Micro RobotsMicroswimmers ForBiomedicalApplications

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Micro-Robots/Microswimmers for Biomedical Applications
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Chapter One
Micro-robots/swimmers for bio-medical

applications
Naveen Kumar Agrawal, Pallab Sinha Mahapatra

Department of Mechanical Engineering, Indian Institute of Technology Madras, Chennai
600036, India
Tuhin Subhra Santra

Department of Engineering Design, Indian Institute of Technology Madras, Chennai
600036, India
Corresponding author, Email: pallab@iitm.ac.in
Abstract
The microfluidic platforms, lab-on-a-chip devices and micro-swimmers of dif-

ferent kinds attract the researchers in various bio-medical applications. Micro-
swimmers propel themselves in the medium with their self-propelled forces.
Micro-swimmers are now slowly changing many aspects of bio-medical and
health-care sectors. Remotely controlled artificial micro-robots, as well as living
micro-swimmers, have the potential of targeted drug delivery, micro system steer-
ing, chemical mixing, etc. Biodegradable protein based rockets are used for effi-
cient drug encapsulation and targeted release. Researchers have created artificial
Janus micro-robots that can be controlled externally from the micro-scale device,
for cancer cell treatment. Sometimes external fields like electrical or ultrasounds
are also used to release the drugs into the targeted areas. Here, we provide a com-
prehensive review of the different types of micro-swimmers and micro-swimmer
based devices for bio-medical and health-care applications. Finally, we have dis-
cussed the existing challenges and future potentials of the micro-robots and micro-
swimmers.
Pan Stanford Publishing: Microfluidics and Bio-MEMS: Devices and Applications

Copyright c 2009 by Pan Stanford Publishing Pte Ltd
www.panstanford.com
978-981-nnnn-nn-n
2 Micro-robots/swimmers for bio-medical applications
1.1 Introduction
The advancement in the technology of micro-actuation, micro-controlling, micro-

fabrication as well as micro-sensors opened new horizons in the development of
untethered, miniaturized robots. These miniaturized robots have vast potential ap-
plications in various fields like bio-medical [Iddan et al. (2000); Balasubramanian
et al. (2011); Kagan et al. (2011); Orozco et al. (2011); Xi et al. (2013); Mhanna et al.
(2014); Yu et al. (2014); Breger et al. (2015); Iacovacci et al. (2015); Soto et al. (2015);
Van Nguyen and Minteer (2015); Wu et al. (2016); de Ávila et al. (2017); Go et al.
(2018); Kafash Hoshiar et al. (2018); Chen et al. (2019)], environmental remediation
[Orozco et al. (2012); Gao et al. (2013); Orozco et al. (2014b); Kong et al. (2018); Villa
et al. (2018)], industrial [Suzumori et al. (1999); Anthierens et al. (2000); Takeda et al.
(2000)], Food [Rojas et al. (2016)] etc. Research in the sophistication of the micro-
robots, efficient propulsion mechanism, and precision steering method has been
increased in the past few years. The small scale robots are envisaged to perform
tasks which are difficult or impossible, in an environment, and out of the human
reach. The advancement in electronics and communication, control technology
advanced the untethered control of miniaturized robots and scaled down the large
scale movement to the sub-millimeter scale. The miniaturized untethered robots
have a large potential of performing complex tasks at the micro and cellular length
scales. Specifically in the field of bio-medical, for targeted therapeutic delivery
[Mhanna et al. (2014); Iacovacci et al. (2015); Lu et al. (2016); Wu et al. (2016); de Ávila
et al. (2017)], medical diagnosis [Iddan et al. (2000); Carpi et al. (2011)], sensing [Bal-
asubramanian et al. (2011); Kagan et al. (2011); Kuralay et al. (2012); Van Nguyen
and Minteer (2015)], minimally invasive surgery [Xi et al. (2013); Breger et al. (2015);
Soto et al. (2015); Chatzipirpiridis et al. (2015)] and detoxification [Wu et al. (2015)].
A significant revolution in the bio-medical field occurred in 2001 with the FDA ap-
proval of capsule endoscopy. These endoscopy capsules are capable of real-time
image/video capturing and wireless data transmission. These type of capsules are
easily available in the market and are used to diagnose the gastrointestinal (GI)
tract [Iddan et al. (2000)].
Mobile, untethered, miniature robots can be classified depending upon the size
and the operational method as [Sitti et al. (2015)]:
(1) Based upon the size of the robot:

(a) Micro-robot: Size of the mobile, miniaturized robot ranges from 1µm to
1mm. The dynamics of these robots are dominated by micro-scale forces like
surface tension and viscous forces.
(b) Milli-robot: Size of the mobile, miniaturized, robot ranges from 1mm to the
palm size. The dynamics at millimeter sale is governed by macro-scale forces
like buoyancy and inertial forces.
(2) Based upon operation:
(a) On-board approach: All the necessary components required for the opera-
tion of a robot like an actuator, sensor, battery, etc. are mounted on the robot
itself. The robot can be controlled autonomously or with the use of a remote.
(b) Off-board approach: The mobile robot does not have all the components
1.2. Propulsion mechanism 3
aboard. Few components are outside of the working domain of the robot.
These types of robots are sensed, operated, controlled, and powered by using
external components.
The mobile robots of micro-scale size and operated with the on-board approach
are best suited for the biomedical applications. However, at the microscale level,
the necessary components of a robot are not readily available. Therefore, the mi-
crorobots with the off-board approach are prominent in the biomedical and other
fields. At the micro-scale, the locomotion of a robot/swimmer is challenged by
the low Reynolds number (Re < 1) flow and Brownian motion, in a fluid. The
propulsion dynamics at micro-scale is far different than that in the macro/large
scale where Re 1 condition prevails. The Scallop theorem [Purcell (1977)] sets
the condition for net non zero displacement at the low Re condition. A variety of
propulsion mechanisms (detailed in Sec.1.2) have been conceptualized and are be-
ing explored in the research, like magnetic propulsion [Khalil et al. (2014); Mhanna
et al. (2014); Iacovacci et al. (2015); Khalil et al. (2016a); El-Etriby et al. (2018)], bubble
propulsion [Gao et al. (2015); Lu et al. (2016); Li et al. (2017); de Ávila et al. (2017)],
biological propulsion [Shechter and Martel (2010); Khalil et al. (2013); Singh and
Sitti (2016); Zhuang and Sitti (2016)], self-thermophoresis [Jiang et al. (2010); Bara-
ban et al. (2013); Qin et al. (2017)] etc. The advantage of untethered microrobot
is the accessibility to the closed and confined regions, which are difficult or not
possible to reach with conventional tethered robots. The primary objective of this
chapter is to discuss the miniaturized, mobile, untethered robots, which are used
or conceptualized to have potential use in the bio-medical field. The chapter is di-
vided into multiple subsections. The different types of propulsion mechanisms are
discussed in Sec. 1.2. The existing fabrication techniques are discussed in Sec. 1.3.
The applications of different types of microrobots and swimmers are discussed in
Sec. 1.4. Lastly, the future scope of the microrobots is discussed in Sec. 1.5.
1.2 Propulsion mechanism
The propulsion mechanism of a robot in a fluid is far different in microscale than

that in its macroscale counterpart. In the microscale, the fluid dynamics is domi-
nated by forces like viscous force, surface tension, and drag. Whereas, the forces
dominating the dynamics at macro-scale like inertial force and buoyancy are neg-
ligible in micro-scale dynamics. According to Purcell’s scallop theorem [Purcell
(1977)], in a Newtonian fluid a microswimmer can have a nonzero displacement
by performing non-reciprocal motion only. Also, the microswimmer has to have
more than one degrees of freedom to produce a nonzero displacement. With only
one degree of freedom, the microswimmer undergoes a reciprocal motion only,
therefore produces a net zero displacement [Purcell (1977)]. However, most of the
biological fluids are non-Newtonian, and thus, the Scallop theorem is no longer
valid [Qiu et al. (2014)].
The motion of a microrobot/microswimmer is prominent mainly in a low
Reynolds number (Re << 1) regime. In the low Re regime, the fluid dynamics
is governed by the Stokes equations as given by the following Eqs.

∇·u = 0 (1.1)
−∇ p + µ∇2 u = 0 (1.2)
Here p is the pressure, µ is the dynamic viscosity, and u is the velocity of the
fluid. The drag force experienced by a spherical body immersed in an infinite ex-
tent of fluid is linearly dependent on the velocity. From the Stokes law of resistance
at low Reynolds number (Re < 1) condition the drag force is given as:
Fdrag = 3πµdU (1.3)
Here Fdrag is the magnitude of the drag force exerted by the surrounding fluid
on the spherical body, µ is the dynamic viscosity of the fluid, d is the diameter of
the spherical body, U is the speed of the body. The drag force is exerted along the
direction, opposite to the direction of the velocity of the body. The force balance
on a self-propelling body (micro-swimmer/robot) can be given by:
Fnet = Fresistance + Fpropulsion (1.4)

Here Fnet is the net force acting on a microswimmer body, Fresistance is the sum of
Fdrag and other forces opposing the propulsion of a body, Fpropulsion includes all the
forces contributing in the propulsion of the body. At equilibrium Fnet = 0. There-
fore for producing a net displacement of a microswimmer in a fluid, the propul-
sion force (Fpropulsion ) should be greater than (or at least equal to) the resistive force
(Fresistance ) experienced by the microswimmer.
The propulsive force on a microrobots can be provided either by external power
sources like magnetic and electric fields, optical, thermal gradients or onboard
mechanisms like bacterial swimming, chemical reaction, bubble generation, etc.
Some of these mechanisms are shown in Fig. 1.1. and are discussed below.
1.2.1 Magnetic propulsion

There are researches advocating the successful propulsion and steering of micro-
robots exploiting external magnetic fields [Carpi et al. (2007, 2011); Mhanna et al.
(2014); Iacovacci et al. (2015)]. The reasons behind the popularity of magnetic field
include wireless transmission of high forces and torques with all 6 degrees of free-
dom. It can penetrate in almost any environment, and its use facilitates fuel-free
propulsion of untethered microrobots. Fig. 1.1.(a) shows a schematic view of a
magnetic microrobot. The microrobots embedded with magnetically responsive
materials (like Ni, Co, NdFeB, Fe), can be used to exploit external magnetic fields
for navigation and orientation. The external magnetic field can be generated by
using magnetic resonance imaging (MRI) system [Mathieu et al. (2006)], a coil sys-
tem [Ghosh and Fischer (2009); Zhang et al. (2009); Li et al. (2014)] or permanent
magnets [Carpi et al. (2007); Iacovacci et al. (2015)]. The microrobot can be oriented
by application of magnetic torque and can propel by applying magnetic force. The
magnetic force acting on a microrobot is given by [Abbott et al. (2009)]:
~Fmagnetic = µ0 V ( M
~ · ∇) H
~ (1.5)
(a) (b)
Magnetic particles Catalytic part
Gas bubbles
(c) (d)
Temperature
Sperm cells Synthetic component
v
Figure 1.1. Schematic view of different type of propulsion mechanisms: (a) Magnetic propulsion. (b)
Bubble propulsion. (c) Biological propulsion. (d) Self-thermophoresis. Green arrow shows the direction
of microrobot propulsion.
and the magnetic torque is given by [Abbott et al. (2009)]:

