 m T (lower than 0.35 m T used in ref [40]).
Due to the chain formation of magnetosomes, magnetotaxis has the
predominant influence on the swimming direction of MTB over che-
motaxis and aerotaxis after the MTB is being subjected to a magnetic
field slightly higher than the geomagnetic field strength [40]. There are
several types of promising MTB candidates that could be integrated into
a biohybrid magnetotactic microbot in order to provide steering and
actuation purpose, as shown in Table 2. It is noticeable that the average
swimming speed of the MTB increases with its body size. By considering
the swimming speed alone, which is also the key performance indicator
of the microrobotic applications, MC-1 would definitely be chosen in
the application where higher swimming speed is required as it could
achieve a faster performance. On the other hand, if the size of the MTB
becomes a critical aspect to be considered, such as maneuvering within
a confined geometry within a microchannel, MV-4 is preferable as it has
the smallest body size. The obvious drawback of using MV-4 is its
slower swimming speed and slow performance.
Depending on the arrangement of flagella, MTB can be classified
Fig. 4. A schematic diagram showing an ani-
sotropic object aligned with the magnetic field
leading to a translational motion. For the case
of magnetotatic bacteria, due to the chaining of
magnetosomes, the shape anisotropy assump-
tion should be quite appropriate under most
circumstances.
W.M. Ng, et al. Chemical Engineering & Processing: Process Intensification 141 (2019) 107530

Fig. 5. Natural magnetotactic microbot. (a) Internal chain of magnetosomes of a magnetotactic bacterium. Image is adapted from L. Chen et al. work published in
Nature Education [80]. (b) The trajectory of a microbead propelled by a single MTB with a direction change with respect to the change in the orientation of magnetic
field as indicated by B1 and B2 (at t = 2.5 s) and the respective time lapse images showing the instantaneous of the microbot. Copyright 2006 American Institute of
Physics Adapted with permission from Ref. [40]. (c) Design of a self-propelled therapeutic microbots by the carbodiimide binding of nanoliposome to the surface of
MTB. Copyright 2014 American Chemical Society. Adapted with permission from Ref. [78].

Table 2 other ingested food particles [64]. Upon the magnetization, the mi-
Type of MTB used, their body sizes and respective average unbound swimming crobot was controlled to move by its endogenous motility and the speed
speed. achieved could be as high as 786.7 μm/s by an external time-varying
Magnetotactic bacteria (MTB) Body size Average swimming Ref magnetic field of 2 m T [64]. Instead of magnetic force, the magnetic
(μm) speed (μm/s) field exerts a torque, which allows for manipulation of the swimming
direction of the microbot. Besides, different feedback control study of
Marine spirillium (MV-4) ˜ 0.5 30-80 [82]
the magnetotactic microbot were presented using the rapid-exploring
M. gryphiswaldense ˜ 1–3 ˜ 40–80 [40]
Marine magnetotactic ovoid (MO- 1.85 150 [39] random tree (RRT) method [84], model predictive control (MPC)
1) method [85], and ensemble control with control-Lyapunov function
M. marinus (MC-1) ˜2 200 [83] (CLF) for the steering of a swarm of such microbot [86]. All the studies
have the same ultimate objective, which is to achieve a precise and
robust control for the magnetic steering of the microbot in the desired
into either polar or axial. Axial MTB like M. gryphiswaldense, have two position and orientation. On the other hand, Giulia et al. presented the
flagella on both ends of the cell and they can swim in either direction magnetotactic control of a microbot created via the incorporation of
along the lines of magnetic field. Unlike axial MTB, polar MTB such as terbium into a green microalgae C. reinhardtii [87]. Interestingly, this
MV-4, MO-1 and MC-1, have flagella on only one side of the cell and was the first among any prominent works in the biohybrid micro-
they swim persistently in one direction along the magnetic field, either systems that the magnetotactic control is provided by the magnetiza-
toward the north pole or the south pole [81]. In term of magnetic tion of a lanthanide element, terbium (Tb). The uptake of trivalent
controllability, polar MTB are practically more desirable as they are cations of terbium (Tb3+) by the microalgal cell offers the magneto-
more predictable under the controlled manipulation of the microbot tactic control and the traceability of such microbot due to the photo-
[75]. luminescence of the lanthanide. Besides the magnetotactic control
study, they present the biocompability and viability study of the mi-
crobots with mammalian cells. These non-toxic and biocompatible
3.2. Artificial magnetotactic microbot
microbots showed a directional motion parallel to the direction of an
applied uniform magnetic field with the strength of 161.3 m T and
Inspired by natural magnetotactic bacteria, the artificial magneto-
achieved a mean speed of 21.7 μm/s.
taxis of biohybrid microbot can be achieved via the incorporation of
The artificial magnetotactic microbot created via the internalization
magnetic nanoparticles onto the nonmagnetic motile microorganism,
of magnetic nanoparticles are somehow similar to the MTB whereby the
either internally or externally (see Table 3 for detail summary). The
magnetic nanoparticles are kept within the cell body. The magneto-
introductory demonstration of creating an artificial magnetotactic mi-
tactic control of such microbot and MTB is provided through the
crobot via internalization of SPIONs was proposed by Kim et al using a
magnetization of the internalized magnetic nanoparticles by an applied
eukaryotic ciliate, T. pyriformis (see Fig. 6) [64]. Instead of being
uniform magnetic field, acting like a compass needle for magnetic
functionalized onto the surface, the magnetite Fe3O4 nanoparticles
guidance. Under a magnetic field, a magnetic dipole is induced as de-
were completely ingested through the oral cilia located at the anterior
scribed by the following relationship [81,88]:
end of the cell, and were stored in the membrane bounded vesicles like

