Progress in Neurobiology Vol. 55, pp.

433 to 461, 1998

# 1998 Elsevier Science Ltd. All rights reserved
Printed in Great Britain
0301-0082/98/$19.00

PII: S0301-0082(98)00013-6

IMPLANTABLE BIOELECTRONIC INTERFACES FOR LOST

NERVE FUNCTIONS

P. HEIDUSCHKA* and S. THANOS*$

*University Eye Hospital MuÈnster, Experimental Ophthalmology, Domagkstraûe 15,
D-48149 MuÈnster, Germany

(Received 6 January 1998)

AbstractÐNeuronal cells are unique within the organism. In addition to forming long-distance connec-
tions with other nerve cells and non-neuronal targets, they lose the ability to regenerate their neurites
and to divide during maturation. Consequently, external violations like trauma or disease frequently
lead to their disappearance and replacement by non-neuronal, and thus not properly functioning cells.
The advent of microtechnology and construction of arti®cial implants prompted to create particular
devices for specialised regions of the nervous system, in order to compensate for the loss of function.
The scope of the present work is to review the current devices in connection with their applicability
and functional perspectives. (1) Successful implants like the cochlea implant and peripherally implanta-
ble stimulators are discussed. (2) Less developed and not yet applicable devices like retinal or cortical
implants are introduced, with particular emphasis given to the reasons for their failure to replace very
complex functions like vision. (3) Material research is presented both from the technological aspect and
from their biocompatibility as prerequisite of any implantation. (4) Finally, basic studies are presented,
which deal with methods of shaping the implants, procedures of testing biocompatibility and modi®-
cations of improving the interfaces between a technical device and the biological environment. The
review ends by pointing to future perspectives in neuroimplantation and restoration of interrupted neur-
onal pathways. # 1998 Elsevier Science Ltd. All rights reserved

CONTENTS

1. Introduction 434
2. Implantable electrodes 435
2.1. General remarks 435
2.2. Electrodes implanted without nerve cut 435
2.2.1. Cu€ electrodes 435
2.2.2. Penetrating electrodes 437
2.3. Electrodes for regenerating nerves 438
3. Biocompatibility 441
3.1. General remarks 441
3.2. Implant materials 441
3.3. Response to implantation 442
3.4. Surface modi®cation 443
3.4.1. Surface roughening 443
3.4.2. Chemical modi®cation 443
3.4.3. Speci®c modi®cations 444
4. Auditory implants 445
4.1. Brain stem implants 446
4.2. Cochlea implants 446
5. Visual implants 449
5.1. Retinal prostheses 449
5.2. Cortical prostheses 451
6. Other neuroprosthetic implants 452
6.1. Bladder stimulation 452
6.2. Stimulation of spinal cord and brain 454
7. Final conclusions 455
References 455

$ Author for correspondence. Tel.: 49 251 83 56915; Fax: 49 251 83 56916; e-mail: solon@uni-muenster.de.