~Tmagnetic = µ0 V ( M
~ ×H
~) (1.6)
where V is the volume (m3 ) of the microrobot, µ0 = 4π × 10−7 T · m/A is per-
meability of free space, M~ is the magnetization (A/m) of the microrobot and H ~ is
the magnetic field (A/m). Both the Eqs. 1.5 and 1.6 are based on the assumptions
that the size of microrobot is very small as compared to the spatial changes of the
magnetic field H and the magnetic field is uniform across the microrobot. From
Eq. 1.5, applied magnetic force can be altered by altering the magnetic field gradi-
ent for a given microrobot. From Eq. 1.6, it is clear that applied magnetic torque
can be varied by varying the angle between the magnetization of the microrobot
and the magnetic field or by varying the magnetic field strength for a given micro-
robot. We can broadly classify the different types of magnetic propulsion in three
categories: (a) Magnetic gradient pulling (b) Helical propulsion (c) Planner wave
propulsion. The Helical and Planner propulsion of microrobots are inspired by
the biological microswimmers like E. coli and spermatozoa respectively. Fig. 1.2.
shows the schematic view of these three types of magnetic propulsion methods
and are discussed below.
(a) Magnetic gradient pulling: A microrobot with magnetization M ~ in a mag-
~ can be propelled by a magnetic force applied on it due to the mag-
netic field of H
netic gradient, as given in the Eq. 1.5. A schematic view of a magnetic gradient
pulled microrobot is shown in Fig. 1.2.(a). Mathieu et al. [Mathieu et al. (2006)]
demonstrated the first use of an MRI system for gradient pulling of a ferromag-
H
H
(a) (b)
M M
(c)
M
Figure 1.2. Different type of magnetic propulsion. Red arrows show the direction of applied external
magnetic field (H). (a) Magnetic gradient pulling. The magnetic field strength is increasing while mov-
ing from right to left. (b) Hellical propulsion under the application of a rotational magnetic field. (c)
Planner wave propulsion under the application of an oscillating magnetic field. All the microrobots are
moving from right to left.
netic spherical body. Carpi et al. [Carpi et al. (2007)] demonstrated translation, ro-
tation, and roto-translation of the wireless endoscope capsule (WEC) within tubu-
lar structures coated with bovine tissues. The hand operated, permanent magnets
NdFeB, were used to generate external magnetic fields for the capsule locomotion.
In another work, Carpi et al. [Carpi et al. (2011)] demonstrated the magnetic steer-
ing of the wireless capsule in the main regions of the GI tract: esophagus, stomach,
small bowel and colon of a domestic pig. They used the static field of the already
available Stereotaxis instrument for the magnetic maneuvering of the WEC. As the
commercially available WEC does not have any motion controlling mechanism;
therefore, they glued a magnetic-rubber shell to control the WEC magnetically.
Iacovacci et al. [Iacovacci et al. (2015)] demonstrated individual steering of compo-
nents (carrier and piston) of a near neutrally buoyant, millimeter-sized robot, ex-
ploiting the distinct magnetic property of the two-component as shown in Fig. 1.3.
Permanent magnets were used to generate a magnetic field of 5.2mT and a mag-
netic field gradient of 0.05T/m for the individual propulsion of the components to
the target. An additional 50mT magnetic field was used for holding the carrier at
the target while the piston was moved to the docking site. At the docking site, the
magnetic force between the two component caused docking of the piston in the
carrier, and thus compression of hydrogel releases the embedded drug, through
the holes in the carrier. Controlled navigation of a swarm of microrobots is also
possible by using magnetic gradient pulling. For individual controlling of each
microrobot in a swarm, they can be made heterogeneous. The heterogeneity can
be included in the swarm through the variation in geometrical design or the mag-
netic property of the microrobots. The heterogeneity causes a different magnetic
torque on each microrobot in a rotating magnetic field. The first demonstration of
independent 3D control of multiple microrobots is done by Diller et al. [Diller et al.
Figure 1.3. The propulsion, docking, and release of the drug at the target by the bicomponent, mi-
crorobot. The microrobot components are magnetically pulled. (a) Individual navigation of the drug-
loaded carrier to the target. (b) Then the piston was individually navigated to the docking site while
maintaining the carrier at the target. (c) The piston was brought to the critical docking distance. At this
docking site, the magnetic force between the components dominated the external magnetic field force.
(d) Docking occurs, causing the release of the drug. Reprinted by permission from Springer Nature,
Biomedical Microdevices [Iacovacci et al. (2015)], copyright 2015.
(2013)]. The microrobots were distinct in design, resulted in individual control of

the microrobots by application of different magnetic force in the same magnetic
field.
(b) Helical wave propulsion: Bacteria (like E. coli) propel by performing cork-
screw-like motion by rotation of the flagellum producing helical waves. The tactic
of the bacteria can also be mimicked for the propulsion of a microrobot in a low
Reynolds number regime. Honda et al. [Honda et al. (1996)] demonstrated the first
use of a centimeter-sized, magnetically propelled, spiral robot. Microrobots with
helical propeller are also called artificial bacterial flagella (ABF). These ABFs con-
vert rotational motion into translational motion, as shown in Fig. 1.2.(b). These
ABFs have at least one of the components magnetized, either the head [Honda
et al. (1996); Zhang et al. (2009)] or the helical tail [Ghosh and Fischer (2009); Li et al.
(2014)]. The microrobot component is magnetized in a way such that its magnetic
moment is perpendicular to the longitudinal axis of the microrobot. A uniform,
rotating magnetic field is applied in a plane perpendicular to the axis of the helical
propeller, which employs a torque as given in Eq. 1.6 and rotates the microrobot
along its longitudinal axis. With the rotation of this microrobot, helical waves are
generated and propagated along the tail, in turn, the microrobot propels by con-
verting rotational motion into linear motion. The main control parameter for con-
trolling the propulsion of the microrobot is the frequency of the rotating magnetic
field. The swimming velocity of the microrobot increases linearly with the fre-
quency up to a step-out frequency, beyond which the swimming velocity decreases

drasticall [Abbott et al. (2009); Mhanna et al. (2014)]. Therefore, for optimum perfor-
mance, the helical microrobots should operate at the step-out frequency, for which
the applied magnetic torque on the microrobot is maximum. Steering of the mi-
crorobot can be done by rotating the axis of the external magnetic field so that the
magnetic dipole of the microrobot tries to align itself along the external magnetic
field. One of the merits of the Helical microrobot is that it can be made to propel in
the backward direction just by reversing the direction of the applied rotating mag-
netic field and without actually turning the microrobot, as shown in the schematic
Fig. 1.4. Helical propulsion is suitable for precise navigation of even smaller mi-
V V
Figure 1.4. Forward and backward movement of the Helical microrobot. The rotational magnetic
field is applied perpendicular to the x-axis. The microrobot is moving towards the left (a). When
the direction of magnetic field rotation is reversed, the microrobot started moving towards the right,
without actual turning of the microrobot. Reprinted from [Zhang et al. (2009)], with the permission of
AIP Publishing
crorobots of lengths 1 − 2µm [Ghosh and Fischer (2009)]. Tung et al. [Tung et al.
(2013)] demonstrated propulsion of a rectangularly shaped microrobot called Rod-
Bot on a surface immersed in a solution of DI water and polyethylene glycol (PEG).
They reported the formation of vertex parallel and above to the RodBot, which can
be used to entrap and transport an object.
(c) Planner wave propulsion: The magnetic microrobots can also be propelled
by mimicking the propulsion mechanism of spermatozoa. The spermatozoa pro-
duce planer waves along their tail, to propel in a liquid medium. Mimicking the
same kind of mechanism a microrobot can also be propelled by producing planner
waves along its thin elastic tail. These microrobots are having a magnetic head
attached to an elastic tail, as shown in Fig. 1.2.(c). The head provides the magnetic
dipole, and the tail produces the propulsive force by producing planner waves. A
uniform magnetic field oscillating in time can be employed to propel the microbot.
The uniform magnetic fields are oriented towards the direction of motion with
a periodic component orthogonal to the direction of propulsion [El-Etriby et al.
(2018)]. The oscillating magnetic field applies torque as given in the Eq. 1.6, on the
magnetic head of the microrobot to align it along the magnetic field H, ~ thus oscil-
lating the microrobot. This oscillation generates local bending moment along the
tail and causes the elastic tail to produce planner waves, similar to spermatozoa.
The tail surface governs the ratio of the perpendicular viscous coefficient (ζ ⊥ ) to
the tangential viscous coefficient (ζ k ) [Dreyfus et al. (2005)] which in turn depicts
the flow of microrobot in the direction of wave propagation or along the direction
opposite to it. Khalil et al. [Khalil et al. (2014)] demonstrated propulsion of a mag-
neto sperm having an elliptic head (patterned with Co80 Ni20 for magnetic steering)
and flexible tail, using the external weak magnetic field (less than 5mT). El-Etriby
et al. [El-Etriby et al. (2018)] demonstrated the micro-manipulation of two non-
magnetic payload (100 µm diameter each), moving with an average speed of 0.16
bodylength/s and 0.035 bodylength/s during collision free locomotion and manip-
ulation respectively. Dreyfus et al. [Dreyfus et al. (2005)] fabricated a microrobot
with the flexible magnetic flagellum. Their microrobot propelled towards the free
end, unlike the other microrobots discussed above, which propelled towards their
head. Khalil et al. [Khalil et al. (2016a)] reported a nonlinear increase in the drag
force with an increase in the frequency of the oscillating magnetic field and swim-
ming speed. For improved functionality, these microrobots can also be made with
multiple flagella. The speed of the microrobot increases linearly with an increase
in the number of flagella [Ye et al. (2014)].
1.2.2 Bubble propulsion

Similar to the propulsion of rockets by the exhaust gases, robots at the microscale
can also be propelled by the ejected gas bubbles, as shown in Fig. 1.1.(b). Gas
bubbles can be produced during a chemical reaction in a fuel medium. These
gas bubbles after ejection propel the microrobots in the opposite direction. Bub-
ble propelled microrobots can perform autonomous motion by locally converting
chemical energy, from the surrounding, into kinetic energy. These microrobots are
embedded with a metallic catalyst like gold (Au), copper (Cu), platinum (Pt) or re-
active metal like zinc (Zn), magnesium (Mg), aluminum (Al), which decomposes
the fuels like H2 O2 , acid, water into gases like oxygen and hydrogen. Propulsion
reactions involving different combinations of catalyst/reactant material and fuel
are shown in the Table 1.1.
Table 1.1. Chemical reactions for different fuel and material com-
binations for bubble propulsion.
Fuel material reaction
H2 O2 Pt 2 H2 O2 −−→ 2 H2 O + O2
acid Zn 2 H+ (aq) + Zn(s) −−→ Zn2+ (aq) + H2 (g)
acid Mg Mg(s) + 2 H+ (aq) −−→ Mg2+ (aq) + H2 (g)
water Al 2 Al(s) + 6 H2 O(l) −−→ 2 Al(OH)3 (aq) + 3 H2 (g)
water Mg Mg + 2 H2 O −−→ Mg(OH)2 + H2 (g)
The speed of catalytic microrobots ranges from 100-1000 µm/s [Lu et al. (2016)]
which is very high as compared to the other microrobots. The speed of these mi-
crorobots increases with the increase in the frequency of gas bubble generation
and ejection due to the increase in the concentration of the fuel [Gao et al. (2011)].
However, the speed decreases with the decrease in the size of ejected bubble [Li
et al. (2016)]. The microrobot speed is almost equal to the product of ejected bub-
ble radius and frequency of bubble ejection [Solovev et al. (2009); Gao et al. (2011)].
Presence of surfactant also affects the speed of a bubble propelled microrobot. Ad-
dition of surfactant reduces the surface tension, and bubble radius but increases
the frequency of bubble generation. Manesh et al. [Manesh et al. (2010)] reported
a decrease in the speed of bubble propelled, tubular microrobot by addition of

