Implantable Biomedical
BIOMIMETIC SYSTEMS
Microsystems for
Neural Prostheses
Flexible, Polyimide-Based, and Modular
© IMAGE SOURCE, PHOTO DISC,
EYEWIRE
BY THOMAS STIEGLITZ,
MARTIN SCHUETTLER,
AND KLAUS PETER KOCH
iomedical microsystems open up tremendous oppor-
B tunities for neural prostheses with respect to the
degree of miniaturization and system complexity,
especially when implants are the method of choice to
establish a man-machine interface to the central or
peripheral nervous system. In recent decades, many different
approaches to contact nerves and muscles at different anatomi-
cal levels have been investigated. Electrodes have been recog-
nized as one key component for establishing a functional
electrical connection to record nerve signals and to stimulate
neurons and muscles for the control of limbs and organs or to
elicit sensory sensations for feeling, hearing, or seeing. A vari-
ety of interface concepts have been invented, ranging from
simple wires in the precision mechanics range up to complex
microsystems with integrated electronics and experiments that
incorporate living cells into technical substrates [1]–[3].
These approaches cross-fertilize many disciplines, which
range from mechanical and electrical engineering to molecular
biology and neurosurgery. However, most have been placed
into basic research or are still under development to prove their
reliability. Few concepts have actually been transferred to clini-
cal implants for neural prostheses. In the past 35 years, many
success stories have been written, but implanted neural prosthe-
ses often remain in the background [4]. Existing clinical
devices are often unknown to physicians, patients, and health
insurance companies, which need to be convinced to reimburse
costs for every single patient. Currently, the best-known neural
prosthesis may be the cochlea implant [5], which had a devel-
opmental period of nearly two decades until it became accepted
in clinical practice. Among examples of the first applications
that could assist paralyzed individuals with daily living were
the drop foot stimulator [6] for patients suffering from hemiple-
gia after a stroke and the phrenic pacemaker [7] for tetraplegics
with high spinal cord lesions as an alternative for the iron lung.
More and more paralyzed patients are also benefiting from
implants for bladder and bowel management [8]. The more
complex physiological functions are, the greater is the need for
more complex implants.
The Freehand system from Neurocontrol, Inc. is a neuro-
prosthesis for the rehabilitation of the upper extremity to resti-
tute palmar and lateral grasp in C5/C6 tetraplegics. Eight
epimysial electrodes control two grasp patterns by neuromus-
58 IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE
Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.
cular stimulation of hand and arm muscles [9]. The only thing
clinical neural systems have in common is that they all drive a
low number of electrode channels with simple control pat-
terns. By means of precision mechanics, they have become
robust and reliable over decades of implantation in the human
body. Their simple technological approach seems to be the
major reason for their success, but the low degree of miniatur-
ization often limits their applications because of a demand for
more electrode channels and implantation sites with strict
anatomical limitations.
Clinical applications for central nervous system (CNS)
applications include extracorporal devices for simple brain-
computer interfaces, e.g., for neural prostheses control [10].
Even in implantable systems such as brain stem implants that
can restore hearing after loss of the acoustic nerve [11], the
direct interface is a simple grid array that limits resolution for
the sophisticated restoration of hearing.
The most prominent example for a need to switch to micro-
system technology (to achieve smaller and smarter implants)
may be the visionary approach to develop a system that is
totally implantable within a human eye and that can restore
vision [12]. In applications that must be extremely small, there
is a need for thin, flexible substrates with a high number of
electrode sites to obtain sufficiently high spatial selectivity and
methods for encapsulation but that will not alter the size of the
implant too much to match anatomical constraints.
Apart from retinal implants, other peripheral and central
nervous interfaces may benefit from a new and modular con-
cept of biomedical microdevices. Presently, silicon-based
microsystems have been established as a research tool in the
neurosciences to investigate the CNS [1]–[3]. Thus far, some
research groups have focused on flexible, micromachined
electrodes to interface different levels of the CNS and periph-
eral nervous system. Polyimide was used as a substrate to
develop epidural [13] and intracortical recording arrays with
compartments that deliver bioactive substances [14]. Three-
dimensional (3-D) forming of the planar devices can be
accomplished during thermal postprocessing steps or with
magnetic forces if a thin nickel layer is integrated into the flex-
ible electrode array [15].
In our group at IBMT (Fraunhofer Institute for Biomedical
Engineering) we not only established flexible electrode arrays,
0739-5175/05/$20.00©2005IEEE SEPTEMBER/OCTOBER 2005
 but we also developed concepts that combine different materi-
als with flexible electrodes in implantable biomedical
microsystems. In the following article, we present the tech-
nologies to fabricate polyimide-based thin and flexible sub-
strates with monolithically integrated electrode arrays and
printed circuit boards (PCB) for hybrid electronic assemblies
as well as an assembling technique that connects bare elec-
tronic dice with flexible PCBs. The concept of modular, flexi-
ble biomedical microsystems is introduced in general and
described in detail in three examples. A cuff electrode with
integrated multiplexer circuitry and standard implantable
cables represents the combination of microtechnology with
precision mechanics; a sieve electrode used as an implant in
peripheral nerve regeneration studies demonstrates the next
level of integration density but still uses a cable connection;
and last, we briefly comment on the joint effort to fabricate the
demonstrator of a vision prosthesis that is completely
implantable in the eye with a wireless link for energy supply
and data transmission. System design, hybrid assembling tech-
nology, and flexible multilayer encapsulation using parylene
and silicone rubber are the key components for creating a new
generation of neural prostheses for complex and challenging
new applications.