433
434 P. Heiduschka and S. Thanos
ABBREVIATIONS
ABI Auditory brain stem implant
ANN Arti®cial neural network
BDNF Brain-derived neurotrophic factor
CNS Central nervous system
ECM Extracellular matrix
FES Functional electrical stimulation
IFN Interferon
IL Interleukin
1. INTRODUCTION
Diseases and accidents associated with damage of
nerves, in particular within the CNS, often have dra-
matic consequences. The ®rst reason is that appro-
priate regeneration of the central neuronal
connections and restoration of synaptic connections
are not possible in most cases. This results in failure
of functional recovery. The second reason is that
dying and disposed neurons cannot be replaced by
new neurons. This cascade of interactive events
results in glial proliferation and in inadequate
repair, called gliosis. In contrast to CNS, bundles of
the peripheral nerve system like in the limbs display
di€erent responses to experimental or accidental cut:
the axons can regenerate, the cell bodies do not
degenerate and there is virtually no need for gliosis
and replacement of the lost neurons. De®cits along
peripheral nerves may be reconstructed spon-
taneously or surgically, and physiological properties
of the function are regained after regeneration of
axons and synapse formation. The ®nal functional
use of the corresponding target deserves some train-
ing, as directly associated with synaptic reorganisa-
tion, potentiation and trophic in¯uences at the
neuromuscular endplates. However, such restorative
events are limited to less complex and unilaterally
oriented pathways, like the innervation of a single
muscle or the arrangement of nerves with topologi-
cally and functionally distinctive targets.
In spite of the ability of peripheral nerves to re-
generate, surgical repair of nerve damage is not as
easy or even not possible for several reasons:
. the nerve is not accessible to surgically join the
proximal with the distal stump,
. some neurons die inevitably due to hereditary
neuromuscular diseases,
. the axons cannot be guided through the proper
pathway for their regeneration, and/or
. regenerating axons do not ®nd their targets for
synaptic connections.
Diculties in surgery apply especially to the CNS
where most surgical interventions are not possible
without destroying neighbouring parts of the nerve
tissue, where the network-like highest complexity of
multiple circuits has been formed during develop-
ment. In this network, molecular guidance does not
properly work any more, and oligodendrocytes seem
to form an environment which inhibits axonal
growth. Moreover, damaged neurons can be
destroyed by additional local mechanisms, probably
developed to eciently remove the sick elements
and preserve the remaining structural and functional
MEA Microelectrode array
NT-3 Neurotrophin-3
PET Polyethylene terephthalate
PTFE Polytetra¯uoroethylene
RGC Retinal ganglion cells
RP Retinis pigmentosa
TNF Tumour necrosis factor
VEP Visually evoked potential.
integrity of the tissue. Finally, astrocytes are respon-
sible to ®ll the structural gaps with proliferation and
to communicate will all other elements, thus balan-
cing the de®cits.
Frequently, whole organs or part of the body are
removed or destroyed, e.g. a limb is lost which can-
not be replaced naturally, ultimately demanding an
external intervention. In such cases, rudimentary
organ of body functions (stability, standing up,
walking) can be in part compensated with external
mechanical prosthetics. However, they are not act-
ing on the neural function, but replace the periph-
eral muscular, bone or joint functions. It seems
desirable, but only in extremely rare cases possible
to date, to develop prosthetic interfaces between the
nervous system and its various peripheral targets.
These diculties are multiple and require ®rst the
profound understanding of the neuronal circuitry
and function and second a directed ¯ow of neuronal
information from its natural origin through a sen-
sing prostheses into a ®nal target in a functionally
remodelled form.
A classical injury resulting in devastating func-
tional impairments is the incision of spinal cord
with usually combined lesions of ascending and des-
cending paths, in addition to local necrosis of
intraspinal neurons. One of the predominant ®elds
of prosthetic intervention in the future will be the
cure of paraplegic and paralytic individuals with
best results until now towards to reconstruct the
simpler re¯exes like that of the urinary bladder func-
tion. Other work is carried out in order to stimulate
muscles of the legs and the back in order to make
possible getting up, standing or even walking. First
attempts to achieve regeneration of neural connec-
tions through regenerating nerves in the spinal cord
have been made, but they are still far away from
restorative applicability.
Smaller, well integrated sensory organs and com-
partments may be more accessible to so-called arti®-
cial sensors where a direct connection between
electronic devices and nerves is needed. The prob-
ably most popular application where di€erent
devices work bene®cially is the cochlear implant.
Conceptually, further sensory organs may be
replaced by miniaturised and adaptable devices too.
However, their success is limited up to date,
although various concepts have been developed, e.g.
to replace the retinal function with subretinal or
epiretinal implants. In addition, further approaches
were devoted to replacing the optic nerve with per-
ipheral nerve implants, with limited success in
regaining function, but encouraging results towards
understanding the mechanisms of axonal regener-
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
ation and opening a new ®eld of natural neuopros-
thetics in combination with arti®cial prosthetic
devices.
It is desirable, however, that all arti®cial
approaches are accompanied by endeavours to fa-
