Electrodes for Nerve Recording and

Stimulation

Jing-Quan Liu, Hong-Chang Tian, Xiao-Yang Kang, and

Ming-Hao Wang

Abstract
With the rapid development of MEMS fabrication technologies, versatile micro-
electrodes with different structures and functions have been designed and fabri-
cated. The flexible MEMS microelectrodes exhibit multiaspect excellent
characteristics compared to stiff microelectrodes based on silicon or SU-8,
which comprising: lighter weight, smaller volume, better conforming to neural
tissue, and lower fabrication cost.
This chapter mainly reviewed key technologies on flexible MEMS microelec-
trodes for neural interface in recent years, including: design and fabrication
technology, fluidic channels, μLEDs, and electrode-tissue interface modification
technology for performance improvement. Furthermore, the future directions of
flexible MEMS microelectrodes were described including transparent and
stretchable microelectrodes with characteristics of multifunction, high-density,
biodegradation, and next-generation electrode-tissue interface modifications
facilitated electrode efficacy and implantation safety.
The goal of this chapter is to provide the reader a broader overview of flexible
MEMS technologies that can be applied together to solve problems in neural
interface.

Keywords
MEMS • Microelectrodes • Neural Interface • Conducting Polymer •
Nanotechnology

Contents
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Flexible Microelectrodes for Recording and Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

J.-Q. Liu (*) • H.-C. Tian • X.-Y. Kang • M.-H. Wang

Shanghai Jiao Tong University, Shanghai, China
e-mail: jqliu@sjtu.edu.cn; hchtian@sjtu.edu.cn; xykang@sjtu.edu.cn; M.H.Wang89@sjtu.edu.cn

# Springer Nature Singapore Pte Ltd. 2017 1

Q.-A. Huang (ed.), Micro Electro Mechanical Systems, Micro/Nano Technologies,
https://doi.org/10.1007/978-981-10-2798-7_43-1
2 J.-Q. Liu et al.

Materials for Flexible Microelectrodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Research Progress of Flexible Microelectrodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Flexible Microelectrodes for Neural Interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Flexible Microelectrodes with Fluidic Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Flexible MEMS Microelectrodes with μLEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Research Progress of Materials for Flexible Microelectrodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Future Development Prospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Background

The typical configuration of implantable artificial nerve system is illustrated in Fig. 1.

As the tissue-machine interface, the MEMS microelectrodes are interconnected with
the biological tissue through the implantable devices, which can transmit electrophys-
iological signals and coordinate brain, nerve, and muscle orderly. Therefore, the
MEMS microelectrodes play an important role in the overall efficiency of whole
nerve system.
With the rapid development of microfabrication technologies, tiny biomedical
devices with diverse structures can be manufactured, which can minimize the tissue
damage during and after implantation for both short-term and long-term requirement
(Receveur et al. 2007; Hong et al. 2014). Nowadays, some dense electrode arrays
and tenuous electrodes are developed to perform the complex and precise electro-
physiological study, which can provide excellent spatial selectivity and low power
consumption (Kim et al. 2009; Kozai et al. 2012). Even though these electrodes with
smaller size.
could reduce the damage to the tissue, it would inevitably weaken the perfor-
mance and safety of the electrodes (Grill et al. 2009). That is because as the size of
electrode decrease, its impedance will increase accordingly that induce the drop in
charge storage capacity (CSC). As a result, it will generate the poor recording signal
and require high current density for stimulation that may damage the tissue. Under
this circumstance, the interface materials play a significant role in improving the
electrode performance. The ideal materials for electrode-tissue interface should have
several properties. First, it should be with electrical property containing low imped-
ance, high CSC, and high charge injection limit. The electrode impedance contrib-
utes noise, and higher impedance electrodes are expected to have a lower signal-to-
noise ratio. In addition, high electrode impedance in combination with the distrib-
uted capacitance between the electrode and the recording amplifier will reduce the
electrodes’ high-frequency response. Second, it can stabilize for long-term working
after implantation without significant property variation. The stability of microelec-
trodes is important because possible irreversible or harmful electrochemical reac-
tions that might occur during stimulation and glial coatings are always accompanied
by the chronic implantations. Third, it should be biocompatible with tissue without
inducing severe tissue response, toxicity, or even necrosis. Figure 2 shows the
characteristics for ideal implantable electrode-tissue interface.
Electrodes for Nerve Recording and Stimulation 3

Fig. 1 Structural illustration of implantable artificial nerve system

Fig. 2 Characteristics of
ideal implantable electrode-
tissue interface
4 J.-Q. Liu et al.