Triton X-100 surfactant in H2 O2 fuel, whereas in contrast, Gao et al. [Gao et al.
(2011)] reported the increase in the speed by adding sodium cholate surfactant in
the H2 O2 fuel. Effect of physiological temperature on the speed is also reported
[Wu et al. (2013)]. Performance of microrobot in the presence and absence of salt in
the propulsion medium is reported [Manesh et al. (2010)]. Manesh et al. [Manesh
et al. (2010)] observed the bubble generation and microrobot speed in the salt-free
and salt reach (NaCl, up to 1 M) media and reported a small (1-3%) decrease in
the speed of microrobot in the latter condition. Two key requirements in a bub-
ble propelled microrobot to cause bubble ejection along a specific direction are [Lu
et al. (2016)]: (1) microrobot structure needs to be anisotropic (2) catalyst/reactant
should be located only at a portion and not on the overall microrobot. Pt and H2 O2
are one of the widely explored catalyst and fuel combination [Solovev et al. (2009);
Khalil et al. (2013); Wu et al. (2013); Wehner et al. (2016); Lu et al. (2016)] in the devel-
opment of bubble propelled microrobots. Lu et al. [Lu et al. (2016)] demonstrated
the autonomous, linear, and circular motion of a soft, catalytic (Pt) microrobot in
H2 O2 solution. Their microrobot was embedded with Pt/Fe nanoparticles. Pt shell
was exploited for the bubble generation and Fe core for magnetic navigation con-
trol using neodymium magnet with a field strength of 0.57 T, as shown in Fig. 1.5.
The speed observed was 300 µm/s in 8 wt % H2 O2 solution. As shown in Fig. 1.5.,
Figure 1.5. Pt/Fe NPs embedded soft catalytic microrobot. The top panel shows the schematic view,
and the bottom panel shows the experiment images. (a)Pick-up: the microrobot is propelled to the
cargo location under the influence of an external magnet. With a head-on collision, the cargo attached
to the microrobot. (b) Transport: the adhered cargo is transported to the target location. (c) Drop-off:
At the target location, the cargo is dropped-off with a flick in the external magnet. Reprinted with
permission from [Lu et al. (2016)]. Copyright (2016) American Chemical Society.
their microrobot was able to successfully pick-up, transport and drop-off a larger,
soft, inert cargo (without NPs) made with the same material. With a particular po-
larity of the external magnet, the microrobot was moved to the cargo location (Fig.
1.5.-a). Then microrobot and cargo were made to have a head-on collision and
due to soft nature cargo adhered to microrobot (Fig. 1.5.-b). Now the microrobot-
cargo system was moved to the targeted location by magnetic steering. There, by
a flick in the magnet, cargo got detached from the microrobot and dropped-off at
the destination (Fig. 1.5.-c). Bubble propelled microrobots based on the other com-
binations of the catalyst/reactant and fuel Mg + acid [Li et al. (2017); de Ávila et al.
(2017)], Zn + acid [Gao et al. (2015)], Al + water, Mg + water [Wu et al. (2015)]
have also been explored. Mg based soft microrobot propelled in the gastric acidic
fluid is tested by de Avila et al. [de Ávila et al. (2017)] to perform in vivo targeted
drug delivery in a mouse. Wu et al. [Wu et al. (2015)] reported, a first, of its kind,
cell mimicking (RBC coated) water-powered microrobot.
Use of enzymes instead of metallic catalyst in microrobots [Sanchez et al. (2010);
Orozco et al. (2012)] pave the way for designing biocompatible, bubble propelled
microrobots. Enzymes are biological catalysts. First effective use of enzymes (cata-
lase) as a catalyst in a bubble propelled, tubular microrobot is reported by Sanchez
et al. [Sanchez et al. (2010)]. Enzymes are useful in finding alternative fuels for
high-speed propulsion along with cutting down the threshold fuel concentration
required for the propulsion of bubble propelled microrobots. Wu et al. [Wu et al.
(2014)] showed the catalase could propel the microrobot even at a low concen-
tration of 0.1% of H2 O2 fuel. Catalase is among the most efficient enzymes. Each
catalase molecule can decompose millions of H2 O2 molecules in a second [Sanchez
et al. (2010)]. The microrobots with biocatalyst (catalase) are reported to be more
efficient than their metallic catalyst counterparts [Sanchez et al. (2010)]. Sanchez et
al. [Sanchez et al. (2010)] demonstrated a hybrid microrobot functionalized with
3-mercaptopropionic acid (3-MPA) propelling in H2 O2 solution with an average
speed of 226.1 ± 21.1 µm/s. They also observed the rotation of the microrobot due
to the bubble formed at the mouth of the tubular microrobot. This bubble for-
mation at the microrobot mouth can be used for the autonomous steering of the
tubular microrobot.
Bubble propelled microrobots can be controlled by using light [Solovev et al.
(2011)], ultrasound [Xu et al. (2014)], temperature [Sanchez et al. (2011)] etc. as
shown in Fig. 1.6. Solovev et al. [Solovev et al. (2011)] demonstrated the control on
propulsion of Ti/Cr/Pt catalytic microrobot by using white light. The illumination
of white light causes a local decrease in the H2 O2 fuel and surfactant concentration,
thus decreasing or switching off the bubble generation and thus the propulsion of
the microrobot. By using these external stimuli, the bubble propelled microrobot
can be switched on/off as well. Use of the UV spectrum is an effective method but
harmful to the living entities. There is also a chance that by exposure of the UV
spectrum, the microrobot material may dissolve. More researches are required on
the control of the bubble propelled microrobots.
(a) Reaction chamber Bubble

(b)
Fuel
(c)
Figure 1.6. (a) Schematic view of bubble propelled microrobot in the tubular shape. Showing the inlet
of fuel from front opening, then bubble production in the reaction chamber and ejection of the bubbles
from the rear opening. (b) Effect of ultrasound on the microrobot propulsion. Reprinted with permis-
sion from [Xu et al. (2014)]. Copyright, 2014, American Chemical Society. (c) Effect of temperature on
the acceleration of the microrobot. Reprinted with permission from [Sanchez et al. (2011)]. Copyright
2011, American Chemical Society.
1.2.3 Biological propulsion

Biological microswimmers have evolved over millions of years and developed ex-
cellent swimming capability in a low Reynolds number environment. These bio-
logical microswimmers propel themselves by using flagella (Fig. 1.7.(a)) and cilia
(Fig. 1.7.(b)) extended from their body and navigate by using senses and taxes.
Taxis is the motive response of microorganism towards the gradient of a stimulus.
Biological propulsion of microrobot is achieved by the aid of bio-microswimmers
like bacteria, algae, contractile cells integrated with the microrobots. These micro-
robots are termed as Biohybrid microrobots. A Biohybrid microrobot propelled
by attached bacteria is shown in Fig. 1.7.(c). The use of bio-microswimmers to
propel a microrobot is a very promising actuation method. It eliminates the need
of onboard synthetic propulsion mechanism and power source, thus, sophisticates
the microrobots for the bio-medical use. The bio-swimmer component of a Bio-
hybrid microrobot can also function as a biosensor and navigation controller. In
the Biohybrid microrobots, the bio-microswimmers can be integrated to the mi-
crorobot by free or fixed attachment. The freely attached bio-microswimmers can
be replaced at the end of their life span. Whereas this flexibility is not available
if the bio-microswimmers are fixed on the microrobots. As the whole microrobot
has to be changed after the fixed bio-microswimmers are dead. Escherichia Coli
(a) Microswimmer (b) Microswimmer
Flagella
Cilia
(c) (d)
(i) (ii) (iii)
Figure 1.7. Schematic view of bio-microswimmers. Showing Flagella (a) and Cilia (b). (c) Fluores-
cent image of a Biohybrid microrobot. Multiple bacteria (yellow-green) are attached to the spherical
polystyrene bead (red). Reprinted with permission from [Zhuang et al. (2015)]. Copyright (2015), Sci-
entific Reports, Nature Research. (d) An artificial magnetization of Tetrahymena pyriformis cell. (i)
Normal T. pyriformis cell. (ii) T. pyriformis cells with internalized iron oxide particles (magnetite) by
oral ingestion. (iii) After magnetization, the magnetite nanoparticles arranged in a line. The scale bar
is 10µm. Reprinted from [Kim et al. (2010)], with the permission of AIP Publishing.
(E. Coli) [Singh and Sitti (2016)], Serratia marcescens (S. marcescens) [Steager et al.
(2007); Kim et al. (2011); Steager et al. (2011); Zhuang et al. (2015); Zhuang and Sitti
(2016)], Salmonella typhimurium, Vibrio alginolyticus, Bacillus subtilis, Tetrahy-
mena pyriformis [Kim et al. (2010)], strains of magnetotactic bacteria (MTB): MC-1
[Shechter and Martel (2010)], AMB-1 [Khalil et al. (2013); Yu et al. (2015)], muscle
cells (myocytes), algae like Chlamydomonas reinhardtii [Weibel et al. (2005)] and
others can be used for the syntheses of a Biohybrid microrobot. The propulsion
of a Biohybrid microrobot is limited by the stochastic random walk nature of the
motion of bio-microswimmers [Kim et al. (2011)]. Therefore navigation control is
required and can be achieved by using external fields and taxes like chemotaxis
[Kim et al. (2011); Zhuang and Sitti (2016)], aerotaxis [Shechter and Martel (2010)],
magnetotaxis [Khalil et al. (2013); Yu et al. (2015)], phototaxis [Weibel et al. (2005);
Steager et al. (2007, 2011)], pH-taxis [Zhuang et al. (2015)], thermotaxis, galvano-
taxis etc.
Zhuang et al. [Zhuang et al. (2015)] demonstrated pH-taxis of Biohybrid micro-
robots (polystyrene bead attached with multiple S. marcescence bacteria). The mi-
crorobot is shown in Fig. 1.7.(c). They reported the propulsion behaviour of micro-
robots in three different types of pH gradients: gradient-1 (pH: 6.0-7.6), gradient-2
(pH: 3.8-5.4) and gradient-3 (pH: 8.2-9.8). For the gradient-1 system, they found a
bidirectional pH-taxis of microrobots, i.e. away from both strongly acidic and alka-
line regions. A dense band of microrobots was observed at optimal pH of slightly
more than 7.0. A unidirectional movement was observed for the gradient-2 and
gradient-3 systems, i.e. away from strong acidic and alkaline regions respectively.
They also reported the persistent orientation and higher speed of the microrobots
while moving towards the favorable pH region.
Weibel et al. [Weibel et al. (2005)] demonstrated steering of polystyrene bead
actuated by Chlamydomonas reinhardtii, using LED light with wavelengths λ ∼
500nm. At the high intensity of the light, cells showed negative phototaxis (move-
ment away from the light source) and positive phototaxis (movement towards
the light source) at low intensity of light. They also demonstrated the release
of microscale cargo using UV irradiation (λ = 365nm). Steager et al. [Steager
et al. (2011)] demonstrated the exposure of UV light on microrobot propelled by S.
marcescens reduces the rotational rate of the microrobot. Other taxis like Chemo-
taxis and Magnetotaxis are discussed below,
Chemotaxis: Chemotactic microrobots can be steered using chemoattractant or
chemorepellent. Microrobots move towards increasing concentration of a chemical
(positive chemotaxis) in the presence of a chemoattractant and move towards de-
creasing concentration of the chemical (negative chemotaxis) in the presence of a
chemorepellent. Chemoattractants like L-threonine [Kim et al. (2011)], L-aspartate
[Kim et al. (2012)], L-glutamate, glycine are favourable for attracting flagellated
bacteria [Kim et al. (2011)]. The first study of chemotaxis steering of S. marcescens
propelled Biohybrid microrobot is done by Kim et al. [Kim et al. (2011)]. They
investigated the chemotactic effects on the microrobots near the wall. Their micro-
robots exhibited positive chemotaxis with an increase of 64.2% in propulsion speed
as compared to the speed in the absence of any stimulus. The diffusion of the in-
jected chemical plays an important factor in chemotaxis. If the chemical diffuses
fast, then the concentration gradient can not be maintained for a long time, and
long-lasting steering is not possible. The chemical should be administered near to
the microrobot; otherwise, the concentration might be lower than that detectable
by the bio-actuator attached to the microrobot.
Magnetotaxis: Magnetic field used for navigation control of a synthetic micro-
robot is described in Sec. 1.2.1, can also be exploited for controlling of the Bio-
hybrid microrobots. The advantage of the magnetic field is that it can penetrate
in almost all environments without any physical contact. Magnetotactic bacteria
(MTB) posses chain of magnetosomes, which causes them to orient along the mag-
netic field lines as weak as the earth’s magnetic field and propel by the force of
flagellar rotation. Strains of MTB are used as actuators in the Biohybrid micro-
robots [Khalil et al. (2013)]. Yu et al. [Yu et al. (2015)] have demonstrated the con-
trolled steering of MTB, AMB-1 for delivery of magnetic microparticles as cargoes.
They showed the bacterium made a U-turn by reversing the direction of the mag-
netic field. The diameter of the U-turn trajectory was found to decrease with an
increase in the magnetic field strength. The bio-microswimmers can also be mag-
netized artificially to exploit external magnetic field, for navigation control of the
Biohybrid microrobots [Kim et al. (2010)]. Kim et al. [Kim et al. (2010)] prepared
artificially magnetized microswimmers. In their experiment, magnetite nanoparti-
cles of size 50nm were orally ingested by Tetrahymena pyriformis cells. A normal
T. pyriformis cell is shown in Fig. 1.7.(d(i)). After the magnetite nanoparticles