cilitate the natural approach, i.e. the regeneration of
axons towards their natural targets and fresh for-
mation of new synapses leading to at least partial
functional recovery.
The goal of this work is to critically review some
aspects of these approaches, particularly the
required functional abilities of implants, the design
of microelectrode arrays (MEAs) for optimal func-
tion and bio-(neuro-)compatibility, their biologically
proper implantation and their function for recording
of nerve signals and/or stimulation of nerves and/or
muscles.
2. IMPLANTABLE ELECTRODES
2.1. General Remarks
The nervous system is the most complex biologi-
cal system and is therefore characterised by high
vulnerability to external violence and genetic dis-
turbances. Profound knowledge about its develop-
ment, functional consolidation and structural
organisation is prerequisite for any attempt to estab-
lish good recording or stimulation in order to treat
defects in a proper way. A number of proposed
ideas for electronic implants is based on a more ``en-
gineer-like'' way of thinking than considering the
complexity of the biological systems. For instance,
nerve ®bres are not ``wires'' or ``cables'' in the mech-
anical point of view, but long, sensitive structures
consisting of biological membranes with multiple
receptors and delicate interactive elements for on-
line sensing the environment and transmitting infor-
mation via molecules, potentials and changes in the
chemo-electrical activity. The principal requirements
to any implantable structures are therefore features
mimicking some of the biological functions of nerves
and replacing these functions depending on the
scope of implantation.
Many e€orts have been undertaken to interface
electronics to nerves, and there is a reasonable num-
ber of successful applications with di€erent goals.
The aim of using implants in basic research is to
understand working principles of the brain, to ana-
lyse processing of information, to unravel principles
of connectivity within the nervous system and to
study cell±cell interactions in subsets of neuronal
populations. Another goal is to replace functions
which are lost due to damage of the nervous system.
In this context, some attempts are concentrated on
sensory functions and stimulation of muscles by
implanted electrodes and on development of closed-
loop ``neuronal prostheses''. Microtechnology and
microelectronics have obtained impressing capabili-
ties which have to be combined with possibilities of
modern biology and medicine under careful con-
sideration of possibilities and constraints of neuroa-
natomy and neurophysiology. In fact, implantation
of electrodes for nerve signal recording and nerve
stimulation has been carried out for some couples of
435
years with success, and there are also some promis-
ing concepts for the future and interesting
approaches for special applications. A review about
the basics and di€erent aspects of neural prostheses
is given by Agnew and McCreery (1990a).
The success of neural prostheses depends basically
on their capability to record nerve signals and/or to
stimulate nerves and muscles. It is obvious that such
implants must ful®l very special requirements which
are directed to the electrodes and the substrate
which carries the electrodes. Prerequisite of attach-
ment to nerves and sustaining there is the biocom-
patibility for nerve-speci®c implants, or more strictly
spoken, their neurocompatibility as shall be
addressed later.
The substrate which carries the electrodes must be
completely insulating to prevent cross-talking
between them. The choice of the material will also
depend on the possibilities and restrictions arising
from the fabrication process. In microelectronics,
silicon is most frequently used. However, in the ma-
jority of implantation cases, it will be of favour to
use ¯exible material for the implants in order to
mimic biological tissue and to reduce the possibility
of mechanical damage. As one of these ¯exible ma-
terials, polyimide obtained attention in the last
years.
As they are directly in contact with the nerve of
interest, the appropriate construction of the
implanted electrodes is of key importance for the
success of the whole arti®cial system. They have to
be of a size comparable with the size of the neurons
in order to interact only with few or even one neur-
on. If electrodes are intended to interact with nerve
®bres, i.e. axons, in the case of myelination their
``radius of action'' has to be sucient to reach the
nearest node of Ranvier. The small size requires
optimised geometry and electrical properties for suf-
®cient recording ability and a high relative charge
transfer capacity. Moreover, all components have to
be adapted to this, i.e. electronic units are needed
with a high sensitivity, a high signal-to-noise ratio,
and sucient shielding between single channels
within the device and against external interferences.
2.2. Electrodes Implanted Without Nerve Cut
2.2.1. Cu€ Electrodes
The term ``cu€ electrodes'' applies to those
devices which engulf the entire circumference of a
nerve. The shape of these electrodes or of the array
of electrodes has to be adapted to the natural
arrangement and thickness of neurons or axons by
also taking in account the vascularisation at the site
of implantation.
Cu€ electrodes are applied preferably at periph-
eral nerves. The advantage of cu€ electrodes is that
implantation is relatively easy and that the nerve is
not damaged by proper surgical implantation.
Possible displacement along the nerve bundle can be
circumvented by mechanical ®xation at the site of
interest. First models carried only one or two elec-
trodes. They were made using a platinum foil
(``split-cylinder'', Avery, 1973) or platinum wires
embedded into insulating material (``wrap-around'',
436 P. Heiduschka and S. Thanos