Flexible Microelectrodes for Recording and Stimulation

One of the most important components for artificial prostheses is the microelectrodes
acting as tissue-machine interface (Cogan 2008; Yoshida et al. 2010; Ortiz-Catalan
et al. 2012). To better functionalize in living muscle and nerve tissue, the biomedical
microelectrodes should meet the following requirements: (1) small dimensions that
reduce the tissue damage, (2) excellent performances that ensure the effective
operation of the prostheses device, and (3) good biocompatibility that enables
relatively long-term implantation without inducing severe immune response.
Based on these requirements, various microelectrodes have been developed to
perform electrical stimulation and electrophysiological signal recording for paralysis
recovery after spinal cord injury. Among these electrodes, neural probes made by
University of Michigan and electrodes array made by University of Utah were
widely used in central nerve prostheses applications (Hochberg et al. 2006; Wise
et al. 2008), while longitudinal intrafascicular (LIFEs) electrodes were commonly
applied in peripheral nerve and intramuscular studies (Yoshida et al. 2010; Farina et
al. 2008). LIFEs offer a means of interfacing to restricted subsets of axons within
fasciculated peripheral nerves and they are constructed from thin insulated
conducting wires, such as Pt-Ir or metallized Kevlar fibers (Navarro et al. 2005).
Cuff electrodes are composed of an insulating tubular sheath that completely encir-
cles the nerve and contains two or more electrode contacts exposed at their inner
surface that are connected to insulated lead wires. Cuff electrodes are extraneural
electrodes which can provide simultaneous interface with many axons in the nerve,
whereas intrafascicular and sieve electrodes inserted in the nerve may interface small
groups of axons within a nerve fascicle.
There is a significant symptom if only the electrical interaction between elec-
trodes and muscle/nerve tissue were performed without nutrition factor delivery that
would eventually lead to denervation-induced skeletal muscle atrophy (Mitch and
Goldberg 1996; Thomas et al. 1997; Midrio 2006). In recent years, the microelec-
trodes integrated with microchannels for fluidic drug delivery were developed to
solve this problem (Jessin et al. 2011; Altuna et al. 2013; Pongrácz et al. 2013).
Moreover, microfluidic neural interfaces hold immense potential for basic neurosci-
ence research and clinical medicine (Jeong et al. 2015). In vivo neuropharmacology
enables delivery of pharmacological agents deep into the brain to help dissect
complex neural circuits and neurotransmitter/receptor systems (Anthony et al.
2014) and treat neurodegenerative diseases and brain tumors. However, most studies
focused on stiff electrodes made of silicon or SU-8 for applications on central nerve
system, only a few flexible electrodes made of parylene, polyimide (PI), and
polydimethylsiloxane (PDMS) were proposed (Metz et al. 2004; Takeuchi et al.
2005; Gao et al. 2013). And, the problem which limits the precise stimulation with
the polymer-based flexible electrodes mentioned above is the electrode sites distrib-
uted on one side of the electrode only. Moreover, most of the microelectrodes
mentioned above were developed for neural applications, and few electrodes were
designed for intramuscular research. Recently, the microelectrodes for intramuscular
electrical stimulation and electromyogram (EMG) recording were generally
Electrodes for Nerve Recording and Stimulation 5

restricted to crude wire electrodes with simple construction and single function (Jarc
et al. 2013; Memberg et al. 2014). For the current situations, it is necessary to design
and fabricate the multifunctional microelectrodes with circumferential distributed
electrode sites for intramuscular prostheses. However, its limitations such as
unpredictable current pathways, electrical artifacts, and nonselectivity of the target
neurons increase the demands for a new technology. Direct optical stimulation of
neural cells in the brain tissue, genetically modified by expressing channelr-
hodopsin-2 (ChR2), has drawn much attention over the past few years. This tech-
nique, called optogenetics, can target specific types of neurons with submillisecond
temporal precision. For in vitro and head-fixed in vivo applications, numerous
optical stimulation systems have been reported such as a laser-coupled optical
fiber (Zhang et al. 2007), light-emitting diodes (LEDs), band-filtered white light,
and a focused laser beam through a microscope (Hira et al. 2009). For experiments
with freely behaving subjects, however, only limited light delivery methods such as
a laser-coupled optical fiber and a head-mountable single LED system (Iwai et al.
2011) are available because the tethered optical fiber restricts a natural behavior of
the subjects.

Materials for Flexible Microelectrodes

In order to enhance the electrode performance of implantable MEMS microelec-

trodes, the ideal materials for implantable electrode-tissue interface should satisfy
requirements of excellent electrochemical performance, high stability, and well
biocompatibility. For neural stimulation electrodes, possible irreversible or harmful
electrochemical reactions might occur during stimulation. In vivo studies have
identified Pt dissolution (Robblee et al. 1983) and iridium oxide delamination
(Cogan et al. 2004) as electrode degradation processes. Thus, the materials for
stimulation electrodes should be stable without corrosion under in vivo implantation.
In general, electrodes used in neural stimulation can be divided into two categories.
Macroelectrodes exhibit high CSC and low charge density; they are typically placed
on the surface of the target tissue and have a GSA larger than approximately
100,000 μm2. Microelectrodes have the opposite behavior, exhibiting low CSC
and high charge density. Microelectrodes typically penetrate the target and have
surface areas that are smaller than approximately 10,000 μm2. An obvious advantage
of microelectrodes is the ability to stimulate a comparatively small volume of tissue,
which should, with a sufficient number of electrodes, improve the selectivity and
spatial resolution of functional responses. For neural recording electrodes, action
potentials are recorded in close proximity to the target neurons, and, for single-unit
recording, the microelectrode GSA should be no larger than approximately
2000–4000 μm2. The objective with single-unit neural recording is to measure action
potentials with a useful signal-to-noise ratio, 3:1 or greater, and to do this chron-
ically. The amplitude of action potentials in the CNS can be quite large, more than
500 μV, but is more typically on the order of 100 μV, and often is smaller. In general,
the majority of the noise signal encountered in single-unit recording arises from the
6 J.-Q. Liu et al.