6
W.M. Ng, et al. Chemical Engineering & Processing: Process Intensification 141 (2019) 107530

Table 3
Different type of magnetotactic microbots and their performances under the influence of magnetic field.
Microswimmer Artificial substrate [sizea (μm)] Attachment method Magnetic control Magnetotactic speed (μm/s) Ref
strategyb

Natural magnetotactic microbot (MTB-based microbot)

M. gryphiswaldense Melamineformaldehyde resin bead (Ø ≈ 3) Random adhesion 0.35 m T 7.5 [40]
MC-1 Liposomes (Ø ≈ 0.17) Carbodiimide bonding 2mT 80 [78]
MC-1 Liposomes (Ø ≈ 0.17) Carbodiimide bonding 1.5 mT Not reported [79]
MO-1 PS bead (Ø ≈ 2) Antibody bonding 0.2 m T 21 [39]
Artificial magnetotactic microbot
Method of internalization/intake of magnetic nanoparticles
T. pyriformis Magnetite Fe3O4 nanoparticles None 2mT 786.7 [64]
C. reinhardtii Trivalent cation of terbium, Tb3+ None 161.3 m T 21.7 [87]
Method of external-attachment of magnetic substrate
S. marcescens Magnetic bead (Ø ≈ 6) Biotin-streptavidin 10 m T 7.3 [33]
S. typhimurium Magnetic bead (Ø ≈ 10) Plasma patterning 23.6 m T 5.82 [89]
E. coli Fe/PS Janus particles (Ø ≈ 2) Metal patterning Not reportedc < 1 [90]
E. coli PPY/Ni/PDA tube (l ≈ 8–11, Ø ≈ 1–2) Shape-guided adhesion, electrostatic 8 mT 5 [91]
interaction
Bovine sperm cell Ti/Fe tube (l ≈ 50, Ø ≈ 5–8) Shape-guided adhesion 22 m T 10 [92]
Bovine sperm cell Ti/Fe tube (l ≈ 20, Ø ≈ 6–7) Shape-guided adhesion 22 m T 33.3 [93]
Bovine sperm cell Ti/Fe/PNIPAM tube (l ≈ 50, Ø ≈ 6–12) Shape-guided adhesion 22 m T 15 [94]
Bovine sperm cell Ni/Ti microhelix (l ≈ 21.5–26, pitch ≈ 6.5–7) Shape-guided adhesion Not reportedc 17.6 [95]
C. reinhardtii Magnetic bead (Ø ≈ 1) Electrostatic interaction 26 m T 51.44 [96]
C. reinhardtii Magnetic bead (Ø ≈ 2/4.5) Electrostatic interaction < 67 T/m Varyingd [50]