Hagfors, 1972). The ®rst models have been rather
sti€, often resulting in damage of nerves due to
mechanical displacement, or pressing the nerve
®bres, or disturbing the vascularisation and causing
ischemia. Modern cu€ electrodes try to avoid this
by the introduction of ¯exible materials and adapt-
able geometries, like a helix-shaped electrode
(Agnew et al., 1988) or a spiral-cu€ electrode
(Rozman, 1991) which allow adjustment of the
implant to the actual diameter of the nerve ®bre
bundle. Another possibility is the application of so-
called ``half-cu€'' electrodes ®rstly described by Kim
et al. (1983) and patented by Testerman and
Bierbaum (1994). A particular design is the arrange-
ment of ¯exible interdigitating sub-units with micro-
electrodes along a backbone-like carrier (Klepinski,
1994; Meyer et al., 1995). Models of these two de-
signs are shown in Fig. 1.
First models of cu€ electrodes did not completely
ful®l the requirements for accurate measurements,
because they only allowed recording of super®cial
sum potentials with the axons in the centre of the
nerve cylinder to contribute less signi®cantly to the
measured signal. In accordance, the inner axons
were less a€ected by stimulation than the super®cial
axons of the bundle. For this reason, advanced
models of cu€ electrodes have been developed with
more smaller electrodes arranged around the per-
imeter of the ®bre bundle which allowed to
approach central axons too. Topographic stimu-
lation of nerve ®bres within a given nerve bundle
may sometimes be important, because di€erent
muscles may be innervated by the ®bres of selective
localisation within the bundle, and often a mixture
of e€erent and a€erent ®bres occurs in the nerve.
Such mixed populations may lead to undesirable
sensations during stimulation. In the case of several
nerve ®bres innervating di€erent muscle ®bres of
one muscle, cyclic stimulation can be performed
which guarantees overall stimulation frequency,
while stimulation frequency and thus fatigue of a
single muscle ®bre can be low (Happak et al., 1989;
Talonen et al., 1990). With a sucient number of
electrodes within the cu€, high selectivity of stimu-
lation can be achieved by either longitudinal or
transversal currents produced by appropriately
switched electrodes (Veraart et al., 1993). However,
there is still the problem of possibly di€erent ®bre
diameters which leads to di€erent activation
thresholds of the ®bres. Goodall et al. (1996) found
that large ®bres were activated before smaller with a
cu€ electrode containing 12 electrodes arranged in
four longitudinal tripoles, irrespective of ®bre pos-
ition. Position selectivity could be enhanced by a
higher ratio of transversal to longitudinal currents.
Nevertheless, the main prerequisite for successful