multitude of undifferentiated background action potentials (neural noise). However,

electrode impedance does contribute noise, and higher impedance electrodes are
expected to have a lower signal-to-noise ratio. Thus, the materials for recording
electrodes should have low impedance.
Even though various materials for electrode-tissue interface have been developed,
the most widely used materials remain noble metals, such as platinum, gold, iridium,
tungsten, and their alloys. These metals are chosen to be the materials for electrode-
tissue interface due to their excellent chemical stability without serious erosion after
implantation. However, the electrochemical performance of MEMS microelectrodes
are restricted mostly by their high electrochemical impedance and low CSC of bare
metallic electrode-tissue interface. Some electrode-tissue interfaces were processed
with porous structure in a special profile to form a rough surface, which would
consequently improve the effective surface area of electrode sites. In recent years,
emerging carbon nanomaterials, such as carbon nanotubes and grapheme, etc., act as
electrode-tissue interface to improve MEMS microelectrode performance for their
multiaspect excellent properties. Although the carbon nanomaterials possess the
advantages of extremely large specific area and excellent electrochemical perfor-
mance, they have the poor bonding with electrode substrate and may induce nano-
toxicity by litters in tissue that will highly limit their applications.
Conducting polymers have attracted much attention and broadly applied in
different biomedical research due to their unique characteristics of low electrochem-
ical impedance, high CSC, favorable plasticity, electrostriction, and biocompatibil-
ity. Meanwhile, conducting polymers are capable to meet the requirements of
materials for electro-tissue interface. In addition, conducting polymers also possess
the other characteristics, including modification through doping, electrically con-
trolled drug releasing, molding through micro-nano processing and electro-spinning,
and surface modification by biochemical molecules, as shown in Fig. 3 (Vallejo-
Giraldo and Biggs 2014). As two kinds of conducting polymers that are widely used
as electrode-tissue interface, poly (3,4-ethylenedioxythiophene) (PEDOT) exhibits
better performance than polypyrrole (PPy) in terms of electrical stimulation (better
electrochemical performance) and cell culture (longer neurites growth) (Vallejo-
Giraldo and Biggs 2014).

Research Progress of Flexible Microelectrodes

Flexible Microelectrodes for Neural Interface

With the rapid development of MEMS fabrication technologies, researchers have

developed various kinds of biomedical microelectrodes applied on electrical stimu-
lation and electrophysiological signal recording for paralysis recovery. Among these
microelectrodes, neural probes University of Michigan and electrodes array made by
University of Utah are widely utilized in central nerve system studies as stiff MEMS
microelectrodes for neural prosthesis (Hochberg et al. 2006; Wise et al. 2008). Many
Electrodes for Nerve Recording and Stimulation 7

Fig. 3 Schematic illustration of characteristics of conducting polymers (Vallejo-Giraldo and Biggs 2014)

research efforts have been devoted to developing novel flexible MEMS microelec-
trodes due to their excellent characteristics compared with stiff microelectrodes, such
as lighter weight, smaller volume, better conforming to neural tissue, and lower
fabrication cost (Kozai et al. 2012; Ferguson et al. 2009; Kim et al. 2010; Rui et al.
2011). Owning to these advantages, the flexible MEMS microelectrodes for neural
interface have attracted extensive attentions and considered to have broad prospects
in future. As described below, the flexible MEMS microelectrodes can be classified
into three types: wire electrode, thin film electrode, and mesh electrode. As shown in
Table 1, the comparison results of different kinds of the flexible MEMS microelec-
trodes for neural interface are discussed in this chapter.
John E. Ferguson and A. David Redish et al. from University of Minnesota
developed a tetrode made from four microwire electrodes for neural signal recording
on living animals in 2009 (Ferguson et al. 2009). As shown in Fig. 4a, the tetrode
was composed of four Ni-Cr alloy microwires with diameter of 12.7 μm, which are
coated with polyimide as insulation on the surface. The microwire electrodes were
cut to expose the cross section as electrode sites, and the electrode sites were
electrodeposited with gold to improve their electrochemical performance. The
microwire electrode was easy to be fabricated, and the electrode with micro-
dimension was suitable for cortical implantation with little tissue damage. However,
the microwire electrode was inconvenient to be implanted into target position at deep
brain area precisely.
8 J.-Q. Liu et al.

Table 1 Flexible MEMS microelectrodes for neural interface

Materials Dimension of Fluidic
Type Conduction Insulation electrode site channels References
Wire Ni/Cr Polyimide 12.7 μm of Without Ferguson et al.
electrode diameter (2009)
Mesh Au Polyimide/ 500 μm  500 μm Without Kim et al. (2010)
electrode fibroin
Wire Carbon Poly-p- 7 μm of diameter Without Kozai et al.
electrode xylene (2012)
Thin film Pt Parylene 50 μm of diameter Without Rui et al. (2011)
electrode
Wire Pt Parylene 100 μm of Without Rui et al. (2012)
electrode diameter
Thin film Pt Polyimide 50 μm  50 μm With Metz et al.
electrode (2004)
Thin film Au Parylene 40 μm  40 μm With Ziegler and
electrode Takeuchi (2006)
Thin film Pt PDMS/ – With Gao et al. (2013)
electrode polyimide
Wire Au Parylene/ 100 μm of With Tian et al.
electrode Teflon diameter (2014a)