were ingested orally by the cells (Fig. 1.7.(d(ii))), the magnetite nanoparticles were
magnetized with the help of external magnetic field (Fig. 1.7.(d(iii))). Magnetized
cells could be steered using external magnetic fields. Another method of magnetic
steering control is using the magnetic property of the synthetic part of the micro-
robot. Carlsen et al. [Carlsen et al. (2014)] have demonstrated the magnetic steering
of super-paramagnetic bead actuated by Serratia Marcescens bacteria.
Bioswimmers propel by producing a range of propulsive force. Propulsive
force ranging from 0.5 pN for Escherichia coli and Serratia marcescens to 4 pN
for Magnetospirillum marine coccus (MC-1) have been observed [Carlsen and Sitti
(2014)]. Therefore the propulsive force required for a microrobot decides the min-
imum number of bio-microswimmers to be attached on it. For controlled naviga-
tion, the maximum torque exerted by the external field should be greater than the
propulsive torque produced by the cells, to control the orientation of the micro-
robot. Therefore, the maximum external torque that can be applied on the micro-
robot for navigation control limits the maximum number of bio-microswimmers in
a microrobot. The positions of the bio-microswimmers on a microrobot may also
affect the net propulsive force and the speed of a Biohybrid microrobot.
1.2.4 Self-Thermophoresis
Propulsion of a micro/nanoparticle along a temperature gradient in a fluidic en-
vironment is known as thermophoresis. Self-thermophoresis is different from the
usual thermophoresis in a sense that, in self-thermophoresis, the local tempera-
ture gradient is induced by the particle itself under an external stimulus. Micro-
robots can also be propelled by self-thermophoresis in a fluidic environment, as
shown in Fig. 1.1.(d). A unidirectional movement of the microrobot can be ob-
tained by generating an asymmetric temperature gradient across it. The asym-
metric temperature gradient can be created by using magnetic field [Baraban et al.
(2013)], ultrasonic waves, light irradiation [Jiang et al. (2010)] or by heat released
during a catalytic reaction [Qin et al. (2017)]. The propulsion mechanism by self-
thermophoresis lies in the imbalance of momentum transfer between the faces of
microrobot and the surrounding. As shown in Fig. 1.1.(d), due to the temperature
gradient across the Janus microrobot in a fluid, the collision between the right (yel-
low) face of microrobot and the surrounding molecules (blue particles) are stronger
as compared to the collisions of molecules at the other (left) face, which causes a
net thermophoretic force and propels the microrobot towards the left (away from
the yellow face).
Jiang et al. [Jiang et al. (2010)] measured the temperature distribution and the
thermal slip flow field around a Janus microparticle. They propelled Au-silica
Janus microparticle by self-thermophoresis using a defused laser beam. Their
Janus microrobot moved towards the colder region (positive Soret coefficient) in
water. They observed that the Janus microrobot moved towards the hotter region
(negative Soret coefficient) by adding surfactant Triton X-100 (0.05 wt%) to the so-
lution, which shows the change in the thermophoretic property of the microrobot
by absorption of the surfactant on the microrobot surface. They also showed rota-
tion of two, Au-silica microparticles system (diameter 1 µm each). The twin micro-
particle started rotating after a threshold laser power, and the rotational speed was
found to be increased linearly with the laser power.
The effect of Janus microrobot size on the propulsion is reported by Wu et al.
[Wu et al. (2016)]. Wu et al. found the large-sized microrobot produces more heat
than the smaller one, but smaller microrobot moves faster under the same laser
power. The reason behind such a phenomenon is the stronger temperature gradi-
ent across the smaller microrobot than that across the larger microrobot. Also,
at higher laser power, the thermophoretic force is higher, resulting in a higher
velocity of the microrobot [Lin et al. (2017)]. The other phoretic effects like self-
electrophoresis [Dong et al. (2015); Wong and Sen (2016); Kong et al. (2018)], self-
diffusiophoresis [Golestanian et al. (2005); Zhou et al. (2018)] are also explored for
the self-propulsion mechanism of a microrobot in a fluidic environment. The ad-
vantage of self-phoretic propulsion is that the state of motion (on/off) can be con-
trolled by switching the external stimuli source on/off.
1.3 Materials and Fabrication techniques
Material and fabrication technique depends upon the type of microrobot and its
application environment. Synthesis of a microscale robot is a major challenge,
especially for the biomedical applications. For the secure application in biolog-
ical mediums, the microrobot material needs to be biocompatible. For example
Polydimethylsiloxane (PDMS) [Carpi et al. (2007); Iacovacci et al. (2015)], Hydro-
gels [Iacovacci et al. (2015)], Polycarbonate (PC), IP-L [Tottori et al. (2012)], SU-8
polymer [Tottori et al. (2012); Tung et al. (2013)], Chitosan biopolymer [Wu et al.
(2013); Lu et al. (2016)], Sodium alginate (ALG) [Wu et al. (2013)] are widely used
in fabrication of microrobots for potential biomedical applications. Commercial
polydimethylsiloxane (PDMS): Dow Corning Sylgard-184 (Midland, MI) is bio-
compatible and has good stiffness for the use in bio-microrobot fabrication [Carpi
et al. (2007)]. Hydrogels are 3D networks comprised of chemically or physically
cross-linked hydrophilic polymer chains [Iacovacci et al. (2015)]. A hydrogel can
be cast into almost any shape, size or form and can absorb thousands of times their
dry weight of water. Hydrogel, based on agar and gelatin, is bio-compatible and
used for drug embedding [Iacovacci et al. (2015)]. Its compressive strength can
be varied by varying the composition of agar and gelatin [Iacovacci et al. (2015)].
For fabricating magnetically actuated or navigated microrobots, magnetically ac-
tive materials are used to make the microrobot responsive to the applied external
magnetic fields. For example SmCo5 [Honda et al. (1996)], Co [Ghosh and Fischer
(2009); Tung et al. (2013)] , Ni [Tung et al. (2013); Li et al. (2014)], Fe [Solovev et al.
(2009)] etc. are used to fabricate magnetically actuated/controlled microrobots.
In case of the biomedical applications, the microrobots have to be employed
in the difficult to reach and very delicate regions (like the central nervous system,
pancreas, heart, etc.) of the living body. Therefore, specific fabrication methods are
required to control the dimensions of the microrobots at sub-mm scale precisely.
Some widely used fabrication techniques for different types of microrobots are
1.3. Materials and Fabrication techniques 17
discussed below.
1.3.1 Tubular microrobots

The shape of the tubular microrobot is required to be anisotropic for the propulsion
in the low Reynolds number environment, as stated earlier in Sec. 1.2.2. The coni-
cal shape of the tubular microrobots has been reported with excellent performance
for the directional specific propulsion [Manesh et al. (2010)]. The propulsion speed
and steering of these microrobots also depend upon the diameter of opening and
length of the microrobot [Li et al. (2011)]. The outer surface of the microrobot is
generally made up of nonreactive, stable material and should reduce viscous drag
for efficient propulsion. The outer layer of tubular microrobots can also be func-
tionalized to perform specific tasks, as discussed in Sec. 1.4.3. For bubble propelled
tubular microrobots, the catalytic/reactive layer cannot be exposed to the working
fluid and fuel directly [Li et al. (2016)]. Rather used as the inner layer of the tubular
microrobot. Thus, the inner space serves as a reaction chamber and gas-collecting
cavity [Solovev et al. (2009)] for the controlled generation and ejection of the bub-
ble. The gas bubble moves towards the wider opening due to the Laplace pressure
difference and gets ejected from the wider opening of the tube. Microrobots having
a rocket like tubular shape are fabricated widely either by Rolled-up Technology
or by Template synthesis. The schematic view of the two techniques is shown in
Fig. 1.8. and discussed below.
1.3.1.1 Rolled-up technology