Process Technology for
Flexible Electrodes and Substrates
Biomedical microsystems must fulfill different requirements
for acute and chronic implantation. They have to be stable in
the physiologic environment, i.e., no degeneration should
occur. All of the components of an implant must either be non-
toxic to cells or must be encapsulated with nontoxic materials
that can serve as a diffusion barrier to prevent elusion into the and stimulation purposes. Application-specific integrated cir-
body. Conducting materials for interconnects and electrodes
should have little tendency to create corrosion products in a
physiological environment without a voltage bias and during
stimulation with current pulses. Additionally, the devices must
have a biomechanically safe type of
design with respect to geometry,
flexibility, and weight. The ideal
material combines biocompatibility
with adequate mechanical character-
istics while applying standard micro-
machining technologies.
We have chosen polyimide as the
(a)
material for several reasons [16]. It
has been proven to be a nontoxic
material in biomedical applications
and has already been used for neural
implants. We also chose the poly-
imide Pyralin PI 2611 (HD Micro-
systems, Bad Homburg, Germany)
(c)
as the substrate and insulation mater-
ial because of its mechanical and
electrical material properties. The
process technology can overcome
the classic separation of substrate
and insulation layers, the integration
of interconnects, and the generation
(e)
of arbitrary outer geometries of both
electrodes and substrates (Figure 1).
First, a 5-µm- thick layer of poly- Fig. 1. A schematic overview of the polyimide process technology for flexible substrates
imide resin was spun onto a silicon with integrated electrodes and interconnects.
IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE
Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.
wafer, which then served as a support structure during the
entire process [Figure 1(a)]. The polyimide was cured in a
polyimide oven (PB 6-2, Yes, San Jose, California). The first
metallization layer of gold (300 nm) was sputter deposited (L
420 SP, Leybold, Dresden, Germany), then structured using
lift-off technology for the connection pads, interconnect lines,
and electrode sites [Figure 1(b)]. Functional electrode materi-
als such as platinum were deposited and structured using the
same technology [Figure 1(c)]. A second polyimide layer with
a thickness of 5 µm was then spun on and cured as top layer
insulation. An aluminum etching mask was then deposited and
structured with wet etching to define electrode sites, contact
pads, and the outer geometry of the devices [Figure 1(d)].
Reactive ion etching (RIE) with a STS 320 PC generator
(Surface Technology Systems) was used to expose contact
pads and electrode sites and to separate the devices by etching
the perimeters down to the support wafer [Figure 1(e)]. The
remaining aluminum etch mask was removed with aluminum
etchant. The wafers were then cleaned with isopropanol and
deionized water in an ultrasonic bath. Using tweezers, the
devices were mechanically stripped from the wafer, thereby
obtaining flexible electrode microdevices in which the poly-
imide serves as both a substrate and as insulation, respectively
[Figure 1(f)]. In a postprocessing temper step (340 ◦ C for 2
h), the planar devices may be formed to 3-D shapes, e.g.,
into cuff-type devices, if desired.
Chip Assembly with the
Microflex Interconnection Technology
Biomedical microimplants need electronic circuitry for signal
transmission and power management as well as for recording
cuits (ASICs) are the solution with the highest integration den-
sity. For individual PCB applications and small volume
production, we developed a technology that allows the use of
standard integrated circuits without the need for special
Polyimide Gold
Silicon Wafer Metallization
(Mechanical (Interconnection
Lines)
Support)
(b)
Aluminum
Platinum Mask
Metallization Polyimide
(Stimulation
Sites)
(d)
Reactive
Ion
Etching
Substrate
(f) Separation
SEPTEMBER/OCTOBER 2005 59
 The more complex physiological
functions are, the greater is the need
for more complex implants.

metallization layers and diffusion barriers. Its integration densi- and electrically stable interconnects. For the bonding
ty is comparable to flip-chip technology with pitches below process, we used a wire bonder (K&S 4524 digital,
100 µm It is a modified stud-ball bond-technique that has been Germering, Germany) equipped with an electronic flame-off
named the MicroFlex Interconnection (MFI) technique [17]. controller. We chose a 25-µm gold wire (AW6 Müller
The basic process of this new technology is based on the Feindraht, Thalwil, Switherland) and a bond capillary with a
common thermosonic ball-wedge bonding process. A gold small neck for bonding the smallest pitches. For the MFI
ball is bonded by force, temperature, and ultrasound onto a technique, the standard ball-wedge bonding process has been
metal layer, e.g., aluminum, gold, copper, or nickel. The modified. Flexible substrates have been designed with con-
metal pair is then welded together, resulting in mechanically nection pads that have a through-hole in their center and
match the locations and pitches of the integrated circuit (IC)
connection pads. The flexible polyimide substrate, which is
optically transparent, and the IC were aligned under visual
Bond Capillary
(b)
inspection in a first step [Figure 2(a)]. A gold ball is formed
Connection Pad with a flame-off electrode by melting the tip of the gold wire
from Integrated
Interconnect
[Figure 2(b)]. The bond is set through the hole in the sub-
strate on the IC pad. By lifting the capillary, the gold wire is
Flexible
Tape
torn off, and the equipment is ready to repeat the bonding
steps. The welding of the ball with the underlying IC pad in
Connection
combination with the ball deformation produced an electrical
Pad
connection to the conductor in the flexible substrate by a
(a) form fit and a closed linkage. To improve the stability of the
connection and to prevent short circuits, parylene C is
deposited around the ribbon cable and the substrate.