Dae-Hyeong Kim and John A. Rogers et al. from University of Illinois at Urbana-
Champaign developed a thin film microelectrode array based on polyimide for
electrocorticogram (ECoG) recording in 2010. The microelectrode array was
reinforced by silk fibroin, which functioned as biodegradable substrate, to improve
the conformal attachment on the brain tissue surface (Kim et al. 2010). As displayed
in Fig. 4b, the thickness of 5  6 grid-like thin film microelectrode array was
approximately 2.5 μm, and the area of the electrode site was 500 μm  500 μm.
In addition, as shown in Fig. 4b, the thin film microelectrode array could be attached
on the sphere surface tightly, when the silk fibroin dissolved. The biodegradable
surface coating with silk fibroin facilitated the conformal cover of the mesh electrode
on the rough surface of brain. Moreover, the mesh electrode could be fabricated
thinner and the electrode sites could be designed smaller to further improve the
conformal attachment on brain and accuracy of neural recording.
Takashi D. Yoshida Kozai, Nicholas A. Kotov, and Daryl R. Kipke et al. from
University of Michigan developed composite fiber electrodes consisting of carbon
fiber core and poly-p-xylene insulation coating in 2012 (Kozai et al. 2012). As shown
in Fig. 4c, the diameter of carbon fiber core was 7 μm. The poly-p-xylene insulation layer
with thickness of 800 nm was coated on the carbon fiber surface by chemical vapor
deposition. Moreover, conducting polymer was electrochemically deposited on its cross
section to improve the electrochemical performance. The ultra-small dimension facili-
tated the penetration of microelectrode into brain tissue and induced little tissue damage.
In addition, the mechanical property of the carbon fiber microelectrodes was well suited
for the inherent mechanical property of brain tissue. The carbon fiber electrode could be
further fabricated into multiple channels to realize the complex neural recording.
Electrodes for Nerve Recording and Stimulation 9

10µm

200 PEDOT
Amplitude (µV)

100
0
-100
-200
0 1 2
Time (s)
200 um

Multiple electrode sites

Parylene Platinum wire

Fig. 4 Research progress of flexible MEMS microelectrodes for neural interface. (a) Tetrode
composed of four microwire electrodes (Ferguson et al. 2009); (b) Thin film microelectrode array
with silk fibroin covered as substrate (Kim et al. 2010); (c) Carbon fiber microelectrode (Kozai et al.
2012); (d) Thin film microelectrode with 3D raised hemispherical electrode sites (Rui et al. 2011);
(e) Microwire electrode with multiple cylindrical electrode sites (Rui et al. 2012)

Yuefeng Rui and Jingquan Liu et al. from Shanghai Jiao Tong University
developed the flexible 3D microelectrode array with raised hemispherical electrode
sites in 2011 (Rui et al. 2011). The electrode sites with diameter of 50 μm were
arranged in 5  5 array, and the gap between two adjacent electrodes was 600 μm.
As demonstrated in Fig. 4d, compared with flat electrode sites, the microscale 3D
hemispherical electrode sites facilitated the contact with nerve tissue by increasing
the effective contact area and reducing the interfacial resistance, which could
improve the electrical stimulation and neural signal recording performance. In
addition, the research group developed flexible microwire electrodes in 2012 (Rui
et al. 2012). As shown in Fig. 4e, compared with flat microelectrode array, the
microwire electrodes could not only facilitate the implantation process and reduce
the tissue damage but also be arbitrarily bended to adapt specific circumstances. The
cylindrical electrode sites of microwire electrode contacted well with the bioactive
tissue, thus the impedance per unit area was decreased. Furthermore, the electrode
sites with diameter of 100 μm were electrodeposited with platinum black by ultra-
sonic current pulses to improve their electrochemical performance. Compared with
10 J.-Q. Liu et al.

conventional microwire electrode, the cylindrical electrode sites facilitated the tight
attachment on the nerve and muscle tissue. The area of the electrode sites could be
further reduced to improve the spatial selectivity.

Flexible Microelectrodes with Fluidic Channels

While the researchers focus on developing MEMS microelectrodes with smaller

dimension, more complex structure and denser electrode sites distribution, they are
also devoting many efforts to multifunctionalizing the MEMS microelectrodes. The
nerve conduction and muscle contraction actions of denervated paralyzed nerve and
muscle tissue could be restored by electrical stimulation based on MEMS micro-
electrodes in artificial neural system (Yoshida et al. 2010; Farina et al. 2008).
However, long-term lack of neural nutritional factors would eventually lead to
denervation atrophy of nerve and muscle tissue, which would result in irreversible
loss of natural conduction of nerve system and contraction function of muscle (Mitch
and Goldberg 1996; Thomas et al. 1997; Midrio 2006). Therefore, some MEMS
microelectrodes integrated with fluidic channels have been developed for drug
delivery (Metz et al. 2004; Gao et al. 2013; Ziegler and Takeuchi 2006; Tian et al.
2014a, 2015). Based on the inherent electrical stimulation and electrophysiological
signal recording properties, the novel MEMS microelectrodes can also be utilized to
deliver fluidic drugs, nutritional factors, and neural transmitters to target nerve and
muscle tissue sites. The flexible MEMS microelectrodes with fluidic channels were
mainly made from polyimide, PDMS, and parylene.
S. Metz and A. Bertsch et al. from École polytechnique fédérale de Lausanne
developed flexible MEMS microelectrodes with fluidic channels based on polyimide
(PI) in 2004 (Metz et al. 2004). As displayed in Fig. 5a, the thickness of microelec-
trode array was 10 ~ 60 μm, and the dimension of electrode sites was 50 μm  50 μm.
The cross-section dimension of inner fluidic channels was 5 μm  50 μm or
20 μm  200 μm, and the cross-section dimension of fluidic channel exits was
30 μm  30 μm or 50 μm  50 μm. The thickness of PI microelectrode array was
relatively small, which was suitable for cortical implantation and neural recording.
However, the one-sided distribution of electrode sites affected the functional scope
of neural recording and stimulation.
Shoji Takeuchi and Dominik Ziegler et al. from Institute of Industrial Science and
University of Tokyo developed flexible MEMS microelectrodes with fluidic chan-
nels based on parylene in 2006 (Ziegler and Takeuchi 2006). The thickness of
microelectrode array was 18 μm, and the dimension of electrode sites was
40 μm  40 μm. The cross-section dimension of inner fluidic channels was
15 μm  80 μm, and the cross-section dimension of fluidic channel exits was
100 μm  100 μm. The parylene microelectrode array was very thin, which could
facilitate the conformal cover on brain cortex. However, the parylene thin film
electrode was too thin to withstand the internal pressure produced by tissue motion,
which might lead to the closure of the fluidic channel and disability of drug delivery.
Electrodes for Nerve Recording and Stimulation 11