a
Diameter Ø or longitudinal length l.
b
The magnetic control strategy is based on force if the field gradient is reported, or, torque if the field strength is reported.
c
The control strategy is based on magnetic torque, however, the field strength is not reported.
d
The magnetotactic speed reported is a spatial function of the microbot’s location in the field gradient.

→→ →→ interfere the cellular functions of the organism. Besides, the perfor-

⎛ μB ⎞ ⎛ μB ⎞ kB T
cosθi = L ⎜ = coth ⎜ kB T ⎟ − →→
kB T ⎟ μB
⎝ ⎠ ⎝ ⎠
where θi represents the angle between the direction of the magnetic
→
moment → μ and the applied magnetic field B , kB is the Boltzmann
constant, T is the absolute temperature and L is the Langevin function
[L (x ) = coth(x ) − 1/ x ]. This relationship forms the underlying design
rule of any magnetotactic microbotic system with internalized magnetic
nanoparticles (including MTB). The magnetotactic directional con-
trollability of the microbot is dictated by the alignment of the cell in the
applied magnetic field, which is given by the ratio of the magnetic
energy (μB ) to the thermal energy (kB T ) . The magnetic field applied
must be sufficient to produce a magnetic energy higher than the
thermal energy which contribute to the Brownian motion that tends to
randomize the cell orientation and overcome the effect of other po-
tential taxis (e.g. chemotaxis or aerotaxis) and viscous drag that could
weaken the magnetotactic motion [81]. However, this strategy is lim-
ited to specific type of microbes because the cells must be able to re-
main viable after the intake of the magnetic nanoparticles [33]. The
magnetic nanoparticles may penetrate through the cell membrane and
mance of the microbot is also highly dependent on the magnetic sensing
(3)
capability (or magnetic moment) of the cell, which is given by the
maximum concentration of the magnetic nanoparticles that can be
taken by the cell. Practically, an optimal intake concentration of mag-
netic nanoparticles should be determined beforehand to allow a more
consistent magnetotactic control over the entire duration of applica-
tion.
Another way of creating artificial magnetotactic microbot is the
external-attachment strategy to bind the magnetic artificial substrates
onto the motile biological cells. The strategy employs the means of
interaction between the magnetic substrate and the cell envelope for
the attachment, which highly rely on the surface chemistry, surface
topography, surface charge and the hydrophobicity [28]. The surfaces
of these magnetic substrates are chemically modified to promote par-
ticle-to-cell adhesion. Carlsen et al. proposed the magnetic steering
control of the microbot by introducing a 6 μm-diameter super-
paramagnetic bead attached by multiple S. marcescens bacteria via
biotin-streptavidin binding [33]. Such microbot could achieve two-di-
mensional swimming speed up to 7.3 μm/s under a weak magnetic field

Fig. 6. Microscopy images of T. pyriformis with the scale bars shown for 10 μm (a) normal condition, (b) after ingestion of SPIONs and (c) after magnetization of
ingested SPIONs. Copyright 2010 American Institute of Physcis. Adapted with permission from Ref. [64].