Rolled-up technology is a strain engineered fabrication method. It utilizes the
strain gradient of the different deposited layers for fabrication of a microtube. The
schematic view of the technique is shown in Fig. 1.8.(a). It consists of a substrate, a
sacrificial layer and then deposited layers of the materials, to be fabricated as a mi-
crotube. The sacrificial layer can be made up of a polymer (e.g., photoresist). Over
the sacrificial layer, the pre-stressed material layers are sequentially deposited by
any of the deposition methods e.g. dip-coating [Luchnikov et al. (2005)], e-beam
deposition [Solovev et al. (2009)], atomic layer deposition [Mei et al. (2008)] etc.
The outer most layer of a microrobot is deposited at the bottom (the first layer)
over the sacrificial layer, and the innermost layer of the microrobot is deposited
at the top (the last layer) over the sacrificial layer. In between these two layers,
other functional layers can be deposited, for example, a layer of Fe [Solovev et al.
(2009)] for magnetic steering of the microrobot. The material layers are removed
from the substrate by etching the sacrificial layer, which also rolls-up the layers
in a microtubular structure. Selective etching of the sacrificial layer is required to
avoid dissolution of the microrobot material itself. The diameter of the microrobot
depends upon the thickness of the deposited layers and the built-in strain gradi-
ent [Mei et al. (2008)]. The thickness of the layers can be controlled by controlling
the rate of deposition. Whereas the strain state of the deposited layers can be con-
trolled by [Mei et al. (2008)]:
(1) Difference in the thermal expansion: The thermal expansion of a layer depends
(a) Microtube (c)
Material 2
Material 1
Sacrificial layer
Substrate Substrate
(i) (ii)
(b)
(i)
(ii)
(iii)
Figure 1.8. (a) Fabrication of tubular microrobot by Rolled-up technology. (b) Fabrication of PANI/Pt
microtubes by template synthesis. Reprinted with permission from [Gao et al. (2011)]. Copyright
2011 American Chemical Society. (c) Fabrication of Au/Pt microrobot by simplified template method.
Reprinted with permission from [Manesh et al. (2010)]. Copyright 2010 American Chemical Society.
upon the thermal expansion coefficient (TEC). Therefore, by controlling the

difference in the thermal expansion coefficients (TEC) of the deposited layers
and substrate, the strain state of the layers can be controlled. This effect can
also be enhanced by using different temperature of the substrate for each layer
deposition.
(2) Deposition rate: Variation in the deposition rate may lead to the formation of
different grain size, which exerts different stress levels in the deposited layers.
Thus, the strain state can also be controlled by controlling the deposition rate
of the layers.
(3) Stress development during the deposition itself.
An extensive exploration of this fabrication technique is done by Mei et al. [Mei

et al. (2008)]. Their group has verified this fabrication technique by using var-
ious materials like metals, oxide layers and different depositing techniques like
e-beam evaporator, plasma immersion ion implantation & deposition (PIII&D)

method, atomic layer deposition (ALD). They also used different photoresist sac-
rificial layers like ARP-3510, PMMA (Poly Methyl Methacrylate), polydimethyl-
siloxane (PDMS) and hydrogel. For removing the sacrificial layer, they used ace-
tone, ethanol or isopropanol. A new mechanism of rolling by selective swelling
of the bottom layer of the deposited polymer or composite bilayer film is demon-
strated by Luchnikov et al. [Luchnikov et al. (2005)]. In their method, the lay-
ers bend due to the unequal changes in the specific volume of the layers. They
fabricated micro and nano-sized tubes with bilayer film of polystyrene (PS) and
poly(4-vinyl pyridine) (P4VP). Sanchez et al. [Sanchez et al. (2010)] demonstrated
a novel approach of fabricating high efficient biocatalytic tubular microrobot. Xi et
al. [Xi et al. (2013)] fabricated sharp-edged micro-drillers with Ti/Fe/Cr material
by Rolled-up technology. Nearly any type of inorganic layers can be deposited and
rolled-up to make tubular microrobots. The process consists of complex photo-
lithographic processes and also requires a clean room facility, which plays a factor
in the increased cost of the method.
1.3.1.2 Template synthesis

Template synthesis involves the deposition of materials inside a template. The
tubular microrobot can be fabricated by the layer by layer deposition of materials
inside the pores of a template. After that, the tubular microrobots can be obtained
by dissolution of the template. The diameter of the tube is determined by the diam-
eter of the pores in the template membranes. Gao et al. [Gao et al. (2011)] fabricated
polyaniline/Pt bilayer microrobot in double conical micropores of cyclopore poly-
carbonate (PC) membranes. The fabrication procedure is shown in Fig. 1.8.(b). The
fabrication steps followed by them, are: (i) First the deposited aniline monomers
were allowed to polymerize on the inner wall of the membrane, forming polyani-
line (PANI) film. (ii) Using the galvanostatic method Pt layer was plated inside
the PANI tube. (iii) The bilayer tube was obtained by the dissolution of the tem-
plate. Their microrobot exhibited a maximum speed of more than 3mm/s (i.e.
more than 375 bodylength/s) corresponding to 10% H2 O2 and 1.6% sodium cholate
solution. As compared to the smooth surface of a rolled-up microrobot, template
electrodeposition produces rough inner catalytic surface, which increases the ac-
tivity of the catalyst. For the same reason the required minimum concentration of
the H2 O2 fuel is reported as 0.2% for templated microrobot [Gao et al. (2011)] as
compared to 1.5% for rolled-up microrobot [Sanchez et al. (2010)]. Wu et al. [Wu
et al. (2013)] fabricated a tubular microrobot using biodegradable chitosan (CHI)
and sodium alginate (ALG). CHI and ALG were alternately absorbed into porous
polycarbonate membranes, and Pt nanoparticles were subsequently assembled in-
side the CHI/ALG nanotubes. The microrobots were obtained by dissolving the
PC templates in CH2 Cl2 . Manesh et al. [Manesh et al. (2010)] used a simplified
template synthesis to fabricate concave, conical Au/Pt microrobots using Ag wire
templates as shown in Fig. 1.8.(c). Ag wire was etched at evenly spaced segments
(for conical shape) using 30% HNO3 for 30 s. Pt was galvanostatically deposited
over the etched Ag wire, and Au was electrodeposited over Pt. Then these coated
wires were diced at the desired location. The Au/Pt microrobots were obtained by
dissolving Ag wire template in 25% (v/v) HNO3 for 5 min.
As compared to the Rolled-up technology, the cost of clean room requirement
can be eliminated by using the Template synthesis method. By eliminating strain
engineering (as in the Rolled-up method), the Template synthesis method also sim-
plifies the geometric consideration of the microrobot to the choice of porous tem-
plate and control on the thickness of the deposited layers.
1.3.2 Helical microrobots

The Helical microrobots propel by generating helical waves as discussed in Sec.
1.2.1(b). The Helical microrobot consists of a helical tail and a head attached to
it. These microrobots are also called artificial bacterial flagella (ABF). Under the
influence of an external rotating magnetic field, the helical tail of the microrobot
produces helical waves, which causes propulsion of the microrobot. The Heli-
cal microrobot can be fabricated by the template synthesis [Li et al. (2014)], self-
scrolling technology [Zhang et al. (2009)], glancing angle deposition (GLAD) [Brett
and Hawkeye (2008)].
Template synthesis method discussed for the fabrication of the tubular micro-
robots in the above Sec. 1.3.1.2 can also be used to fabricate helical microrobots.
It involves electrodeposition of different materials into cylindrical micro-pores of
the template membranes followed by the dissolution of the template. It is a fast
method, by which thousands of microrobots can be prepared in a few hours. The
diameter of the helix can be controlled by selecting the proper pore size of the
template membrane. Length of the helical tail can be controlled by charge den-
sity transported through electrodeposition [Li et al. (2014)]. The tailoring of helical
pitch can be done through controlling the composition of plating solution [Li et al.
(2014)]. Polycarbonate (PC) membranes are commercially available (110605 and
110607, Whatman, NJ, USA) with pore diameter ranging from 0.015 µm to 12 µm,
can be used as a template to fabricate helical tail of a microrobot [Li et al. (2014)].
Anodized aluminum oxide (AAO) available in the market (6809-6022, Whatman,
Maidstone, UK) can also be used as a template [Liu et al. (2011); Li et al. (2014)]. The
process flow of template synthesis of helical microrobot is schematically shown in
Fig. 1.9.(a).
Zhang et al. [Zhang et al. (2009)] fabricated helical microrobots by self-scrolling
technique. They fabricated two types of InGaAs/GaAs semiconductor bilayer and
InGaAs/GaAs/Cr hybrid semiconductor-metal trilayer tails attached with a soft
magnetic head made up of Cr/Ni/Au. The trilayer tail was fabricated as shown in
Fig.1.9.(b(i-vi)) and a field emission scanning electron microscopy (FESEM) im-
age of the untethered Helical microrobot is shown in Fig. 1.9.(b(vii)). The In-
GaAs/GaAs bilayer was epigrown by molecular beam epitaxy over AlGaAs sac-
rificial layer on GaAs (001) wafer substrate. Then Cr layer was deposited on the
bilayer by e-beam evaporation. The InGaAs/GaAs/Cr trilayer was patterned to
a ribbonlike mesa for making a helical tail, by reactive ion etching. Then the soft
magnetic head was prepared by e-beam evaporation of Cr/Ni/Au thin layers and
lift-off process. Finally, the AlGaAs sacrificial layer is selectively etched, by which
(a) (c) Vaccum chamber

(i) (ii)
Step motor
(iii)
(v) (iv)
rotation Substrate
(b) (i) (iv)
(ii) (v)
Atom stream
(iii) (vi)
Vapour source
(vii)
Figure 1.9. (a) Template synthesis of Pd, Helical microrobot in AAO template. (i) Deposition of gold.
(ii) Deposition of Pd/Cu. (iii) Dissolution of AAO template. (iv) Etching of copper from the Pd/Cu
micro-rods. (v) Magnetic nickel layer deposition on Pd micro-rods to make magnetically propelled,
Helical microrobots. Republished with permission of RSC publication copyright 2014, from [Li et al.
(2014)]; permission conveyed through Copyright Clearance Center, Inc. (b) Fabrication steps of trilayer
Helical microrobot by self-scrolling method (i)-(vi). FESEM image of an untethered Helical tail with a
soft magnetic head (vii). Reprinted from [Zhang et al. (2009)], with the permission of AIP Publishing.
(c) Schematic view of the GLAD method for fabrication of helical microrobot. The substrate is rotating
by a step motor and atoms are deposited obliquely on the substrate.
the ribbons, self-organized to form ABF. Then the ABF was untethered from the
substrate by micromanipulation: cut, pick, and release.
Another method of fabricating the helical microrobot is glancing angle deposi-
tion (GLAD) [Brett and Hawkeye (2008)]. In this method, the substrate is highly
tilted (i.e., away from the perpendicular to the stream of atoms) and materials are
deposited obliquely over the substrate, inside a vacuum chamber as shown in the
schematic view of the method in Fig. 1.9.(c). The atoms condense on the substrate
and continuous deposition of atoms results in the columnar structure, oriented
towards the vapor source. Ghosh and Fischer [Ghosh and Fischer (2009)] fabri-
cated one of the smallest artificial microrobot of width: 0.2-0.3 µm and length: 1-2
µm with SiO2 , using the GLAD technique. The helical tail can be grown by slow
continuous rotation (∼ 0.07rpm) of the substrate during the material deposition
[Ghosh and Fischer (2009)].
Some of the materials used for making helical tail are Ni − Ti [Mhanna et al.
(2014)], Cu [Honda et al. (1996)], SiO2 [Ghosh and Fischer (2009)], Pd [Liu et al.
(2011); Li et al. (2014)].
1.3.3 Flexible tail microrobot

The Flexible tail microrobots propel by generating planner waves as discussed ear-
lier in the Sec. 1.2.1(c). The main structural feature of a flexible tail microrobot is
its ultra-thin, flexible tail, as shown in the schematic Fig. 1.10.(a-iii,iv). The flexible
tail is generally attached to a magnetic head which can be made by using the mag-
netically active materials as discussed in the Sec. 1.3, to provide magnetic dipole
moment. The flexible tail produces planar waves under the influence of an oscil-
lating magnetic field, which results in the microrobot propulsion.
Electrospinning is the fabrication technique widely used for the fabrication of
the Flexible tail microrobot [Khalil et al. (2014, 2016a,b); El-Etriby et al. (2018)]. This
method is capable of fabricating ultrafine fibers with a diameter in the range of
micrometer to the nanometer. In the electrospinning process, a polymer solution
is pumped out from a syringe pump in a controlled rate and deposited on a collec-
tor. A strong electric potential difference generally 1-30 kV is created between the
needle of the syringe and the collector, which draws the solution to the collector
[Li and Xia (2004)]. The solution solidifies while traveling to the collector and gets
deposited on the collector. The main components of the Electrospinning appara-
tus are shown in Fig. 1.10.(a-i).The morphology and diameter of the electrospun
fiber depend on various parameters [Li and Xia (2004)] like the type of polymer,
concentration, the viscosity of the solution, electrical conductivity, surface tension
of solvent, distance between collector and needle, the strength of the electric field,
etc. The formation of beads occurs due to Rayleigh instability [Li and Xia (2004)].
After the solidification, the collected beaded fibers are cut and extracted by using
tweezers under high magnification [Khalil et al. (2016b)]. Khalil et al. [Khalil et al.
(2016a)] fabricated microrobotic sperm from polystyrene dissolved in dimethyl-
formamide and mixed with iron-oxide, as shown in Fig. 1.10.(a). The iron oxide
nanoparticles were contained in the beads of fibers, forming the magnetic head of
the microrobots.
Dreyfus et al. [Dreyfus et al. (2005)] fabricated a flexible tail microrobot made
up of superparamagnetic particles, as shown in the schematic of Fig. 1.10.(b). In
their study, the superparamagnetic particles were coated with streptavidin (red
cross symbols). The particles were attached by double-stranded DNA having bi-
otin at each end, via streptavidin-biotin interaction.
1.3.4 Janus microrobot