a interconnection polyimide structure probe tip

contact pads
buried channels fluid outlets
fluid inlets

microelectrodes buried leads microelectrodes

inside channels

b Boading pads Microchannel Pt conducting wire

Microelectrode film
Outlet

Microelectrode sites

Molded PDMS film

Microchannel

c
Teflon capillary
casing Part I:
Subcutaneous Implant
Electrode with coated
with conduction polymer

Polymide based Parylene insulated

Fluidic channel micro wire electrode

Part II:
Intramuscular Implant

Fig. 5 Research progress of flexible MEMS microelectrodes with fluidic channels for neural
interface. (a) Thin film microelectrode array based on polyimide (PI) (Metz et al. 2004); (b) Thin
film microelectrode array based on poly-dimethylsiloxane (PDMS) (Gao et al. 2013); (c) micro-
electrodes-integrated polyimide microfluidic channels and parylene microwire electrodes (Tian et
al. 2015)

Kunpeng Gao and Gang Li et al. from Shanghai Institute of Micro-System and
Information Technology (Chinese Academy of Sciences) developed flexible MEMS
microelectrodes with fluidic channels based on poly-dimethylsiloxane (PDMS) in
2013 (Gao et al. 2013). As shown in Fig. 5b, the thickness of the microelectrode
array was 125 μm. The cross-section dimension of inner fluidic channels was
50 μm  200 μm. The thickness of the PDMS microelectrode array was relatively
large, since it was unsuitable for conformal attachment on tissue with high flexibility.
Hongchang Tian and Jingquan Liu et al. from Shanghai Jiao Tong University
developed flexible MEMS microelectrodes integrated with polyimide microfluidic
channels and parylene microwire electrodes in 2014 (Tian et al. 2014a, 2015). As
shown in Fig. 5c, the integrated flexible microelectrode was composed of three parts:
(1) the microwire electrodes as electrical interfaces, (2) the PI capillaries (outer
12 J.-Q. Liu et al.

diameter of 110 μm and wall thickness of 10 μm) for fluidic drug releasing as
chemical interfaces, and (3) the Teflon capillary (outer diameter of 650 μm and
wall thickness of 140 μm) for packaging. The integrated microelectrode with drug
delivery function was easy to be fabricated and change its parameters. More elec-
trode sites and fluidic channels with smaller dimensions were required to realize
more complex and precise neural recording and stimulation.
Minghao Wang and Jingquan Liu et al. of Shanghai Jiao Tong University reports
a novel flexible neural probe fabricated by cylindrical substrates lithography for
Brain-Computer-Interface (BCI) applications (Wang et al. 2017). The electrode sites
were patterned on cylindrical surface to acquire high space selectivity and the
microchannel was integrated to deliver drugs or optical stimulation. The unique
cylindrical substrates lithography has been reported to have high pattern resolutions
(1 μm alignment precision) and high reliability (Yang et al. 2014). Using this
technology, postcrimping process of the substrate is not needed compared to the
plane lithography. Therefore, this method was more time-saving and reliable. Fig.
6a–d shows the photographs of the whole design of the flexible probe. The probe has
an outer diameter of 330 μm and an inner diameter of 250 μm and the total length is
3.2 cm. There are eight electrode sites with a diameter of 30 μm and a counter
electrode site with a width of 200 μm distributed on the surface of the probe. Figure
6e, f shows the assembled probe inserted into agarose and delivering drug. The drug-
delivering ability makes the probe suitable for chronic implantation by releasing
anti-inflammatory agent or nerve growth factor (NGF).

Flexible MEMS Microelectrodes with mLEDs

Attribute to the development of MEMS technology, microelectrocorticography

(μECoG) electrodes can record from large-area cortical surface filed potentials
with high-density electrodes at mesoscopic scales. On the other hand, optogenetics
has gained substantial interest over the last 10 years, which can excite or inhibit a
specific neuron type with expression of light sensitive ion channels or pumps. It
provides an ideal possibility to manipulate specific neural circuits with the combi-
nation of μECoG electrodes. As the stimulation light source, μLED is a superior
choice than laser, whereas only few researches on μECoG are reported using μLEDs.
Thus, it is urgent to develop a novel photoelectric neural interface combing LEDs
and μECoG electrodes for precise simultaneous optical stimulation and recording.
Ki Yong Kwon and Wen Li et al. of Michigan State University presents a wireless-
enabled, flexible optrode array with multichannel microlight-emitting diodes (μLED)
for bidirectional wireless neural interface (Kwon et al. 2014). The array integrates
wirelessly addressable μLED chips with a slanted polymer optrode array for precise
light delivery and neural recording at multiple cortical layers simultaneously. The
wirelessly powered-slanted optrode array contains 32 embedded μLED light sources
on a 2.5  2.5 mm2 flexible substrate, with 4  4 channels per each hemisphere to
cover both visual cortices in rats. Integrated LED light sources powered by the
wireless switched-capacitor stimulator (SCS) enable a truly untethered system.
Electrodes for Nerve Recording and Stimulation 13