Integrated
Circuitry Conception of Modular, Flexible Microimplants
(c) The design and target specifications of implantable biomedical
microsystems strongly depend on the medical requirements and
Ball Stud
anatomy of the implantation site; therefore, each application
needs its own implant design. We suggest a modular concept as a
way to shorten the development time between the first demonstra-
tor and a clinical trial. Electrodes, standard modules for electron-
ics (e.g., amplifiers, stimulators, multiplexers, and wireless
transmission systems as well as cable bound solutions), can be
independently developed if the connections between the single
modules have been defined and standardized in a set of design
Fig. 2. The process sequence for a bond with the microflex
rules. Different assembling techniques are necessary for the con-
interconnection (MFI) technique.
nection of the different parts of the systems.
In our concept (Figure 3), polyimide-based
substrates were used for electrode sites and
Gold Bump Medical-Grade electronic circuitry on different modules.
Gold Bumps SMD Cable
Electronic components were assembled by
Silicone Rubber conductive gluing, soldering, or the MFI
technique. Connections between the modules
Silicon Die were established via a modified MFI. With
Stimulation with IC Ceramic Adapter this modification, two thin polyimide sub-
Site strates were bonded together by two ball
bonds through the holes in the connection
Electrode Substrate for Electronic Circuitry pads [18]. Screen-printed ceramic modules
allow the connection to the thin polyimide
Fig. 3. The system concept of a flexible, modular microimplant; electrodes, elec- substrates by MFI and to standard medical
tronic circuitry, and cables were assembled using different modules. grade cables by welding. The electronic

60 IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE SEPTEMBER/OCTOBER 2005

Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.
 Biomedical microsystems must have a
biomechanically safe type of design with
respect to geometry, flexibility, and weight.

modules and the transitions to the cables and electrodes were cov-
ered homogenously with parylene C in a plasma-deposition-
polymerization process. Consequently, electrical insulation via
pinhole-free coverage, high chemical resistance with respect to
biostability, and a good biocompatibility should be ensured [19].
The parylene insulation without trapped air should prevent the
condensation of water and thereby the corrosion of chip contacts
and metal surfaces. The cytotoxicity of the materials and the
residues of the process technology were tested in the cell culture
laboratories of the Fraunhofer Institute for Biomedical
Engineering according to ISO 10993 (ISO 10993-Part 5: Tests
for cytotoxicity: in vitro methods; Part 12: Sample preparation
and reference materials). Parylene C used as direct contact mate-
rial showed excellent nontoxic results [20]. The surface modifi-
cation of parylene C with oxygen plasma reduced the contact
angle (increased surface energy) and led to better cell-material
interaction. Parts of the implantable systems might be additional-
ly encapsulated with silicone rubber to further protect the under-
lying structure from mechanical impacts or to deliver
mechanically soft structures for the neural implants, respectively.
silicone rubber sheets with integrated platinum electrode
sites and stainless steel wires. They were used to stimulate
peripheral nerves for limb control and to record neural sig-
nals for control purposes, e.g., in the correction of foot drop.
Multiple electrode sites within the cuff and sophisticated
stimulation paradigms allow fiber and fascicle-selective
stimulation of peripheral nerves. A detailed overview of the
electrodes and the stimulation paradigms can be found in
[1]–[3]. Our group developed small polyimide-based micro-
machined cuff electrodes with up to 12 electrode sites that
revealed excellent results in chronic studies on the peripheral
nerve [21]. Unfortunately, the mechanical properties of the
cuff itself were worse when the concept was transferred to
large peripheral nerves needing cuff diameters larger than
2.0 µm. For these applications, the hybrid cufff electrode has
been developed. It consists of a polyimide based thin-film
scaffold with a thickness of 10 µm. It has 18 dot-shaped
platinum electrodes (∅ = 500 µm), arranged to six tripoles.
Each tripole was longitudinally oriented to the cuff axis (10-
mm cuff length) and consisted of two short-circuited anodes

Application Examples
for Neural Prostheses
The idea of flexible and modular bio-
medical microsystems has currently
been transferred into three different sys-
tems in our group. A multiplexer module
has been connected to multipolar cuff
electrodes with silicone rubber backing
to reduce the number of connecting
cables. In another implantation scenario,
a multiplexer unit has been directly 1 cm 1 cm
assembled to a 27-channel sieve elec-
trode. An epiretinal vision prosthesis (a) (b)
includes an inductive energy supply and 500 µm
data receiver as well as electrodes and a
stimulator ASIC on a single substrate to
increase the integration density. The fol-
lowing paragraphs describe the three
examples in detail.