7
W.M. Ng, et al. Chemical Engineering & Processing: Process Intensification 141 (2019) 107530

Fig. 7. Artificial magnetotactic microbot. (a) SEM micrographs showing the selective attachment of E. coli to the metal cap (iron, titanium, platinum, or gold) of the
Janus particle and the tracking of the microbot bound with the iron metal cap of the Janus particle under an applied magnetic field. Copyright 2015 WILEY‐VCH
Verlag GmbH & Co. KGaA, Weinheim. Adapted with permission from Ref [90]. (b) A sperm-driven microbot (spermbot) is consisted of a motile sperm cell trapped
inside a magnetic microtube. Reproduced from Ref [92]. and [93] with permission from WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (c) Assisted delivery of an
immotile sperm to the oocyte for fertilization by a remotely controlled magnetic microhelix. Copyright 2015 American Chemical Society. Adapted with permission
from Ref. [95]. (d) Magnetic microbead tagged Chlamydomonas via electrostatic interaction.

(≤ 10 m T). The proposed magnetic steering control greatly abates the
stochastic motion showed by the similar microbot (with different sizes
of bead attached) under the chemotactic control as reported in the work
of Kim et al. [34,51]. On the other hand, Li et al. proposed and im-
plemented an electromagnetic actuation system for the control of mi-
crobot fabricated from the selective attachment of a clinic bacteria with
tumor-targeting S. typhimurium on an alginate-based magnetic mi-
crobead through plasma exposure [89]. By applying the electro-
magnetic field control, the microbot could move along the desired path
and achieve an average velocity of 5.82 μm/s when the applied mag-
netic field strength was 23.6 m T. Another proof-of-concept microbot
was proposed by Stanton et al. whereby the Escherichia coli bacteria was
favourably adhered to the metal caps on PS Janus particles (see Fig. 7a)
[90]. The microbot bound with the iron metal cap of the Janus particle
could be guided magnetically whilst transporting an anticancer drug
DOX at very slow velocity (< 1 μm/s). An improvised version of the
microbot was then presented by integrating a single E. coli bacterium
with a conical microtube instead of a spherical particle [91]. The PPY/
Ni/PDA composite microtube was made up of three different layers:
polypyrrole (PPY) as the outer layer of the microtube formed in a
membrane scaffold, nickel (Ni) nanoparticles as the intermediate layer
for magnetic guidance, and polydopamine (PDA) as the inner layer to
promote the attachment of the bacterium to the inside of the microtube
via electrostatic interaction. The microtube structure has improved the
swimming speed to 5 μm/s, but less microbots were observed swim-
ming because they did not have sufficient power to propel themselves
together with the tube.
Apart from that, the external-attachment strategy is not limited to
bacteria, but it can be applied to highly motile eukaryote with faster
swimming speed. In fact, Magdanz et al. has developed an external-
attachment strategy using the bovine sperm cell and also the magnetic
microtube for the development of sperm-driven microbot (see Fig. 7b)
[92]. Initially, the sperm-driven microbot was constructed by trapping
a motile sperm cell inside a magnetic tube, which allowed external
manipulation by magnetic field. Under the magnetic guided motion at
22 m T, the reported velocity of the sperm-driven microbot was 10 μm/s
which is higher than any bacteria-based microbots created using ex-
ternal-attachment strategy. Upon optimization, the performance of such
microbot was improved and the microbot could achieve a velocity of
33.3 μm/s by using a smaller microtube and fibronection to obtain a
better coupling between the cell and the microtube [93]. The true
versatility of this approach is its possibility to release the encaged cell in
a controlled way. They utilized a thermoresponsive polymer poly(N-
isopropylacrylamide) (PNIPAM) to fabricate a dynamic structure for
remote-controlled release of a single sperm cell upon an external tem-
perature stimulus [94]. Besides, they further extended their method of
construction by implementing magnetically actuated polymer-metal
composite carrier that can actively capture, transport, and release
single live sperm cell which is otherwise immotile due to pathological
defects. By doing so, the microbots take over the propulsion duty of the
sperm cell (see Fig. 7c) [95]. However, these microbots are proposed to
assist fertilization and the use of these microbots for other intended