Fig. 1. Models of two recent possibilities of the design of cu€ electrodes. Left row: A ``half-cu€'' elec-
trode which surroundes the nerve and is secured with suture. Dots represent microelectrodes which are
placed along the cu€ and allow selective recording and stimulation (Kim et al., 1983). Right row: A ¯ex-
ible interdigitating cu€ electrode (``FLIC'') where microelectrodes are placed along ``®ngers'' which bend
to form a tube for the nerve (Klepinski, 1994; Meyer et al., 1995).
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
application of such sophisticated electrode designs
and stimulation protocols is detailed knowledge of
the distribution of nerve ®bres within the nerve bun-
dle and their function. Moreover, a really reliable
®xation of the cu€ must be achieved because other-
wise the cu€ may rotate around the nerve or shift
along the nerve, both leading to loss of selectivity.
2.2.2. Penetrating Electrodes
The so-called penetrating electrodes are another
type of electrodes aiming to directly approach nerve
®bres situated deeper in the tissue. The ®rst pene-
trating electrodes were simply thin metal wires or
needles which were inserted into the nervous tissue.
They often were insulated except a region on the tip.
The other possibility was to use glass micropipettes
pulled out to very small inner diameters and ®lled
with saline. They also can be inserted into nervous
tissue, and signals are recorded by a thin metal wire
electrode within the pipette. For simplicity, but
wrongly, the glass micropipettes themselves often
are designated as ``electrodes''. One recent example
for the use of such pipettes is given in the work by
Welsh et al. (1995), who investigated the role of the
inferior olive, a major cerebellar a€erent, by record-
ing the activity of the Purkinje cells. For this pur-
pose, they positioned up to 39 glass micropipettes
with electrodes (®lled with saline, 1±2 MO, 2±4 mm
tip diameter) independently 100±125 mm below
3 mm2 of the cortical surface of rats, with a distance
between the electrodes of 250 mm. This procedure is
really time-consuming, and its application is limited
by its complexity. The animals have to be anaesthe-
tised and held in a ®xed position. Moreover, the
position of the electrodes is not optimised with
respect to the location of the desired target, in this
work the Purkinje cell layer, but recorded signals
are used from those electrodes which are placed at
best by chance.
Wedge-shaped microprobes carry a line of elec-
trode sites for recording and stimulation and may
therefore be designated as ``one-dimensional'' arrays
[Fig. 2(A), BeMent et al., 1986; Ensell et al., 1996;
Kewley et al., 1997]. Typical dimensions are in the
range of 2 mm for the shank length, 100 mm for the
width and 20 mm for the thickness, but there are
already smaller structures in development. An on-
chip electronic circuitry would allow pre-ampli®ca-
tion and ®rst processing, but it is not yet realised in
most cases. Howard et al. (1996) built a recording
array where they combined high-impedance micro-
electrodes with low-impedance EEG electrodes, and
activity of human cortical neurons could be
recorded.
For signal recording and stimulation over a larger
area, e.g. areas of the cortex, two-dimensional
MEAs are necessary as they are known as solid pla-
nar arrays for in vitro experiments (Wilson et al.,
1994; Nisch et al., 1994; Gross et al., 1995; Bove et
al., 1997). A ¯exible planar MEA with polyimide as
substrate and 24 gold microelectrodes (40  40 mm,
210 mm spacing) was made for recordings of electri-
cal activity of the cortex (Owens et al., 1995).
Improvement of recording structures was achieved
by silicon microtechnology which made it possible
437
Fig. 2. Di€erent layouts of penetrating electrodes. (A)
Wedge- or shank-shaped electrode carriers are one of the
most common designs developed and applied by several
groups. In many cases, more than one shank are combined.
Typically, the shanks are 1±3 mm long, 30±100 mm wide
and 8±20 mm thick. (B) Proposed structure of an array of
needles carrying multiple electrode sites thus reaching a
really three-dimensional arrangement. (C) A combination
of cu€ and penetrating electrodes (Durand and Tyler,
1995; Tyler and Durand, 1997). Only one possible design
of the implant is shown in opened and closed states. The
electrodes penetrate the nerve when the cu€ is bent around
the nerve. (D) Flexible nerve plate (Meyer et al., 1995)
which can be inserted into nerve tissue, e.g. the retina or
the cortex, or into a peripheral nerve fascicle.
to create not only planar two-dimensional MEAs
but also penetrating electrode structures for in vivo
measurements. The substrate carrying the electrodes
is either needle- or wedge-shaped to allow pen-
etration of the nervous tissue which makes possible
recording from and stimulation of axons not only
on the surface but also in a well-de®ned depth
within the tissue, e.g. within the ®bre bundle or
regions of the brain. Implanting such a device is
also associated with an accidental damage of the tis-
sue, i.e. some neurons will be destroyed, and a cer-
tain portion of the axons will be disrupted.
Moreover, sti€ness of many models may lead to
damage of nervous tissue. That is why the e€orts
are directed to miniaturise the penetrating parts of
the implant and to use more ¯exible materials.
Nordhausen et al. (1996) reported about a silicon-
based two-dimensional MEA shaped as a grid of
10  10 needle electrodes with a spacing of 400 mm.
The needles are approx. 80 mm wide at the base and
1.5 mm in length. They are insulated with polyimide
except for approx. 50 mm at the tip, the latter being
coated with platinum to form the active electrode.
The electrode array was successfully applied for the
recording of local visually evoked responses in the
visual cortex of cats at sub-sets of 15 electrodes
(Nordhausen et al., 1996), and these measurements
were continued in order to re®ne recording and sig-
nal processing procedures (Maynard et al., 1997).
A similar approach was performed by Rutten et
al. (1995). They created a three-dimensional needle
array with 128 recording sites with one electrode on