Multichannel Hybrid
Cuff Electrodes with
Multiplexer Circuitry
Cuff electrodes are well-known devices
that interface with peripheral nerves.
They are easy to implant but may lead
to nerve damage if their size is not well
adjusted to the nerve diameter. Cuff
electrodes were mainly fabricated by
means of precision mechanics using
1 cm
(c) (d)
Fig. 4. The hybrid cuff electrodes with 18 electrode sites: (a) polyimide substrate for
cuffs of 4 mm, 6 mm, and 8 mm in diameter before 3-D temper step; (b) polyimide
substrates after temper step; (c) assembly of polyimide substrate and with silicone cuff
(6- mm diameter) and cables; and (d) a cross section of polyimide-silicone rubber
assembly within a hybrid cuff electrode.

IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE SEPTEMBER/OCTOBER 2005 61

Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.
 and one cathode in between. The electrode pitch was 3 mm.
The tripoles were circumferentially oriented to the cuff, and
were located at 0◦ , 60◦ , 120◦ , 180◦ , 240◦ , and 300◦ , respec-
tively. Three groups of six electrodes were distributed onto
three substrate fingers [Figure 4(a)]; the distance of the
electrode groups varied with the envisioned cuff diameter.
The scaffolds were brought into a 3-D shape in adequate
molds in a postprocess temper step [Figure 4(b)]; they were
then glued to the inner side of a self-sizing spiraling sili-
2 mm
(a)
2 mm
(b)
1 cm
(c)
Fig. 5. The module for tripolar stimulation and cable reduction
polyimide: (a) substrate and electronic components for a
multiplexing unit to select one of six electrode tripoles for stim-
ulation purposes; (b) multiplexer unit after hybrid assembly;
and (c) integration of the stimulator/multiplexer module in a
flexible microimplant with a hybrid cuff electrode and a four-
strand Cooper cable.
62 IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE
Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.
cone cuff [Figure 4(c)]. The transitions between the scaf-
fold and the cuff were smooth, and no sharp edges
remained [Figure 4(d)]. The polyimide scaffold had inte-
grated gold interconnection lines that led to a pad array;
and to the pads, one could either connect a 12-channel
cable or a multiplexer module.
The multiplexer module [18] has been designed from off-
the-shelf components to keep the costs low and the develop-
ment time short. The simple circuitry consisted of three ICs
and five passive electronic components. The ICs—one 7 bit
binary counter (CD4024BH, Motorola, Denver, Colorado) and
two eight-channel analog multiplexers (MAX328, Maxim,
Sunnyvale, California)—were supplied by a symmetric volt-
age of ±12 V. The height of the supply voltages ensured that
the multiplexers could handle stimulation signals in the range
up to ±10 V. Because the device needed to be very small, a
decision was made to use bare ICs (dice) and surface-mounted
device (SMD) components. The SMD components were 0805-
sized (except the diode, which was SOT323 packaged). A
printed circuit board (PCB) was based on the polyimide thin-
film technology [Figure 5(a)]. A small-sized multiplexer mod-
ule was created, which reduced the necessary number of
channels to drive an 18-polar hybrid cuff from 12 to four. The
module enabled the ability to select one cathode and one pair
of anodes at a time. A stimulation signal coming from an
external stimulator could be switched to the cathodes, and one
pair of anodes could be set to ground potential. The electrical
potential of all other poles was free-floating. The independent
selection of anodes and cathodes made longitudinal as well as
transversal current flow possible (relative to the nerve axis).
After MFI, soldering, and folding, the size of the module was
about 3.2 mm wide, 16.8 mm long, and 2 mm high [Figure
5(b)]. The 2 × 2 pad array (on the opposite side of the multi-
plexer module) was bonded to a ceramic substrate using regu-
lar MFI. This Al2 O3 substrate (2.3 × 5.5 mm2 , 0.6 mm thick)
was patterned by platinum screen printing having four bond
pads, interconnection lines, and four welding pads. An
implantable four-channel Coopercable (FineTech Medical
LTD, Herfordshire, England) was connected to the pads using
parallel gap welding. The hybrid cuff electrode was bonded to
the other end of the multiplexer module using the modified
MFI. Parylene C coating can electrically insulate the electron-
ic circuitry. Finally, a medical-grade silicone hose (25 mm
long, with a 3.5-mm inner diameter, and a 4-mm outer diame-
ter) was slipped over the module to cover all delicate parts.
The hose was sealed and filled with silicone rubber (for details
see [18]). The complete system with electrodes, multiplexer,
and cables remained flexible and small by using the described
technologies and concepts [Figure 5(c)].