Microrobots having two regions with a distinct physical/chemical property at
the surface are known as Janus microrobots. Fig. 1.11.(a) shows some com-
mon shapes of Janus microrobots. Different groups fabricated various types of
Janus microrobots using different techniques. Wu et al. [Wu et al. (2016)] fab-
ricated Au functionalized PSS/PAH (poly(styrenesulfonate) and poly(allylamine
hydrochloride) Janus microrobots, demonstrating self-thermophoretic propulsion.
They used template assisted, layer by layer deposition method similar to as dis-
cussed in Sec. 1.3.1.2. In their study, five, bilayers of PSS/PAH were deposited on
spherical silica templates via electrostatic interaction. A Au layer was deposited by
(a)
i ii
iii iv
(b)
Figure 1.10. (a) Fabrication of magnetic micro-sperm by electrospinning method using polystyrene
dissolved in dimethylformamide and mixed with iron-oxide. (i) Use of syringe pump for the fabrication
of flexible tail. (ii) Collecting the microrobots formed by the electrospinning method, the iron-oxide
nanoparticles are contained in the heads of the microrobots. (iii) and (iv) The individual microrobots
with different tail lengths. Reprinted from [Khalil et al. (2016a)], with the permission of AIP Publishing.
(b) Artificial magnetic flagellum. Superparamagnetic particles coated with streptavidin (red cross) and
connected with DNA. Reprinted by permission from Springer Nature, Nature, [Dreyfus et al. (2005)]
2005.
sputtering over the half portion of the PSS/PAH particles (Fig. 1.11.(b-i)). The Au
functionalized ( PSS/PAH )5 microrobots were obtained by dissolution of the silica
template in hydrofluoric acid (Fig. 1.11.(b-ii)). The microrobots can be coated with
biological entities to protect them inside a biological environment. For example, a
coat of RBC membranes on a Janus microrobot prevents the protein fouling on the
microrobot [Wu et al. (2015)]. In this way, the effective working life of a microrobot
can be increased in an in vivo environment. De Avila et al. [de Ávila et al. (2017)]
fabricated Mg based Janus microparticles for propulsion in an acidic fluid. The
fabrication steps are depicted in Fig. 1.11.(c).
(a) Material-1 Material-2 (c) (i)
(b)
Sputter coating
Au (ii)
Core removal
(i) (ii)
Figure 1.11. (a) Janus micrororobots with different shapes. (b) Template fabrication of Au functional-
ized ( PSS/PAH )5 Janus microrobots. Reprinted by permission from Publisher: Springer Nature , Nano
Research, [Wu et al. (2016)], COPYRIGHT 2016. (c) Mg based microrobot for in vivo drug delivery. (i)
Schematic image of preperation steps of drug loaded Mg based microrobot. (ii) Schematic dissection
of the Mg based microrobot. Reprinted with permission from [de Ávila et al. (2017)]. Copyright 2017,
Springer Nature.
Other examples of microrobot fabrication are: Iacovacci et al. [Iacovacci et al.

(2015)] used 3D printed molds to caste a bi-component microrobot made with bio-
compatible PDMS material. Wehner et al. [Wehner et al. (2016)] fabricated a novel
soft octobot (Fig. 1.12.(a)) using moulding and embedded 3D (EMB3D) printing
technique. Ceylan et al. [Ceylan et al. (2019)] 3D printed a double helical, magneti-
cally propelled, biodegradabale microrobot for theranostic cargo delivery applica-
tions (Fig. 1.12.(b)). Lu et al. [Lu et al. (2016)] used a simple microfluidic tubing
(a) (b)
Figure 1.12. (a) Fully soft, autonomous robot, Octobot. Controlled via embedded micro-fluidic soft
controllers. Propelled by the bubble propulsion mechanism. Reprinted by permission from Springer
Nature, Nature, [Wehner et al. (2016)], COPYRIGHT 2016. (b) 3D printed biodegradable, double helical
microrobot. The microrobot propels by application of a rotating magnetic field (left) and releases the
embedded cargo in the presence of matrix metalloproteinase-2 (right). Reprinted with permission from
[Ceylan et al. (2019)]. Copyright 2019 American Chemical Society.
1.4. Bio-medical applications 25
approach for synthesizing soft microrobot as shown in Fig. 1.13. In their fabrication
Figure 1.13. Synthesis of bubble propelled, soft microrobots, using microfluidic tubing approach. (a)
The nanoparticle had magnetic (Fe) core and catalytic (Pt) shell. (b) The nanoparticles were dispersed in
the chitosan solution, and the solution was used as the inner disperse phase in a coflow tubing device,
with the continuous outer phase being oil. This microfluidic approach resulted in the formation of
droplets embedded with nanoparticles. (c) The droplets were collected in a petri dish. Photo 1 shows
the micrograph of the droplets. (d) Then neodymium magnet was used, to collect the nanoparticles at
the bottom of the droplets, as shown in Photo 2. Meanwhile, crosslinker GA converted the droplets into
patchy capsules. (e) Capsules collected in water. Photo 3 shows individual capsules with embedded
nanoparticles. Reprinted with permission from [Lu et al. (2016)]. Copyright 2016, American Chemical
Society.
process crosslinker glutaraldehyde (GA) was used for crosslinking of chitosan to

form soft capsules. These soft capsules encapsulate nanoparticles (NPs) made up
of Fe core and Pt shell. Fe provides magnetic responsiveness, and Pt provides cat-
alytic property. During crosslinking these NPs were collected at the bottom part of
the microrobot forming patches, by using neodymium magnets. These approaches
can be followed to synthesize other soft microrobots as well.
1.4 Bio-medical applications
The advancement in the microrobot fabrication and their bio-compatibility ad-

vanced the reach of biomedical science into the previously difficult to reach, in-
tricate parts of the human body. The sophistication of the robotic system to the
microscale have great potential to develop various applications down to the cel-
lular scale like targeted delivery [Tottori et al. (2012); Traverso et al. (2015); Iaco-
vacci et al. (2015); Lu et al. (2016); Wu et al. (2016); Tandon et al. (2016); de Ávila
et al. (2017); Le et al. (2018); Lee et al. (2018)], active diagnosis [Chisnariandini et al.
(2018); He et al. (2018); Ghosh et al. (2018)], minimally invasive surgery [Xi et al.
(2013); Breger et al. (2015); Soto et al. (2015); Yang et al. (2016)], bio-detoxification
[Wu et al. (2015); Kong et al. (2018); Villa et al. (2018)], tissue engineering [Liu and
Gartner (2012); Tasoglu et al. (2014)], cell manipulation [Lu et al. (2010)], isolation
of biological targets [Balasubramanian et al. (2011); Orozco et al. (2011); Kuralay
et al. (2012)]. The bare microrobot just with a propulsion mechanism can not be
employed for these applications readily. They need some mountings to execute
the desired medical applications like onboard sensors, drug loading, and delivery
mechanisms, surgical tools, computing and feedback components, etc. Some of
the biomedical applications are discussed here. We are classifying these biomedi-
cal applications into three categories of delivery, surgery, and sensing as discussed
below.
1.4.1 Delivery
Routes used for the current drug administration in the body are oral passage, skin
(transdermal), drug injection into blood, and inhalation. In these conventional
drug administration, the drug reaches the site of action by systematic circulation
within the body by blood and other bodily fluids. The current drug administra-
tion methods are the passive way of drug delivery, which does not have the self-
propulsion, controlled navigation, and tissue penetration is limited by the passive
mass transport. The efficacy of oral drug administration depends upon the gas-
trointestinal functioning and faces slow and irregular rate of absorption. In trans-
dermal drug administration, stratum corneum acts as a barrier for drug diffusion.
In case of inhalation, a unique device for the purpose is needed, that is not much
affordable. Whereas injection of drugs directly into the bloodstream increases the
drug concentration rapidly. The need to maximize the therapeutic efficacy only at
some desired location of the body and to reduce the side effects at the other body
parts, driven the need of Targeted Drug Delivery System (TDD). Microrobots pos-
sessing characteristics like self-propulsion, controlled navigation, cargo-towing,
tissue penetration and release of cargo, can be used for in situ delivery of drugs and
biological components like DNA, protein, etc. For example micro-needle [Traverso
et al. (2015)], micro-pump [Tandon et al. (2016)], micro-holder [Tottori et al. (2012)]
are getting attention for TDD system. TDD system allows the rapid transport of
high concentration drug to the diseased tissues directly and reducing the side ef-
fects on the other tissues and thus increasing the efficacy of the drug. Due to the
small size, TDD system has the potential use to release therapeutics in small diame-
ter canals like central nervous system (especially spine), urinary system, excretory
wirsung duct, and ovary, etc. In these regions, the issue of space constraint can
be addressed by providing external power source [Iacovacci et al. (2015)] or using
surrounding [Lu et al. (2016)] for the propulsion of TDD systems.
The first in vivo targeted drug delivery test to treat gastric bacterial (Helicobac-
ter pylori) infection in a mouse was performed by de Avila et al. [de Ávila et al.
(2017)], without any toxicological consequences. A schematic view of drug de-
livery by the microrobot is shown in Fig. 1.14.(a). In vitro tests on T24 human
urinary bladder carcinoma cells were successfully performed by Iacovacci et al.
[Iacovacci et al. (2015)]. Liposomes have greatly attracted researchers’ attention for
potential use in TDD systems [Mhanna et al. (2014); Le et al. (2018)]. Liposomes are
biocompatible and have potential to be used as a drug and bio-component carrier
[Torchilin (2005)]. Mhanna et al. [Mhanna et al. (2014)] used DOPE/DOTAP (1:3)
liposomes for drug encapsulation. They demonstrated in vitro, single cell (C2C12
mouse myoblasts) delivery of the calcein drug. The liposomes were adsorbed on
the surface of artificial bacterial flagella (ABF) and transported to the target loca-
tion by magnetic controlling.
(a) (b)
(i)
(ii)
Figure 1.14. (a) Schematic view of drug delivery in stomach by the bubble propelled microrobots (left)
and an individual microrobot (right). Reprinted with permission from [de Ávila et al. (2017)]. Copyright
2017, Springer Nature. (b) Schematic view of cargo pick-up, transport and drop-off by magnetically
propelled Helical microrobot attached with microholder head.
Iacovacci et al. [Iacovacci et al. (2015)] demonstrated in vitro controlled release