the tip of a needle. The needles are made from sili-
con and are embedded into a glass substrate. They
vary in height from 250 to 600 mm and have a dis-
tance of 120 mm, with a tip size of 15  15 mm. The
di€erent length of the needles should allow reaching
438 P. Heiduschka and S. Thanos
approximately three-dimensional areas of nervous
tissue, e.g. in a peripheral nerve fascicle.
It could be suggested that the optimal MEA
would be one with the possibility to move each
single electrode separately to its best place in order
to optimise recording or stimulation. On the one
hand, this is limited by the possibilities of microtech-
nology, because it would be very complicated to de-
sign and fabricate a MEA with independently
movable and mechanically stable electrodes with
perfect conduction of signals and insulation in the
aqueous surrounding. On the other hand, there is
the biological issue to ®nd out which place within
the nervous tissue is actually the best for the desired
purpose. This is time consuming, and it is dicult to
predict how much of the nervous tissue is damaged
during penetration of the electrodes and their lateral
movement.
In view of these problems, it would be useful to
combine the approaches mentioned above and cre-
ate a three-dimensional MEA by arranging needle
probes in a grid with electrodes placed along the
probe shank as shown in Fig. 2(B). This would pro-
vide a high-density three-dimensional arrangement
of electrode sites, and best of them could then be
found out after successful implantation by testing
recording or stimulation characteristics.
Of course, there is a huge number of technical
problems associated with the very small dimensions
of MEAs and also of the design shown in Fig. 2(B).
One of the problems is that, on the insulating sub-
strate, conducting electrode sites and leads must be
placed. A second problem is that cross-talk between
the leads and leakage have to be avoided. A third
drawback is that with increasing number of electro-
des the number of leads increases too, which
demands an intricate on-chip design and reliable
connections and cables to electronic processing
units. Furthermore, the whole set-up must operate
reliably over a long time period. Last but not least,
processing of a high number of channels requires a
sophisticated microelectronics which may not be too
big and energy-consuming for practical every-day
use.
With the technological advance in the ®eld of con-
structing ¯exible polymeric substrates, so-called
``¯exible nerve plates'' come into development
[Fig. 2(D), Meyer et al., 1995]. They consist of a
¯exible substrate which carries a MEA and possibly
other elements of a microelectronic circuitry. The
¯exible nerve plate could be applied in a big variety
of tissues and organs. For instance, it could be
inserted into the retina or longitudinally between the
®bres of a nerve bundle or a muscle, and act there-
fore as a kind of penetrating electrode in these
cases, or it could be placed onto the surface of
special regions of the cortex depending of the scope
of the experiment. The ¯exibility of the nerve plate
would allow better protection of nerve tissue and
very short distances between electrodes and neurons
or ®bres which are necessary for an optimum decod-
ing of nerve signals or transmitting stimuli to the
nerves.
As for cu€ electrodes, the geometry and the
arrangement of penetrating electrode array vari-
ations are currently optimised to ®t with geometrical
nerve ®bre characteristics (®bre position in a bundle,
diameter of the ®bres and their orientation).
In¯uence of speci®c anode±cathode combinations
and stimulus parameters are also under research.
There are some research projects dealing with the
development of a computer-assisted control of sti-
mulating potential pulses for the formation of
spatially distinguished electric ®eld within the ner-
vous tissue which allow selective stimulation of the
desired neurons. By sophisticated control of the
height and time of applied potential pulses, a more
discrete stimulation of the axons can be achieved.
Such e€orts are undertaken for electrode arrays for
both central and peripheral nerve systems.
2.3. Electrodes for Regenerating Nerves
A di€erent approach is performed by the so-called
``electrodes for regenerating nerves''. They are
designed as a MEA placed on a sieve-shaped (i.e.
perforated) plate which contains holes which can be
round or rectangular or even shaped as long narrow
slots. The microelectrodes are situated nearby the
holes or are part of the hole's wall in order to opti-
mally record or to stimulate. The principal idea can
be described very brie¯y: The nerve is cut ®rstly,
then the electrode array is adapted into the expected
path of the regenerating ®bres in a fashion that the
nerve ®bres are allowed to regenerate through the
perforations of the device (Fig. 3). The distal stump
of the cut nerve is aligned at the opposite side of the
electrode array in order to be used by the axons
exiting from the perforations as a guidance path for
further growth. In most cases, the perineural sheath
of the nerve can be replaced in the area of insertion
with polymeric tubes which act as mechanical stabil-
isers.
The advantage of this approach is that with this
device the electrodes are in intimate contact with the
nerve ®bres, this allowing both accurate recording
and ecient stimulation. Both procedures are
expected to be performed relatively reliable because
with a proper choice of the hole diameter a predict-
able number of axons would regenerate through in-
dividual perforations. Moreover, the micro-
electrodes remain always in the same position rela-
Fig. 3. Principal concept of regenerative electrodes. Axons
regenerating from the proximal stump of a dissected nerve
grow through a permissible array of electrodes carried by a
substrate. The array may be designed as a kind of mesh or
sieve. Latticed arrangements are also possible. The aper-
tures (holes) of the substrate determine and ®x the position
of the regenerating axons relative to the electrodes.
 Implantable Bioelectronic Interfaces for Lost Nerve Functions 439