Sieve Electrodes with Integrated Channel Selection
For more than 30 years sieve electrodes have been investigat-
ed as a possible nerve interface after amputation trauma to
control an artificial limb with thought only, and different
microtechnical approaches have been investigated. First,
implantable sieves were fabricated by drilling holes into a
block of epoxy resin. Most of the micromachined sieves were
based on silicon substrates. The developments were described
in detail from different points of view in the reviews [1]–[3].
The results showed a different success rate, and due to uncer-
tain long-term functionality, the devices have not been trans-
ferred over into human clinical trials yet.
SEPTEMBER/OCTOBER 2005
 Our group developed sieve electrodes [16] on polyimide
substrates with integrated cables, thereby minimizing the
mechanical impact from the interface-cable assembly and
moving the contact sites to a place more distant to the nerve.
The sieves have been investigated in a chronic regeneration
model. The sciatic nerve of the rat was transsected, and the
nerve stumps were inserted into guidance channels that were
glued onto both sides of the sieve interface. In studies that
took place for up to six months, good regeneration was
observed. Neural recordings from mechanoreceptors of the rat
paw were obtained, and compound muscle action potentials
were recorded from plantar and gastronomic muscles after
electrical stimulation over the sieve electrodes [22]. 2 mm
In another study, there were no differences in the immuno-
histochemical patterns after an amputation trauma, with or
without the presence of a sieve electrode at the amputation site
[23]. Recent chronic studies have shown that functional rein- (a)
nervation of hind-limb targets could reach maximum levels at
six months. The majority of myelinated fibers crossing the
via-holes and regenerating through the distal nerve had a nor-
mal appearance. However, in a few cases, a decline of target
reinnervation and a loss of regenerated nerve fibers were
found between six months and 12 months postimplantation
[24]. Therefore, more detailed studies with noninvasive inter-
face access have been planned using a sufficient number of
electrodes for high spatial selectivity and a percutaneous
access for repeated recording and stimulation experiments.
We designed the sieve diameter for the application on the sci-
atic nerve of rats, closely proximal to the trifurcation. The sieve
has 570 holes with a diameter of 40 µm covering a cross-sec-
tion area with a diameter of 2 mm plus a rim for guidance chan-
nel assembly, resulting in a total diameter of 3 mm. 5 mm
Twenty-seven ring electrodes with an inner diameter of 60 µm
and an outer diameter of 80 µm were placed around the holes (b)
over the sieve. Reference electrodes for recording and counter
electrodes for stimulation were placed on the sieve and on
paddle-ike structures [Figure 6(a)]. The paddles reach proxi-
mally and distally into the silicone nerve guidance channels.
The system’s 27 electrodes and two counter and two reference
electrodes resulted in a total number of 31 interconnect lines
on the polyimide substrate. For subcutaneous cables and a per-
cutaneous plug, we decided to integrate a modular multiplexer
to reduce the number of cables to nine. A circuitry was
designed using an approach similar to the one that has been
introduced previously for the cuff electrodes. One counter
(CD4040, Motorola, Denver, Colorado) and two multiplexers 1 cm
(MAX396, Maxim, Sunnyvale, California) were directly
assembled on one side of the sieve electrode device using the
MFI technique [Figure 6(b)]. The complete microdevice with (c)
electronics was assembled to a ceramic substrate with nine
cables and a second ceramic substrate with a plug for chronic Fig. 6. Sieve electrode to interface regenerating nerves in fun-
implantation in a rat animal model [Figure 6(c)]. The electron- damental studies: (a) the sieve electrode with 27 ring elec-
ic circuitry got a conformal coating with parylene C before trodes, two central counter electrodes, and two external
encapsulation in silicone adhesive. The system’s technical counter electrodes (rings and holes at the border help to inte-
function has been proven and initial implantations are due to grate the structure into silicone rubber nerve guidance chan-
be scheduled in the near future. nels and the sieve diameter, the area with holes, is 2.0 mm);
(b) the hybrid assembly of three die size ICs (right: two multi-
An Epiretinal Vision Prosthesis plexers; left: counter) with MFI on the polyimide substrate of
Due to increasing miniaturization efforts and the integration the sieve; and (c) the assembled system with multiplexer cir-
techniques of microelectronic components and microsys- cuitry (Cooner wires and head set for chronic implantation in
tems, the feasibility of biocompatible encapsulation, and animal models and the silicone nerve guidance channels are
rapid developments in microsurgical techniques, the not attached yet).

IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE SEPTEMBER/OCTOBER 2005 63

Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.

Fig. 7. Epiretinal vision prosthesis; substrate with 24 electrodes
and inductive energy and signal receiver; hybrid assembly
before encapsulation.
realization of active implants for the eye has become possi-
ble. Different kinds of approaches have been made to
restore vision. Vision prostheses can interface either the
visual cortex, the optic nerve, or the retina (epiretial or sub-
retinal). All approaches are presented and discussed in detail
in [12] and [25]. We are part of the German EPI-RET team,
coordinated by R. Eckmiller, that has been working on an
epiretinal vision prosthesis.