of drug at the target location by applying a compressive force on the drug-loaded
hydrogel. Helical microrobot having a micro-holder head can be used for drug
and cargo delivery [Tottori et al. (2012)]. In an external rotating magnetic field, the
micro-holder can be propelled to the cargo location (Fig. 1.14.(b-i)). The micro-
holder head can stably hold the cargo while transporting it via ’cork-screw’ mo-
tion. At the target location, the cargo can be dropped-off by merely reversing the
rotational direction of the external magnetic field, which enables the microrobot to
move in the backward direction (Fig. 1.14.(b-ii)).
Research has shown that the TDD system is more efficient than passive drug
delivery [de Ávila et al. (2017)]. The TDD system increases the drug efficacy by di-
rect drug supply to the diseased site, thus reducing the side effects and drug intake
frequency. The TDD system has the potential to achieve therapeutic applications
which are not possible by the existing passive delivery system.
1.4.2 Surgery
The microrobots have the potential capability to navigate through the narrowest
capillaries of the human body and can perform medical procedures down to the
cellular scale. The advancement in the minimally invasive surgery can be done
by scaling down the size of surgical tools to the micro length scale. The wire-
less controlling of surgical microrobot is essential for maneuverability and pre-
cise, noninvasive procedures in a confined space inside the body. The micro-
robots can provide a variety of the minimally invasive surgery to the biological
entities of micro length scale or even down in the line, with flexibility, precision,
and control. Microrobots like microgrippers [Breger et al. (2015)], micro-cannon
[Soto et al. (2015)], micro-drillers [Xi et al. (2013)] have been tested for their capa-
bility of minimally invasive surgery. Xi et al. [Xi et al. (2013)] fabricated rolled-up
micro-drillers and demonstrated ex vivo, drilling procedure on porcine liver tis-
sue, as shown in Fig. 1.15.(a). Breger et al. [Breger et al. (2015)] exploited the
swelling characteristic of a hydrogel to design a soft microgripper. They fabricated
a soft microgripper by sequential photolithography of swellable, soft hydrogel:
poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAM-AAc) and non-swellable,
stiff polymer: polypropylene fumarate (PPF). The microgripper was able to actu-
ate by swelling/deswelling by absorption/desorption of water in response to the
physiological temperature, as shown in Fig. 1.15.(b(i)). They showed that com-
bining the swellable, soft hydrogel with non-swellable, stiff polymer endows suf-
ficient strength to the microgripper to excise cells from a tissue clump as shown in
Figs.1.15.(b(ii, iii)).
The concept of “magic bullet” is envisioned for the supply of drugs deep into
the diseased tissue, in micro-length-scale, at a location not accessible by the con-
ventional medical methods. Soto et al. [Soto et al. (2015)] demonstrated the first use
of acoustically triggered micro-cannons to fire nano-bullets for microscale tissue
penetration of the therapeutic payloads, as shown in Fig. 1.15.(c). They fabricated
biocompatible micro-cannons encapsulating perfluorocarbon (PFC) emulsion with
silica nano-bullets. The use of focused ultrasonic pulse triggered the vaporization
of PFC, leading to rapid expulsion of the gas microbubbles from one opening of
the micro-cannon. The expulsion of microbubbles resulted in the rapid firing of the
nano-bullets and the displacement of the micro-cannons. The high-speed nano-
bullets were found to penetrate 17.5 ± 3.7µm in a tissue phantom gel target [Soto
et al. (2015)]. This kind of high speed, nano-bullet firing can be used for deep de-
livery of drugs into the diseased tissue and for delivering genetic material into cell
nuclei for gene therapy.
The posterior section of an eye is crowded with physiological barriers like vitre-
ous humor, optic nerve, retina, etc. These barriers cause difficulty to perform oph-
thalmic medical procedures. To treat the ophthalmic disease, the present medical
procedures like topical administration of drugs, intravitreal injection, laser surgery,
photodynamic therapy, etc. are used. These methods are limited with invasive-
ness, time consumption, and their efficacy only at the early stage of the disease.
Chatzipirpiridis et al. [Chatzipirpiridis et al. (2015)] have electroformed noninva-
sive surgical instruments for the ophthalmic applications: CoNi microtube, CoNi-
(a) i ii (b) i
ii iii
(c) i (d) i ii
ii
Figure 1.15. (a) SEM image of micro-driller (i) and drilled hole (ii), after removal of the micro-driller,
on porcine liver tissue. Reprinted with permission from [Xi et al. (2013)], copyright 2013, RSC. (b)
Microgripper fabricated with pNIPAM-AAc and PPF layers. (i) Schematic view shows microrobot re-
sponses to the physiological temperature. (ii) Capture and excision of cells from a live fibroblast clump.
(iii) Microgripper with the cell in its grip. The dashed lines show the microgripper and excised cell.
Reprinted with permission from [Breger et al. (2015)]. Copyright 2015 American Chemical Society. (c)
Microcannon with nano-bullets. (i) A schematic view showing microcannon composition before firing
(left) and during firing (right) of the nano-bullets. (ii) SEM image of microcannon loaded with nano-
bullets before firing (left) and unloaded, after firing (right). Scale bar, 20 µm. Reprinted with permission
from [Soto et al. (2015)]. Copyright, 2015, American Chemical Society. (d) Photothermal effect on Hella
cells by exposing Janus microrobot to the NIR irradiation. (i) Before and (ii) after irradiation. The red
colour indicates dead cells. Reprinted by permission from Nature Springer, Nano Research, [Wu et al.
(2016)], COPYRIGHT, 2016.
stainless steel microneedle. They have tested the magnetic maneuverability of the
CoNi microtube in the central vitreous humor of a living Lapine eye and ex vivo
porcine eye. They also performed vein puncture operation with microneedle in
the developing chicken embryo.
Stroke is a common disease behind death. Narrowing or blocking of arteries
causes the reduction in blood flow to the brain called Ischemic stroke. The Ischemic
stroke reduces or stops the oxygen supply to the brain tissues, which has fatal
consequences. The Ischemic stroke is primarily caused by the formation of blood
clots (thrombus) in the arteries to the brain. There are micro-stirrer to generate
scissor type vibration to dissolve thrombus [Yang et al. (2016)] and thus remove
clots with minimal invasion.
Wu et al. [Wu et al. (2016)] demonstrated in vitro targeted photothermal ther-
apy of HeLa cells in a cell media using self-thermophoretic Au-PSS/PAH Janus
microrobot, as shown in Fig. 1.15.(d). The positively charged poly(allylamine hy-
drochloride) (PAH) outer layer of the Janus microrobot attached to the negative
charged HeLa cells due to electrostatic attraction. After the attachment, high in-
tensity near infrared (NIR) irradiation was exposed to the sample, which reduced
the viability of the HeLa cells from 100% to 57%. Their demonstration implies the
combination of Janus microrobot and NIR irradiation can be used for precise ther-
mal therapy and effectively induce the apoptosis of tumor cells. The use of unteth-
ered, microrobots for surgical procedures is beneficial in decreasing the procedural
discomfort, sedation effect, and the post-procedure complications to a patient.
1.4.3 Sensing and Diagnosis

The modern class of biosensors includes bioaffinity sensors. These bioaffinity sen-
sors trigger specific signals after selective recognition of a specific target. The com-
mon bioaffinity sensors rely on the placing of the sample drops over the receptor.
The interaction between analyte and receptor is allowed over an incubation period
under a quiescent condition. After the end of this incubation period, the extent of
analyte-receptor interaction is measured for the assay of the analyte. This droplet-
based bioassay relies solely upon the diffusion transport [Wang (2016)]. Therefore
it is time-consuming and laborious. The bioaffinity interaction can also be used to
isolate a specific target from the unprocessed biological fluid. The isolation of a
biological entity is a challenging task due to the complexity of biological fluids.
The development of wireless, mobile, microrobots has potential application in
sensing, diagnosis, and bioanalytics. The capability of the microrobots does not
only include the efficient alternative of the current sensing procedures but also
involves the capability to sense in the previously inaccessible microscale parts of
the biological environment. The biosensing microrobots can have surface func-
tionalized with bioreceptor [Balasubramanian et al. (2011); Orozco et al. (2011)] or
can have built-in bioreceptor [Kuralay et al. (2012)]. The sensing capability of the
biosensors depends upon the specific interaction of the receptor with an analyte.
Upon interaction with the analyte, the receptor triggers signal which can be traced
and processed to get the qualitative and quantitative measures of the analyte. Mi-
crorobots have potential use in “on-the-fly” sensing, capturing and isolation of the
biological targets. The “on-the-fly” approach relies upon the continuous move-
ment of the receptor modified microrobot throughout the sample domain. The
continuous movement of the receptor turned microrobot enhances the receptor-
analyte interaction as compared to that in the quiescent condition. Specifically,
the continuous movement and long bubble tail generated during the propulsion
of the tubular microrobot are found to enhance the fluid convection and mixing
better than that by spherical Janus and other microrobots [Orozco et al. (2014a)].
The enhancement in the fluid convection and mixing accelerates the bioaffinity
interaction and thus the sensitivity and efficiency of the bioassay.
Microrobotic biosensors can capture and transport a specific biological target
to a clean zone for subsequent tests and analysis. The transportation of the specific
bio target requires optimal propulsion mechanism, direction control, and large
towing force of the microrobot in the complex biological fluid. For such pur-
pose bubble propelled, catalytic, tubular microrobots are widely tested [Orozco
et al. (2011); Balasubramanian et al. (2011); Kagan et al. (2011); Kuralay et al. (2012);
Restrepo-Pérez et al. (2014); Yu et al. (2014); Van Nguyen and Minteer (2015)]. The
reasons behind the popularity of these microrobots are the capability to tow with
large towing force and high propulsion speed, ranging between 100 − 1000µm/s
[Lu et al. (2016)] in complex fluid and high ionic strength solution. The bio-sensing
microrobots with towing capability can be used to detect and isolate the biologi-
cal components like DNA [Van Nguyen and Minteer (2015)], protein [Orozco et al.
(2011)], nucleic acid [Kagan et al. (2011)], cancer cells [Balasubramanian et al. (2011);
Yu et al. (2014)], bacteria [Campuzano et al. (2011)] etc. in a complex biological
fluid.
Figure 1.16. Schematic view of bubble propelled, tubular microrobot with built-in boronic acid. Path
(A) capturing of glucose, path (B) capturing of yeast cells and fructose-induced release of yeast cells.
Inset image shows a microrobot transporting multiple yeast cells. Reprinted with permission from
[Kuralay et al. (2012)]. Copyright 2012, American Chemical Society.
Nguyen and Minteer [Van Nguyen and Minteer (2015)] demonstrated a new
design strategy for “signal-on” detection of DNA target. Their catalytic, tubular
microrobot showed movement in the presence of DNA target only.
The circulating tumor cells (CTCs) are primarily responsible for spawning can-
cer metastasis. Detection of these CTCs provides diagnosis and prognosis of dif-
ferent kind of cancers [Balasubramanian et al. (2011)]. Carcinoembryonic antigen
(CEA) is the most common antigen present in the cancer cells like colorectal, pan-
creatic, gastric [Balasubramanian et al. (2011)]. Balasubramanian et al. [Balasub-
ramanian et al. (2011)] demonstrated in vitro isolation and transport of pancreatic
cancer cells (bearing CEA+ antigen) using bubble propelled tubular microrobot.
They functionalized the microrobot with an anti-CEA monoclonal antibody (mAb)
to selectively capture and transport the cancer cells. Selective capturing and trans-
portation of the tumor cells without preprocessing the biological sample has great
promise in the diagnosis of cancer and other diseases.
Kuralay et al. [Kuralay et al. (2012)] demonstrated “built-in” recognition,
capturing, transportation and release of glucose and yeast cell as shown in Fig.
1.16. They fabricated tubular microrobot with poly(3-aminophenylboronic acid)
(PAPBA) outer layer and Pt catalytic inner layer. The monosaccharide recognition
capability of the outer polymer layer of the microrobot was exploited to capture
the yeast cell (with sugar residues on their wall) and glucose.
Currently available flexible endoscopes and catheters provide invasive, visual