8
W.M. Ng, et al.
application so far have not been reported. On the other hand, the
capability of phototactic microalgae Chlamydomonas to transport mi-
croscale loads at high velocity (> 100 μm/s) has drawn the researcher’s
interest to turn them into the magnetotactic microbot via the external-
attachment method [42]. Yasa et al. presented the design of a biohybrid
algal microbot, which is consisted of a negatively charged intact mi-
croalgae Chlamydomonas, attached to a positively functionalized mag-
netic PS microbead via electrostatic interaction [96]. These algal mi-
crobots have been proven to be noncytotoxic and biocompatible with
both healthy and various human cancerous cells [87,96]. They could be
steered with a uniform magnetic field of 26 m T at a mean swimming
speed of 51.44 μm/s and demonstrated their therapeutic potentials
through an active delivery of drug particles to mammalian cell [96].
Coincidently, our group proposed the similar design of microbot using
Chlamydomonas but with larger size of magnetic microbeads via elec-
trostatic interaction (see Fig. 7d) [50]. Instead of using a uniform
magnetic field, we presented for the first time the artificial magneto-
tactic control of the microbot by the means of magnetic force induced
by a low field gradient (< 100 T/m) and evaluate the effect of self-
swimming behaviour toward randomizing the deterministic motion of
the microbot under artificial magnetoxis. Our findings suggested that
the directional control of the microbot under the influence of a low
gradient magnetic field was achieved based on following the principles:
(1) magnetophoretic force was insignificant on influencing its perpen-
dicular motion, and, (2) its parallel motion was dependent on both self-
swimming and magnetophoresis, in which this cooperative effect was a
function of separation distance from the magnet. As the microbot ap-
proached the magnet, the magnetophoretic force dominated its self-
swimming behavior, leading to a positive magnetotaxis of the microbot
toward the source of magnetic field.
The external-attachment method offers the magnetotactic control of
the microbot through the magnetization of the artificial substrate
bound to the microorganisms by an external magnetic field. When such
microbot is exposed to the magnetic field, the directional control of the
microbot can be characterized by the following equation [33]:
v∙B
cosθe =
|v||B| (4)
where θe represents the alignment of the cell in the applied magnetic
field, which is defined by the angle between the velocity vector v and
the applied magnetic field B . This relationship describes the governing
design criterion of the microbot bound externally with magnetic sub-
strate. The applied magnetic field must be able to align the swimming
direction of the microbot to the direction of the applied field as close as
possible for a precise control. The velocity vector of the microbot here is
actually the net swimming direction of the microbot from the balance
between the self-swimming of the microorganism, the viscous drag and
the magnetic force/torque induced by the magnetic field. This method
can be applied to almost all motile microbes to form a magnetotactic
biohybrid microbot, not limited to MTB or cells that can intake mag-
netic nanoparticles. By having a magnetic artificial substrate, the per-
formance of the microbot is no longer dependent on the magnetic
sensing capability of the biological cells, but is significantly related by
the adhesion of the cells to the substrate and the magnetic moment of
the substrate. A proper coupling between the cell and the substrate
should be achieved to ensure the microbot always as a single entity. If
the attachment becomes unstable leading to the detachment of mag-
netic substrate, the magnetotatic control of the microbot would fail as
the highly motile cell could swim randomly in any direction. Besides,
the introduction of an external substrate onto the cell would definitely
impose additional viscous drag to the microbot and hence reduces the
moving speed of the microbot. A drastic reduction in the swimming
speed of the microalgae after the attachment of the magnetic microbead
was observed in the work of Yasa et al. [96] and our group [50]. The
optimization study should be conducted for the improvement in the
swimming performance of the microbot. Since the additional viscous
9
Chemical Engineering & Processing: Process Intensification 141 (2019) 107530
drag is directly proportional to the size of the magnetic substrate used,
the use of smaller substrate can minimize the viscous drag experienced
and increase the swimming speed of the microbot. Another way to in-
crease the swimming speed of the microbot is to increase the magnetic
mass (magnetic moment) of the artificial substrate. This will increase
the magnetic force or magnetic torque induced in the microbot to