Flexible polyimide-based substrates with two metalliza-
tion layers and 24 integrated electrodes were developed to
assemble electronic circuitry to both address and drive the
electrode arrays. The microimplant uses a transceiver with
inductive coupling to transmit energy and data to a coil
with an integrated electronic circuitry that has been encap-
sulated into an artificial intraocular lens. A miniaturized
cable led to an array of independently addressable elec-
trodes. So far, a stimulation circuit selects and controls 24
electrodes [26]. MFI was used to contact the chips while
SMD components and a wire wound coil were soldered on
the corresponding contact pads. The hybrid assembly of
the system [Figure 7] was completely coated (except for
the electrode area) with parylene C for electrical insula-
tion. The receiver part was encapsulated with silicone rub-
ber to create an artificial intraocular lens. Additionally, the
stimulator part was also encapsulated in silicone to smooth
the sharp edges of the chip.
The present implant has been used for animal experiments
to obtain knowledge about chronic implantation on the reti-
na. Electrically inactive devices have been chronically
implanted on the retina first. Histological and electrophysio-
logical investigations proved the long-term compatibility of
the electrodes on the retina as well as the stability of the
microimplants [27]. Active implants with inductive energy
supply and data receivers have already been successfully
implanted in cats. Optical imaging of the visual cortex
showed increased activity after wireless electrical stimula-
tion of electrode pairs on the implanted vision prosthesis.
The selection of adjacent stimulation sites significantly
changed the corresponding cortical activation zones, thereby
proving the spatial selectivity of the epiretinal stimulation in
the presented implant concept [28].
Conclusions
A new concept for biomedical microsystems as neural pros-
theses has been introduced. Flexible substrates with inte-
grated electrode arrays and printed circuit boards allow for a
variety of possible designs for nerve interface shapes and
electronic systems. Three application scenarios of different
integration densities have shown the potential of hybrid
64 IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE
Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.
assemblies. Thus far, the examples have focused on inter-
faces for the peripheral nervous system. The cuff electrode
with a multiplexer module demonstrated the opportunity to
assemble numerous pre-designed subsystems. The integra-
tion of electronic circuitry on the substrate with additional
cabling and plugs was presented within the sievelike device
to investigate regenerating nerves. Finally, the epiretinal
vision prosthesis paved the way to a degree of miniaturiza-
tion that enables a neural prosthesis with inductive link and
multiple stimulation sites to be implanted into an eye. The
polyimide itself and the polyimide systems with parylene C
coating has proven its stability and functionality in chronic
implantations for up to 12 months, and longer studies are
under consideration. The paradigm to design electrodes and
electronic systems separately and to combine them into
microimplants could be transferred to other devices such as
interfascicular, intraneural, and intracortical electrodes.
With both ideas and results for modularly designed
neural interfaces, we are optimistic about a future that cre-
ates an opportunity to develop a modular construction kit
for neural prostheses. It may become a powerful tool for
varying requirements in the scientific community of neural
engineering by individually choosing the adequate periph-
eral or central nerve interface and adding modules of
amplifiers, stimulators, and telemetric units from a cata-
logue within minutes, instead of the current practice of
needing a lengthy design process for every application.
Presently, that catalogue does not exist, but it might
become comparable to the services of the Center for
Neural Communication Technology at the University of
Michigan (Ann Arbor, Michigan). Their worldwide order-
ing service for micromachined silicon-based electrodes
(for free) has been commercialized to NeuroNexus
Technologies (Ann Arbor, Michigan), recently. Their elec-
trodes can presently be purchased online (http://www.neu-
ronexus.com). While miniaturization is a major topic
within the research field of neural prostheses, the aspects
of time and costs during the U.S. Food and Drug
Administration approval procedure will come to the fore.
Acknowledgments
The authors thank Thomas Doerge, Sascha Kammer, Markus
Hanauer, and Werner Haberer for the process technology and
the assembly of the microsystems. This work was partly sup-
ported by the European Commission (ESPRIT program:
INTER 8897 GRIP 26322; CYBERHAND IST-2001-35094)
and the German Federal Ministry for Education and Research
(EPI-RET, 01 IN 501 Q, Retina Implant 01 KP 0003).
Thomas Stieglitz received the Dipl.-Ing.
degree in electrical engineering with the
special subject biomedical engineering
from the University of Technology
Karlsruhe, Germany, in 1993. He joined
the Fraunhofer-Institute for Biomedical
Engineering in 1993. In 1998, he
received the Dr.-Ing. degree (summa
cum laude) in electrical engineering from the University
of Saarland, Germany, and in 2000, he received the sci-
ence award of the Saarland state for his work on flexible,
neural prostheses. In 2002, he established the Neural
Prosthetics Group at Fraunhofer Institute for Biomedical
SEPTEMBER/OCTOBER 2005
 Engineering (IBMT). Also in 2002, he qualified as a uni-
versity lecturer at the Saarland University about approach-
es for long-term stability of neural prostheses and
biohybrid systems. Since October 2004, he has been a full
professor for biomedical microtechnology at the
University of Freiburg at the Institute for Microsystem
Technology (IMTEK). His research interests include bio-
medical microdevices, neural prostheses, neuromonitor-
ing, functional electrical stimulation, and biohybrid
systems. He is a Member of the IEEE Engineering in
Medicine and Biology Society (EMBS) and a member of
the International Society for Functional Electrical
Stimulation (IFESS), the German Engineering Society
(VDI), and the German Society for Biomedical
Engineering (DGBMT) within the German
Electrotechnical Society (VDE), where he is chair of the
neural prostheses section.