tively to the nerve ®bres because the ®bres are ®xed

by the holes they grow through.
The obvious drawback of this method is that the
nerve has to be cut in order to regenerate through
the implanted device. The success of the whole oper-
ation can be evaluated only several weeks later,
when the axons have regenerated through the
device. The second disadvantage is its applicability
only in peripheral nerves, because central nerve
pathways do not regenerate spontaneously. The
third disadvantage is that the device limits the regen-
eration of some neurites, namely of those, whose
growth cones hit on the device and fail to elongate
within one of the pre-drilled holes. In spite of these
limitations, such electrodes display an elegant way
of application in the peripheral nerves.
Indeed, attempts to develop and utilise such elec-
trodes have been performed continuously since the
sixties (for an overview, see Kovacs and Rosen,
1992). Mannard et al. (1974) combined 10 silver
wires in a conical bundle. They were carried by a
¯attened epoxy bulb where holes have been drilled
in. LlinaÂs et al. (1973) proposed a relatively
advanced concept for an electrode device with a
radial array of gold electrodes surrounding the
holes. Loeb et al. (1977) reported on the fabrication
of an electrode array with 0.3±1.2 mm long tubes
the regenerating axons should be growing through.
Edell (1980) developed a structure with long narrow
slots for nerve ®bre regeneration. Electrodes were
placed on the thin interspaces between the slots. Fig. 4. Electrodes for regenerating nerves as made by (A)
Rosen and Grosser (1986) also proposed a concept Akin and Naja® (1991) and (B) Kovacs et al. (1991).
of ``regenerative electrodes'' in order to ``restore Redrawn from original papers with permission from the
authors and IEEE.
normal nerve impulse communication and hence
nerve function''. A micromachined silicon electrode
was made by Akin and Naja® (1991). After implan- limit per se the number of connections with individ-
tation, nerve regeneration through this device could ual holes. The shortage of surface of a microchip
be achieved with the glossopharyngeal nerve of rats limits both the number and the size of holes for a
as model system (Bradley et al., 1992), and nerve given electrode.
signals could be recorded (Akin et al., 1994), even The minimum requirement for a perforating elec-
over a longer time period (Bradley et al., 1997). A trode is that growth cones ®t within the individual
complete set-up of a perforated electrode with a hole and pass through its lumen without disturb-
MEA was also developed and applied by Kovacs ances in their growth properties, and later on, in
(1991). After implantation into the peroneal nerve in their conduction velocities. It does not seem critical
the hind limb of rats, some spontaneous action po- whether the holes are round or rectangular.
tentials could be recorded (Kovacs et al., 1992). Experiments of di€erent groups showed that,
Later on, more extended recordings from the rat depending on the nerve where the chip is placed, the
peroneal nerve and the bullfrog cranial nerve were minimum size of a hole should be around 2±5 mm,
reported (Kovacs et al., 1994). The two last devices and thus in the range of the thickness of a single
are shown in Fig. 4. Recently, a perforated MEA axon. Some groups use hole sizes between 25 and
was described which was implanted between the cut 50 mm and expect that more than one axon can
ends of the rat sciatic nerve (Navarro et al., 1996). grow through each hole. The natural intention of a
Another description of this MEA was given by quantitatively high performance of regeneration
Dario et al. (1997). requires as many small or larger holes as possible.
The biological and technical aspects concerning Higher density of holes limits, on the other hand,
the electrodes with perforating paths are complex the free space for connecting the electrodes on the
and do not permit a simpli®cation in use, neither a microchip. A compromising way to use fewer con-
generalisation in terms of their applicability, mainly nections with more bioelectronic interfaces is the
due to the traumatic procedure of implantation. multiplexing of the electrodes, although this process
Although techniques of microfabrication have cannot be forced endlessly. Thus, the scope of the
been developed rapidly during the last years, some experimental design in individual cases determines
problems arise if a large number of microelectrodes the ratio between number of perforations and num-
with the accompanying connections has to be placed ber of electrodes, again depending on the cross-sec-
and ®xed on a silicon chip. These problems are tional area of the nerve to be used. As an example,
enhanced in electrodes for regeneration, because the a ratio of 2.5:1 between the area of the chip bearing
holes take a big part of the total surface area and the holes and the cross-sectional area of the nerve is
440 P. Heiduschka and S. Thanos
considered to be good for the regeneration of a big
portion of axons (X. Navarro, personal communi-
cation). The physical need of space for the connec-
tions also determines a minimum possible distance
between neighbouring holes. Nowadays, connection
widths of only some mm can be realised, so that dis-
tances between the edges of holes of 10±20 mm are
possible.
A further critical point that is associated with the
biological constraint of nutrition is the distance the
regenerating axons have to get through the holes. In
technical terms, this corresponds to the thickness of
the chip. There have been some extreme cases, e.g.
by Loeb et al. (1977), where that distance was more
than 1 mm. However, neurites are vulnerable to hy-
poxic conditions which have to be expected for the
1 mm nerve segment within the hole. It may be
speculated that this was the reason for lacking suc-
cess in biological regeneration experiments.
Nowadays, most of the perforated substrates are
constructed with the holes and the electrodes to be
situated on a very thin membrane (4±10 mm) which
is held by a thicker surrounding frame. The frame
(usually 100±300 mm thick) ®rst stabilises the mem-
brane, and secondly carries pre-processing circuitry,
bonding pads for external connections, etc.
In addition, other components of the implant, e.g.
nerve guidance channels, are ®xed on the frame.
These nerve guidance channels also must permit re-
generation of axons, particularly by allowing supply
of the ®bres with oxygen and nutrients.
Despite the good theoretical understanding of the
demands on a device for regenerating nerve ®bres,
the big progress in microfabrication and microelec-
tronics and the hard experimental work on this