Fig. 6 The photographs of (a) the fabricated neural probe and (b) the counter electrode site, (c) the
electrode site and (d) the bonding pad of the probe. (e) The probe inserted to agarose and (f)
delivering drug (Wang et al. 2017; Yang et al. 2014)

Bowen Ji and Jingquan Liu et al. of Shanghai Jiao Tong University developed a
novel integrated μLED-μECoG neural interface using wire-bonding technology
combining with iridium oxide (IrOx) microelectrodes (Ji et al. 2017). An overall
schematic of the μLED microelectrodes was shown in Fig. 7a, with a 2  2 mm2
footprint. The three bare μLED chips (C460TR2227–0328, Cree Inc., USA), with
220  270  50 μm3 in dimension and 460 nm in peak wavelength, were arranged in
a line with luminous surface down and aligned above the holes on PI substrate to
allow the light propagation without obstacle. As can be seen from the downside
view, four electrode sites with a diameter of 200 μm were modified with IrOx and
14 J.-Q. Liu et al.

Fig. 7 (a) Concept diagram

of the μLEDs microelectrode. a Upside
(b) Illustration of the μLEDs To mLED(+)
microelectrode attaching on To mLED(–)
the translucent agar gel mold
FPC connector
(Ji et al. 2017) mLED Epoxy
Alignment hole
Downside To recording
Lighting hole
electrode

FPC
Stiffener
IrOx electrode c
ACF

Mouse Brain
Air
473nm

2mm Cerebral cortex

Air
Walnut

Agar

1mm
5mm
PDMS master mold

distributed around three μLEDs. These two subarrays were individually connected to
flexible printed circuit (FPC) with anisotropic conductive film (ACF, AC2056R,
HITACHI, Japan) using a pulse hot-pressing machine. The illustration of μLED
microelectrodes attaching on the surface of mouse cerebral cortex (model from Allen
Brain Atlas) is shown in Fig. 7b. To assess the attachment effects, a walnut-shaped
agar gel mold from PDMS was applied to mimic mouse cerebral cortex. The μLED
microelectrodes can be attached on the cortical surface of a mouse expressing ChR2
to realize synchronized light modulating and neural signal recording.

Research Progress of Materials for Flexible Microelectrodes

Functional interfaces should have the ability to combine different physical stimula-
tions, such as electrical (Radisic et al. 2004), magnetic (Dobson 2008), mechanical
(Svennersten et al. 2011), or optical (Wells et al. 2005), for further exploration and
manipulation of stimulus-sensitive cell with modified substrates. Majority of
existing studies have already incorporated conductive biomaterials functioning as
electrode-tissue interface in neural engineering studies (Tandon et al. 2009; Cho and
Borgens 2013; Martins et al. 2013). Park et al. and Huang et al. reported that the
Electrodes for Nerve Recording and Stimulation 15

differentiation and maturity of neural stem cells could be promoted by electrical

stimulation on graphene plate and carbon nanotube rope, respectively (Park et al.
2011; Huang et al. 2012). Zhao reported the effects of skeletal myogenesis on comb
pattern substrate adjusted by different frequency of electrical stimulating (Zhao
2009). Lee and his colleagues demonstrated that polypyrrole coated nanofibres
were able to induce directional growth of neurons (Lee et al. 2009). These researches
suggested that conducting substrates with variable structure had great potential on
modulating excitable cells in neural engineering.
Conducting polymer possesses various excellent characteristics including high
CSC, low impedance, excellent plasticity, and volume electrostrictive effect (Abidian
and Martin 2009; Poole-Warren et al. 2010; Yoon and Jang 2009). Meanwhile, due to
the good biocompatibility, conducting polymers is widely applied in various biomed-
ical area such as biomedical imaging (Au et al. 2013), biosensor (Yang et al. 2011;
Arter et al. 2010), artificial muscle (Plesse et al. 2010), drug release controller (Simon
et al. 2009), cancer biomarker (Bangar et al. 2009), and neural interface (Abidian et al.
2009; Asplund et al. 2010). One of the most important application of conducting
polymer is using as the electrode-tissue interface material in neural engineering,
which can be facilely fabricated into multiple structures (Gomez et al. 2007), modified
by different doping (Abidian et al. 2012; Bongo et al. 2013) and regulated to
undertake electrical stimulation (Hsiao et al. 2013; Quigley et al. 2012).
The fundamental properties of conducting polymers including surface morphol-
ogy, electrical stimulating performance, stability, and biocompatibility highly
depend on the characteristics of negatively charged dopants which are also termed
as counterions. For instance, macromolecules with high mechanical properties have
the ability to enhance the stability of conducting polymer composites (Luo et al.
2011). Similarly, nanomaterials with excellent conductivity, such as carbon nano-
tubes, are capable of improving the electrical performance of composite film (Al-
bahrani et al. 2015). Therefore, it is very important to assess the influence on doping
different counterion components into the conducting polymer. As one of the fre-
quently used conducting polymer for interfaces to different cells, polypyrrole (PPy)
was doped with generally accessible molecules as electrode-tissue interface. The
conducting polymer electrode-tissue interface mainly referred to PEDOT, which was
combined with water soluble molecules, biomolecules, carbon nanotube (CNT),
perchlorate (ClO4 ) oxide groups, and graphene oxide (GO). Different kinds of
the conducting polymer (PEDOT) electrode-tissue interface for neural interface are
discussed in this chapter and presented and reviewed in Table 2 for comparison.
Xinyan Cui and David C. Martin et al. from University of Michigan doped
polystyrenesulfonate (PSS) as negatively charged counter ion into PEDOT to form
PEDOT/PSS composite as electrode-tissue interface (Cui and Martin 2003). As
exhibited in Fig. 8a, since the rough and porous structure of PEDOT/PSS composite
greatly increased the effective area of electrode-tissue interface, it would improve the
electrochemical performance. Therefore, the PEDOT/PSS composite became one of
the most widely used conducting polymer materials.
Maria Asplund and Hans von Holst et al. from Royal Institute of Technology
separately doped hyaluronic acid (HA), heparin, and fibrinogen as negatively charged
16 J.-Q. Liu et al.