Martin Schuettler received the Dipl.-
Ing. degree in electrical engineering from
the Technical University of Brunswick,
Germany, in 1998. Subsequently, he
joined the Neural Prosthesis Group of the
Fraunhofer-Institute for Biomedical
Engineering in St.Ingbert, Germany,
focusing his work on micromachined neur-
al electrodes. He received the Dr.-Ing degree in 2002 from
the University of Saarland, Germany. He was head of the
neural electrode section until he joined the Implanted
Devices Group of the University College London, U.K., as a
visiting research fellow in 2003. His research interests are
neural prosthesis and biomedical microdevices. He is also a
Member of the IEEE Engineering in Medicine and Biology
Society (EMBS) and the International Society for Functional
Electrical Stimulation (IFESS).
Klaus Peter Koch obtained his Dipl.-Ing.
(FH) degree in electrical engineering at
the Hochschule fuer Technik und
Wirtschaft des Saarlandes, Germany, in
1997. In 1998, he joined the Fraunhofer
Institute for Biomedical Engineering to
work as engineer and project manager.
His expertise is on system integration for
active implants and bioelectronic systems. In 2003, he com-
pleted his Ph.D. on the topic of integration of intelligent
microimplants for stimulation and recording in neural pros-
thetics. Since July 2004, he has been the manager of the
neural prosthetics group for such devices. He is a Member
of the International Society for Functional Electrical
Stimulation (IFESS) and the German Society for
Biomedical Engineering (DGBMT) within the German
Electrotechnical Society (VDE).
Address for Correspondence: Thomas Stieglitz, Laboratory
for Biomedical Microtechnology, IMTEK-Institute of
Microsystem Technology, University of Freiburg, Georges-
Koehler-Allee 102, D-79110 Freiburg, Germany. Phone: +49
761 203 7471. Fax: + 49 761 203 7472. E-mail:
stieglitz@imtek.de.
IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE
Authorized licensed use limited to: ESCUELA POLITECNICA DEL LITORAL (ESPOL). Downloaded on March 28,2020 at 18:21:21 UTC from IEEE Xplore. Restrictions apply.
References
[1] T. Stieglitz and J.-U. Meyer, “Microtechnical interfaces to neurons,” in Topics in
Current Chemistry Series, Microsystem Technology in Chemistry and Life Science,
A. Manz, and H. Becker, Eds. Berlin: Springer, 1998, vol. 194, pp. 131–162.
[2] P. Heiduschka and S. Thanos, “Implantable bioelectronic interfaces for lost
nerve functions,” Progress in Neurobiology, vol. 55, no. 5, pp. 433–461, 1998.
[3] W.L.C. Rutten, “Selective electrical interfaces with the nervous system,” Annu.
Rev. Biomed. Eng., vol. 4, pp. 407–452, 2002.
[4] J. Cavuoto, “Neural engineering’s image problem,” IEEE Spectrum, vol. 41,
no. 4, pp. 20–25, Apr. 2004.
[5] P. Federspil and P.K. Plinkert, “Restoring hearing with active hearing
implants,” Biomed. Tech., vol. 49, no. 4, pp. 76–82, Apr. 2004.
[6] W.T. Liberson, H.J. Holmquest, D. Scott, and A. Dow, “Functional electrother-
apy: Stimulation of the peroneal nerve synchronized with the swing phase of hemi-
plegic patients,” Arch. Phys. Med. Rehab., vol. 42, pp. 101–105, Feb. 1961.
[7] J.P. Judson and W.W.L. Glen, “Radiofrequency electrophrenic respiration:
Long term application to a patient with primary hypoventilation,” J. Amer. Med.
Assoc., vol. 203, no. 12, pp. 1033–1037, 1968.
[8] D.S. Sauerwein, “Sacral deafferentation with implantation of an anterior root
stimulator. Experience after 15 years in 430 patients,” Eur. Urol., vol 2, no. 1,
p. 565, 2003.
[9] R. Rupp and H.J. Gerner, “Neuroprosthetics of the upper extremity—clinical
application in spinal cord injury and future perspectives,” Biomed. Technol., vol.
49, no. 4, pp. 93–98, Apr. 2004.
[10] G. Pfurtscheller, G.R. Muller, J. Pfurtscheller, H.J. Gerner, and R. Rupp,
“‘Thought’-control of functional electrical stimulation to restore hand grasp in a
patient with tetraplegia,” Neurosci. Lett., vol. 351, no. 1, pp. 33–36, Nov. 2003.
[11] J. Kuchta, “Neuroprosthetic hearing with auditory brainstem implants,”
Biomed. Technol., vol. 49, no. 4, pp. 83–87, Apr. 2004.
[12] N. Alteheld, G. Roessler, M. Vobig, and P. Walter, “The retina implant—a
new approach for a visual prosthesis,” Biomed. Technol., vol. 49, no. 4, pp.