diagnosis of disease for a short duration of time with discomfort to the patients.
An alternative noninvasive, visual diagnosis of disease in the gastrointestinal tract
(GI) is facilitated by swallowable wireless endoscopy capsule (WEC) [Iddan et al.
(2000)]. The WEC capsules are functionalized with illumination, camera for im-
age/video capturing, and wireless data transmission. This pill-sized WEC cap-
sule provides accessibility to previously difficult to reach parts of the GI tract (e.g.,
small bowel). The commercially available wireless endoscopy capsule provides a
passive diagnosis as the operator can not control its position and orientation, and
it moves by gravity and the peristalsis of the GI tract. These WECs can be used for
active diagnosis purpose by controlling its position and orientation by integrating
magnetic control mechanism like magnetic rubber shell [Carpi et al. (2011)]. Sim-
ilar active control can also be used in the wireless capsules for real-time sensing
of pH, temperature, and pressure. The commercially available capsules are ap-
propriate in size for the GI tract, which, with further scaling down and controlled
navigation can be employed for the active diagnosis of the circulatory system, the
urinary system, and central nervous system. Use of microrobots for “on the fly”
sensing avoids the preprocessing of biological samples. Functionalization of the
microrobot with receptor requires additional fabrication steps and surface manip-
ulation.
Wu et al. [Wu et al. (2015)] demonstrated the camouflage of natural red blood
cells on Mg biocompatible Janus microrobot to attract, capture, and neutralize
the toxins in biological fluids. They reported an enhanced detoxification effi-
ciency of the microrobot attributed to the water-powered propulsion of the mi-
crorobot and anti-fouling property of the RBC membrane coating. Wu et al. [Wu
et al. (2015)] also reported the diverse detoxification potential of the RBC-Mg mi-
crorobot with nerve agent simulant, methyl-paraoxon in albumin solution. The
acetylcholinesterase present in the RBC membrane can absorb and remove, and
the water-powered propulsion resulted in improved speed of the decontamination
process.
1.5 Discussions and future scope
Although there exist several sophisticated microrobots, and many of them are cur-
rently used in practical applications, there are still many challenges to overcome in
the existing microrobots. The challenges include precise and safe locomotion and
targeting, minimizing the power consumption for sensing, locomotion, data trans-
fer, computation. The microrobot should not harm the tissues and organs, biocom-
patibility, robust operation in flowing against bloodstream, respiration, peristalsis,
etc. [Sitti et al. (2015)].
The use of a magnetic field for control and navigation of a microrobot is preva-
lent as wireless transmission of high force, and torque is possible with all 6 degrees
of freedom. Still, there are some limitations of the magnetic field, that needs to be
overcome. For example, the magnetic force decays exponentially with the distance
from the field source. Therefore, the use of high strength magnetic field is required
1.5. Discussions and future scope 33
to control the microrobot deep inside the human body. However, the use of max-
imum static magnetic field is limited to 2.5T and for a pregnant woman to 2T by
standard regulation, which limits the use of magnetic steering of a microrobot in-
side a human body. The equipments required to generate the magnetic field for
medical use of microrobot are generally bulky and costly. These bulky equipments
are required to be kept closer to the patient, which may reduce the maneuver-
ability of the operator and patient as well. The helical tail and flexible tail micro-
robots generate flow field during their propulsion. The flow field generated by the
propulsion of flexible tail is found to influence the accuracy of positioning of the
payload [El-Etriby et al. (2018)]. Therefore, further studies are required for charac-
terizing the frequency dependent flow field for flexible tail as well as for helical tail
microrobots. Research shows that gradient pulling is efficient than propulsion of
helical propeller, but when limitations of the magnetic field and it’s generation are
considered then, the helical propeller is far better than the gradient pulling [Abbott
et al. (2009)].
Bubble propulsion is not suitable for in vivo applications. As H2 O2 is the main
fuel for the bubble propelled microrobots, is unable to find in vivo application as
H2 O2 is not a bio-compatible fuel. The self-propulsion of a bubble propelled mi-
crorobot is limited by the availability of fuel. It can only be propelled until the fuel
lasts. The propulsion of catalytic microrobot is limited to low ionic strength fluids
only [Manesh et al. (2010)]. There is a requirement of finding alternative fuels and
corresponding catalytic materials and reactions. It would be beneficial if in situ
fluid can be used as the fuel. Water and acids are readily present in a biological
media; therefore, these can be used as an in situ fuel. Materials like Mg, Al, Zn
based catalytic microrobots propel by depleting proton in an acidic medium. So
they can be readily used in an acidic environment without any external fuel in-
jection. Also, these microrobots can be used for measuring the pH of the fluid
domain. However, on the other hand, the reactive material like Mg, Zn, etc. used
in the microrobots dissolve in the working biological fluid; therefore their working
life is very short and can not be used for long time operations. The use of enzymes
to decompose the fuel is also an alternative way to replace the metal catalyst from
the microrobot, to make it more efficient and biocompatible for the medical appli-
cations [Sanchez et al. (2010); Orozco et al. (2012)].
Electro-phoretic propulsion is a good alternative for chemical free, bubble free
directional propulsion of a microrobot [Dong et al. (2015)]. However, the propul-
sion mechanism of the phoretic effect is not clearly understood [Zhou et al. (2018)].
Biohybrid system faces a challenge to maintain the viability of the living cells at-
tached to the microrobots. The biocompatibility and proper adherence of the syn-
thetic part to the bio-microswimmers are an essential requirement. In the case of
taxis of a microrobot, maintaining a driving gradient of the external stimuli near
the microrobot in a fluidic environment is a tough task to achieve.
Biodegradability and biocompatibility of the microrobot materials are chal-
lenges for their potential use in the medical field. If the material is biodegrad-
able, then the microrobot can dissolve in the biological media and disappear after
completion of the operation. However, if the material is non-biodegradable, then
the retrieving of the microrobot after the completion of the operation is necessary
and is a major challenge. The biological environment inside a human body is very
crowded; therefore, precise control on a microrobot is required. The microrobot
components should be soft and deformable so that they do not cause any injury to
the components inside the body. Rigid and hard micro/nanorobots are generally
non-biodegradable and can also cause problems like rupture of the blood vessels
and tissue injury inside the body. Soft materials like synthetic polymer, and plant
tissues have potential use in the fabrication of a soft and biocompatible microrobot.
Also, the coupling of the natural biological material with the synthetic microrobots
reduces the immune evasion and biofouling effects of the biological environment,
thus maintaining the efficiency and longer working life of a microrobot.
Swimming against the dynamic blood flow is challenging with limited power.
Consistent power source for continued operation is still a milestone to be achieved.
On the other hand, the targeted drug delivery system is challenged by the low
controllability on the release rate of the therapeutics.
Now it is possible to control a microrobot with a wireless remote or just by
the mouse of a workstation [Carpi et al. (2011)]. Challenge for future generation
miniaturized robots are to perform collective swarming and task completion by
interacting with the other microrobots. Future microrobot will mimic the natu-
ral intelligence of their biological counterpart with the adaptable and sustainable
operation, group behavior with swarm intelligence. In future microrobot will be
able to perform any task in coordination with thousands of other microrobots in a
swarm. This collective dynamics of microrobots is required to treat any large size
body parts, to deliver a large quantity of therapeutic to a target location, and to re-
duce the overall operation time. This kind of group communication and coordina-
tion is challenging, which needs to be overcome by future microrobots. Though the
collective dynamics of the microrobots and microswimmers [Sokolov et al. (2009);
Koch and Subramanian (2011); Molina et al. (2013); Mahapatra and Mathew (2019)]
is an active research area, further studies are required to understand the behavior
of the microswimmers both theoretically and experimentally.
New researches on the microrobots would lead to the evolution of the thera-
pies and applications that are not yet conceived. For example, Janus microrobots
can be coated with stem cell membranes for cancer cell recognition for targeted
photothermal therapy [Wu et al. (2016)]. The development of microrobots for the
medical applications will find its way from the lab to the real working environment
if the safety of the patient is insured. It needs to be shown that the microrobots can
work in a dynamic environment inside the human body reliably and robustly.
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Micro-Robots/Microswimmers for Biomedical Applications

Chapter · August 2020

Naveen Kumar Agrawal Pallab Sinha Mahapatra

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Tuhin Subhra Santra

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Micro-robots/swimmers for bio-medical

Naveen Kumar Agrawal, Pallab Sinha Mahapatra

Tuhin Subhra Santra

Corresponding author, Email: pallab@iitm.ac.in

The microfluidic platforms, lab-on-a-chip devices and micro-swimmers of dif-

Pan Stanford Publishing: Microfluidics and Bio-MEMS: Devices and Applications

2 Micro-robots/swimmers for bio-medical applications

The advancement in the technology of micro-actuation, micro-controlling, micro-

(1) Based upon the size of the robot:

1.2. Propulsion mechanism 3

1.2 Propulsion mechanism

The propulsion mechanism of a robot in a fluid is far different in microscale than

4 Micro-robots/swimmers for bio-medical applications

is governed by the Stokes equations as given by the following Eqs.

Fnet = Fresistance + Fpropulsion (1.4)

1.2.1 Magnetic propulsion

1.2. Propulsion mechanism 5

and the magnetic torque is given by [Abbott et al. (2009)]:

6 Micro-robots/swimmers for bio-medical applications

1.2. Propulsion mechanism 7

(2013)]. The microrobots were distinct in design, resulted in individual control of

8 Micro-robots/swimmers for bio-medical applications

quency up to a step-out frequency, beyond which the swimming velocity decreases

1.2. Propulsion mechanism 9

1.2.2 Bubble propulsion

10 Micro-robots/swimmers for bio-medical applications

a decrease in the speed of bubble propelled, tubular microrobot by addition of

1.2. Propulsion mechanism 11

12 Micro-robots/swimmers for bio-medical applications

(a) Reaction chamber Bubble

1.2.3 Biological propulsion

1.2. Propulsion mechanism 13

(a) Microswimmer (b) Microswimmer

14 Micro-robots/swimmers for bio-medical applications

1.2. Propulsion mechanism 15

T. pyriformis cell is shown in Fig. 1.7.(d(i)). After the magnetite nanoparticles

16 Micro-robots/swimmers for bio-medical applications

1.3 Materials and Fabrication techniques

1.3. Materials and Fabrication techniques 17

1.3.1 Tubular microrobots

1.3.1.1 Rolled-up technology

18 Micro-robots/swimmers for bio-medical applications

(a) Microtube (c)

upon the thermal expansion coefficient (TEC). Therefore, by controlling the

An extensive exploration of this fabrication technique is done by Mei et al. [Mei

1.3. Materials and Fabrication techniques 19

e-beam evaporator, plasma immersion ion implantation & deposition (PIII&D)

1.3.1.2 Template synthesis

20 Micro-robots/swimmers for bio-medical applications

1.3.2 Helical microrobots

1.3. Materials and Fabrication techniques 21

(a) (c) Vaccum chamber

(b) (i) (iv)

22 Micro-robots/swimmers for bio-medical applications

1.3.3 Flexible tail microrobot