Table 2 Conducting polymer (PEDOT) electrode-tissue interface for neural interface

Dopant Structure Dopant type References
Polystyrenesulfonate (PSS) Film Soluble Hsiao et al. (2013)
molecule
Hyaluronic acid (HA) Film Biomolecule Quigley et al. (2012)
Heparin Film Biomolecule Quigley et al. (2012)
Fibrinogen Film Biomolecule Quigley et al. (2012)
Carbon nanotube (CNT) Porous Carbon Luo et al. (2011)
nanomaterial
Perchlorate (ClO4 ) Nanotube Negatively Al-bahrani et al. (2015)
charged ion
Graphene oxide (GO) Film Carbon Cui and Martin (2003), Asplund et
nanomaterial al. (2008), Tian et al. (2014b)

counter ion into PEDOT to form PEDOT/biomolecule composites as electrode-tissue

interface (Asplund et al. 2008). These three composite electrode-tissue interface
doped with different biomolecules varies from each other in their characteristics like
surface morphology, effective area determined by surface roughness, and the electro-
chemical performance. The addition of biomolecules might improve the biocompat-
ibility of the conducting polymer electrode-tissue interface. Furthermore, bioactive
drugs and nutrition factors could also be added into the PEDOT/biomolecule com-
posites to produce the drug-loaded functionalized electrode-tissue interface.
Xiliang Luo and Xinyan T. Cui et al. from University of Pittsburgh doped acidified
carbon nanotube (CNT) as negatively charged counter ion separately into PEDOT to
form PEDOT/CNT composite as electrode-tissue interface (Luo et al. 2011). As
exhibited in Fig. 8c, the PEDOT/CNT composite exhibited rougher surface than other
PEDOT electrode-tissue interfaces, which facilitated the improvement of electrochem-
ical performance by increasing the effective area. The neuron cells grew well and tightly
adhered on the PEDOT/CNT composite film, which indicated that the PEDOT/CNT
neural interface possessed good biocompatibility. The porous structure of PEDOT/CNT
composite was attributed to addition of carbon nanotube, which largely increased the
effective area. Moreover, due to its electrical and mechanical performance, the PEDOT/
CNT composite possessed excellent electrochemical property and stability.
Mohammad Reza Abidian and Daryl R. Kipke et al. from University of Michigan
doped perchlorate (ClO4 ) as negatively charged counter ion separately into PEDOT
to form hollow nanotube structure as electrode-tissue interface (Abidian et al. 2009).
The PEDOT nanotube intersected and stacked together to form loose and porous
extensional organization on the electrode surface, which improved the effective
surface area of electrode-tissue interface. The hollow structure of PEDOT nanotube
further increased the electrode-tissue interface area, which resulted in the improve-
ment of electrochemical performance.
Hongchang Tian and Jingquan Liu et al. from Shanghai Jiao Tong University
doped graphene oxide (GO) as negatively charged counter ion separately into
PEDOT to form PEDOT/GO nanocomposite film as electrode-tissue interface
Electrodes for Nerve Recording and Stimulation 17

Fig. 8 Research progress of the electrode-tissue interface modification technology of flexible

MEMS microelectrodes for neural interface. (a) PEDOT/PSS composite film (Cui and Martin
2003); (b) PEDOT/carbon nanotube (CNT) composite film (Luo et al. 2011); (c) PEDOT/graphene
oxide (GO) composite film (Tian et al. 2014b)

(Tian et al. 2014b, c, d). As shown in Fig. 8c, in PEDOT/GO composite film, GO
was randomly distributed as the structural material to form three-dimensional cross-
over networks, while PEDOT which served as stable charge transfer medium was
interspersed among the interspaces of graphene nets. Like rebar in concrete, GO
doping enhanced the mechanical property of conducting polymer film. Meanwhile,
the encapsulated conducting polymer prevents GO from dispersing to tissue during
recording or stimulation process, which greatly reduces the possibility of cytotoxic-
ity induced by the diffusion of carbon nanomaterial. Like carbon nanotube, the
18 J.-Q. Liu et al.