99–103, Apr. 2004.
[13] P.J. Rousche, D.S. Pellinen, D.P. Pivin Jr., J.C. Williams, R.J. Vetter, and
D.R. Kipke, “Flexible polyimide-based intracortical electrode arrays with bioactive
capability,” IEEE Trans. Biomed. Eng. vol. 48, no. 3, pp. 361–371, Mar. 2001.
[14] H. Takahashi, T. Ejiri, M. Nakao, N. Nakamura, K. Kaga, and T. Herve,
“Microelectrode array on folding polyimide ribbon for epidural mapping of func-
tional evoked potentials,” IEEE Trans. Biomed. Eng., vol. 50, no. 4, pp. 510–516,
Apr. 2003.
[15] S. Takeuchi, T. Suzuki, K. Mabuchi, and H. Fujita, “3-D flexible multi-channel
neural probe array,” J. Micromech. Microeng., vol. 14, no. 1, pp. 104–107, Jan. 2004.
[16] T. Stieglitz, H. Beutel, M. Schuettler, and J.-U. Meyer, “Micromachined,
polyimide-based devices for flexible neural interfaces,” Biomed. Microdev., vol. 2,
no. 4, pp. 283–294, 2000.
[17] J.-U. Meyer, T. Stieglitz, O. Scholz, W. Haberer, and H. Beutel, “High densi-
ty interconnects and flexible hybrid assemblies for active biomedical implants,”
IEEE Trans. Adv. Packag., vol. 24 , no. 3, pp. 366–374, Aug. 2001.
[18] M. Schuettler, K.P. Koch, T. Stieglitz, O. Scholz, W. Haberer, R. Keller, and
J.-U. Meyer, “Multichannel neural cuff electrodes with integrated multiplexer cir-
cuit.” in Proc. 1st Annu. Int. IEEE-EMBS Special Topic Conf. Microtechnology
Medicine Biology, Lyon, France, 2000, pp. 624–629.
[19] L. Wolgemuth, “Assessing the performance and suitability of parylen coat-
ing,” Med. Dev. Diag. Ind., vol. 22, pp. 42–49, Aug. 2000.
[20] T. Stieglitz, “Considerations on surface and structural biocompatibility as pre-
requisite for long-term stability of neural prostheses,” J. Nanosci. Nanotechnol.,
vol. 4, no. 6, pp. 1–8, Dec. 2004.
[21] F.J. Rodríguez, D. Ceballos, M. Schuettler, E. Valderrama, T. Stieglitz, and
X. Navarro, “Polyimide cuff electrodes for peripheral nerve stimulation,” J.
Neurosci. Met., vol. 98, no. 2, pp. 105–118, 2000.
[22] X. Navarro, S. Calvet, F.J. Rodríguez, T. Stieglitz, C. Blau, M. Butí, E.
Valderrama, and J.-U. Meyer, “Stimulation and recording from regenerated periph-
eral nerves through polyimide sieve electrodes,” J. Periph. Nerv. Syst., vol. 3, no. 2,
pp. 91–101, 1998.
[23] P.M. Klinge, M.A. Vafa, T. Brinker, A. Brandes, G.F. Walter, T. Stieglitz,
M. Samii, and K. Wewetzer, “Molecular characterization of axonal sprouting and
tissue changes after long-term implantation of a polyimide sieve electrode to the
transsected adult rat sciatic nerve,” Biomat., vol. 22, no. 17, pp. 2333–2343, 2001.
[24] N. Lago, D. Ceballos, F.J. Rodríguez, T. Stieglitz, and X. Navarro, “Long
term assessment of axonal regeneration through polyimide regenerative electrodes
to interface the peripheral nerve,” Biomat., vol. 26, no. 14, pp. 2021–2031, 2005.
[25] C. Veraart, F. Duret, M. Brelén, M. Oozer, and J. Delbeke, “Vision rehabilita-
tion in the case of blindness,” Expert Rev. Med. Devices, vol. 1, no. 1,
pp. 139–153, 2004.
[26] T. Stieglitz, R. Keller, H. Beutel, H.H. Ruf, A.A. Robitzki, and J.-U. Meyer,
“Hybrid integration of a retina implant system for people suffering from retinitis
pigmentosa,” Med. Biol. Eng. Comp., vol. 37, suppl. 2, pp. 1102–1103, 1999.
[27] P. Walter, P. Szurman, M. Vobig, H. Berk, H.C. Lüdtke-Handjery, H. Richter,
C. Mittermayer, K. Heimann, and B. Sellhaus, “Successful long-term implantation
of electrically inactive epiretinal microelectrode arrays in rabbits,” Retina, vol. 19,
no. 6, pp. 546–552, 1999.
[28] P. Walter, Z.F. Kisvárday, M. Görtz, N. Alteheld, G. Rössler, T. Stieglitz, and
U.T. Eysel, “Cortical activation with a completely implanted wireless retinal pros-
thesis,” Inv. Ophthalmol. Vis. Sci., vol. 46, no. 5, pp. 1780–1785, 2005.
SEPTEMBER/OCTOBER 2005 65