overcome the additional drag resistance experienced when it moves. In
addition, the position of the substrate attachment also affects the per-
formance of the microbot. When the substrate is bound to a location
where it disturbs the actuation mechanism of the cell (i.e. the beating of
the flagella or cilia), it will decrease the swimming speed of the entire
microbot as its propulsion comes mainly from the cell actuation. The
selective attachment can be used to increase the motility and direc-
tionality of the microbot where the position of attachment can be
controlled [97–99].
4. Conclusion and outlooks
This paper briefly reviews the present state of the magnetotactic
control of different types of biohybrid microbots as summarized in
Table 2. Currently, the research focus of the magnetotactic biohybrid
microbot on MTB has shifted to non-magnetically responsive microbial
swimmer as the incorporation of magnetic nanoparticles opens up new
avenues for implementing magnetic control on different types of mi-
crobes. Such scenario allows the microbot to perform complex task in
microscale environment both in vivo and in vitro, such as non-invasive
targeted diagnosis and therapies inside human, and microfluidic ma-
nipulation within lab-on-chip devices. From a simple uptake of mag-
netic nanoparticles to the more complex strategy involves the in-
corporation of magnetic substrate created using the advanced
fabrication techniques like roll-up nanotechnology [92–94], direct laser
writing [95] and 3D stereolithographic printing [100], different mag-
netotactic biohybrid microbots have been developed. An important
aspect to be addressed here is the biocompatibility between the mag-
netic nanoparticles/substrate, the microbial swimmer and the working
environment. In fact, they should show mutual compatibility among
themselves to ensure their viability throughout the entire application
timeline, especially the cellular response to the changing environmental
conditions.
As primary magnetic control methods are either based on a homo-
genous magnetic field (magnetic torque) or spatial field gradient
(magnetic force), one of the encountered challenges is to increase the
degree of control under the applied magnetic field as both magnetic
force and torque act on the microbot coexistently [101]. A complete
understanding on the contribution of both magnetic force and torque
toward the overall magnetic controllability would allow a precise
control of the microbot under the applied magnetic field. The combi-
nation of both magnetic force and torque control may be studied under
a well-designed electromagnetic actuation system, comprised of two-
pair coil system generating uniform magnetic field and magnetic field
gradient simultaneously [89,102]. Besides, the manipulation of the
microbot in viscous complex fluids or non-Newtonian fluids indeed
requires intensive research efforts especially when it comes to biome-
dical application. The human body fluids such as blood and saliva are
examples of non-Newtonian fluids, showing shear thinning behavior
[103–106]. Since low Re propulsion in non-Newtonian fluids remains
relatively unexplored [107], there is also a need to develop computa-
tional and analytical models that can capture the swimming behavior of
the microbot within these media. An adequate model for the swimming
behavior of the microbot in a certain fluid is not necessarily suitable in
another fluid because the composition of the body fluids may vary
substantially [108,109]. Both the spatial and temporal resolution of
magnetotactic control are key aspects for the real-time tracking of the
microbot, especially for in vivo applications [110–112]. There is a need
for promising imaging techniques that offer the required resolution for
the visualization and tracking of the microbot under in vivo applications
W.M. Ng, et al.
[102,113,114]. On the other hand, advanced control methods are re-
quired to implement swarm control of a group of microbots to enhance
the task delivery efficacy collectively from the parallel and distributed
task operation of individual microbot [23,106106,114].
In short, the magnetotactic biohybrid microbots have demonstrated
great potentials for various kind of applications, especially in biome-
dical applications. With the fascinating progression made in na-
noscience and technology, the optimization and intensification of these
current microbot will lead to the construction of a well-designed
magnetotactic microrobotic system with a high degree of deterministic
control through an interdisciplinary effort. We believe that such mi-
crorobotic system will make significant contribution to the modern
medicine by providing a better theragnostic strategy especially for the
cancer treatment.
Acknowledgement
This work was supported by FRGS grant from Ministry of Education
Malaysia (MOE) (Grant 203.PJKIMIA.6071388).
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