nanoscale GO also possessed multiple excellent properties, which could improve the
performance of the conducting polymer electrode-tissue interface.
Minghao Wang and Jingquan Liu et al. of Shanghai Jiao Tong University reports for
the first time the use of reduced graphene oxide enhanced conductive polymer (PEDOT:
PSS-rGO) to improve the electrochemical properties, biocompatibility and mechanical
stability of microelectrodes for high-quality neural recording (Wang et al. 2017). A
flexible electrochemical method was adopted to realize the codeposition of PEDOT:
PSS-rGO composites with L-Ascorbic acid on microelectrode sites without post-
reduction. The SEM pictures shown in Fig. 9 illustrate the PEDOT:PSS-rGO has a
porous wrinkle structure with large effective surface area which is beneficial to charge
transfer and storage. The electrochemical tests demonstrate that the PEDOT:PSS-rGO
coatings can decrease the impedance of microelectrodes by two orders of magnitude and
increase the CSC by ten times. The microelectrodes modified with PEDOT:PSS-rGO
recorded higher quality spikes (SNR > 10) than the uncoated. Moreover, the micro-
electrodes modified with PEDOT:PSS-rGO had significantly higher amplitude and
fewer low-frequency artifacts in LFP recordings. The calculated power spectra of the
LFP signals illustrate the PEDOT:PSS-rGO-modified microelectrodes had higher LFPs
sensitivity and common-mode noise suppression capability than the unmodified ones.

8µm

100
141
50 100
50
0µm 0µm

Fig. 9 The SEM pictures of the deposited PEDOT:PSS-rGO on microelectrode site at (a) 1000,
(b) 5000 magnification. (c) The 3D microscopy pictures of the PEDOT:PSS-rGO modified neural
probe at lateral view and (d) the TEM picture of the as-deposited PEDOT:PSS-rGO (Wang et al. 2017)
Electrodes for Nerve Recording and Stimulation 19

Xiaoyang Kang and Jingquan Liu et al. from Shanghai Jiao Tong University also
developed iridium oxide (IrOx) as an important electrochemical modification material
for neural interface, which was extremely valuable in neural stimulation and recording
applications (Kang et al. 2014a, b, c, d, 2015). There were various kinds of prepara-
tion methods for IrOx, which included sputtering iridium oxide film (SIROF), acti-
vated iridium oxide film (AIROF), and electrodeposited iridium oxide film (EIROF),
as shown in Fig. 10a–c. For SIROF, IrOx was formed by the combination of iridium
atom and oxygen atom under vacuum condition. For AIROF, iridium atom reacted
with water to form IrOx hydrate. For EIROF, IrOx hydrate was formed by drawing off
carbon dioxide from iridium complex compound. The SEM of the iridium oxide as
SIROF, AIROF, and EIROF are shown in Fig. 10d–f, respectively. The SIROF
prepared under optimal condition exhibited dendrite surface morphology with porous
structure. The AIROF displayed rough and porous structure which could facilitate fast
ion exchange. The EIROF were suitable for short-time electrical stimulation due to its
relatively high CSC and low impedance. The SIROF possessed better stability than
the other two IrOx, because there was no water existed in sputtered IrOx. Therefore, it
would be more suitable for long-term electrical stimulation. However, the AIROF was
more suited to neural recording, because the phase angle shift of the electrochemically
activated IrOx was the smallest among all these three IrOx.

Fig. 10 Research progress of iridium oxide as an important electrochemical modification material

for neural interface. (a–c) Three preparation methods for iridium oxide as SIROF, AIROF, and
EIROF; (d–f) SEM of the iridium oxide as SIROF, AIROF, and EIROF (Asplund et al. 2008; Tian et
al. 2014b, c, d; Kang et al. 2014a)
20 J.-Q. Liu et al.

Future Development Prospect

In the research field of flexible MEMS microelectrodes for neural interface, the
development of microelectrodes with characteristics of tiny dimension, multifunction,
high density, and biodegradation will be the goals. Moreover, transparent and stretch-
able MEMS microelectrodes which can facilitate fluorescence observation of neural
tissue and promote conformal covering on brain tissue will become a new direction.
Furthermore, in terms of electrode modifications for electrode-tissue interface, the
ideal tissue engineered interface proposed by Ulises A. Aregueta-Robles et al. should
incorporate the combined coating approaches of conductive polymers, hydrogels, and
attachment factors with neural cells, which can give consideration to each requirement
of electrode-tissue interface (Aregueta-Robles et al. 2014).
In recent years, the optogenetics applications in neuroscience have attracted much
attention for neuroscientists. Although electrical stimulation methods exhibit
remarkable advantages in controlling and exploring the function of discrete brain
regions and providing therapeutic solutions, it cannot genetically target specified
neuron types. This defect could be overcome with genetically encoded actuators
(Warden et al. 2014). Therefore, flexible MEMS microelectrodes integrated with the
optical stimulation capability will become a very important issue for neural interface
in future.
In addition, the rising nanotechnology and biomedical engineering will offer a
new opportunity for the development of flexible MEMS microelectrodes for neural
interface. The interdisciplinary research of microfabrication technology with nano-
technology and biomedical engineering will lead the developing orientation in future
(Yang et al. 2012; Aregueta-Robles et al. 2014; Warden et al. 2014; Zhang et al.
2014; Yu et al. 2014). The combination of these interdisciplinary subjects will
undoubtedly collide to burst shining sparks and greatly improve human life and
understanding the world.

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