®eld, the real break-through seems not to have been
achieved until now. Reliable nerve regeneration
through the holes still is not guaranteed, the
researchers often encounter mechanical problems
with the implant (broken connections, etc.), and the
signals recorded ®nally by the device often turn out
to be of non-neuronal origin.
The microsurgical technology for the implantation
of electrodes applies to peripheral nerves whose
axons regenerate and can pass through the o€ered
holes of perforated chips. Since regeneration of cen-
tral nerves is possible only in particular sensory sys-
tems, e.g. optic and olfactory nerves of animals
under conditions of grafting, the contemporary elec-
tronic devices may be ®rst optimised within the per-
ipheral nervous system only. Besides the basic
advantage to regenerate, peripheral nerves are well-
accessible to surgery, are round and thus adjustable
to electronics, and the success of implantation is
easier to investigate. In contrast, most of the central
nerve pathways are hidden within the skull or spinal
cord and intermingled with neighbouring pathways,
thus becoming inaccessible to the microsurgery men-
tioned above. The only example of a central nerve
which may be the target for such a surgery is o€ered
by the optic nerve whose extracerebral portion
becomes of increasing importance in the regener-
ation research.
According to our current knowledge, the optic
nerve may receive key function in the attempt to
transfer the microtechnology from peripheral nerves
into the CNS. One possible approach is sketched in
Fig. 5. It is based on the optic nerve regeneration
model which was established in the eighties (Vidal-
Sanz et al., 1987) and was studied extensively during
the last years (Thanos, 1992; Thanos and Mey,
1995; Thanos et al., 1993, 1996, 1997). After cut of
the optic nerve, the stump of the optic nerve is con-
nected with an autologous peripheral nerve graft
which permits the axons of the retinal ganglion cells
(RGCs) to regenerate and leads the regenerating
axons into their natural area of destination, e.g. the
superior colliculus or the thalamus. Vision of the ani-
mal could be restored partially, as could be shown
by the restoration of the pupilloconstriction re¯ex
(Thanos, 1992) and by behavioural and electro-
physiological experiments (Thanos et al., 1997).
In ongoing studies, a perforated MEA is placed
between the optic nerve stump and the peripheral
nerve graft, i.e. directly into the path of the regener-
ating axons. By this way, it should be possible to
record nerve signals of a part of the surviving and
regenerating RGCs with connections within the su-
perior colliculus. The ®rst results indicate that RGC
axons grow through such a perforated implant and
encourage to use these implants for long-term bio-
compatibility and recording experiments.
Fig. 5. Scheme of proposed application of a MEA for
regenerating nerves in the CNS. The MEA is placed into
the path of the regenerating optic nerve. Axons grow
through the holes into the peripheral graft and may reach
the superior colliculus. In order to visualise the surviving
RGC and their axons, the lipophilic ¯uorescent dye 4-Di-
10-ASP (Molecular Probes, Eugene, OR) was placed at the
site marked by the asterisk. The dye was then transported
retrogradely into the retina as indicated by the open arrow.
The photograph shows surviving RGC and their dendrites
as well as several axons running across the retina. The
MEA was made from perforated polyimide with thin plati-
num electrodes (whole thickness 10 mm) and was kindly
provided by J. U. Meyer and T. Stieglitz, Fraunhofer
Institute for Biomedical Engineering, St Ingbert, Germany.
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
3. BIOCOMPATIBILITY
3.1. General Remarks
The major prerequisite for the application of
implants, e.g. neuroprostheses, is that the organism
accepts the implant, i.e. that the implant is biocom-
patible. It is widely accepted to de®ne biocompatibil-
ity as ``the ability of a material to perform with an
appropriate host response in a speci®c application''
(Williams, 1987). This broad de®nition comprises
aspects of biological, chemical and physical proper-
ties of the implant which will be addressed in this
chapter. Nevertheless, the concept of biocompatibil-
ity is still disputed and depends strongly on the ap-
plication ®eld of implants. Whereas in some cases
surface (chemical) composition of the implant is an
important parameter, in other cases physical proper-
ties (size, shape, sti€ness) are the major determi-
nants of biocompatibility, particularly under the
in¯uence of locomotion (Boss et al., 1995).
An implantation is always a traumatic interven-
tion. However, one important way to minimise the
consequences is a high biocompatibility of the
implant. An implant can be considered to be bio-
compatible if
. it does not evoke a toxic, allergic or immunologic
reaction,
. it does not harm or destroy enzymes, cells or tis-
sues,
. it does not cause thrombosis or tumours,
. it remains for a long term within the organism
without encapsulation or rejection.
For a long-term stable neuroprosthesis, the whole
implant must have mechanical and geometrical
properties which ®t to the site of implantation in
order to minimise traumatic lesions. The concept of
biocompatibility is not limited to non-toxicity, but
encloses physical and chemical surface properties
and whole behaviour of the implant in its biological
environment as well. Therefore, two areas have to
be considered, the ``biosafety'' and the ``biofunction-
ality''. Biosafety means that the implant dos not
harm its host in any way, and biofunctionality
means that the implant acts in the body as it was
intended. In addition, ``biostability'' is important
which means that the implant must not be suscep-
tible to attack of biological ¯uids, proteases, macro-
phages or any substances of the metabolism. For
example, implants may be subject to continuous
attack by hydrolytic enzymes (Salthouse, 1976) or
free radicals produced by monocytes and/or cell
lysis. Stability of implanted material is important
not only for stable function, but also because degra-
dation products may be harmful for the host organ-
ism. Overviews about biological reactions to
implanted materials have been given, e.g. by Hench
and Ethridge (1982), Anderson (1988), Tang and
Eaton (1995), and Ratner et al. (1996).
Once implanted, a neuroprosthesis has to remain
within the body of the patient for many years. In
some cases, it is intended to cover the whole life of
the patient. This is in particular obligatory in
implants for regenerating nerves, because they
would have to be cut again in order to remove the
441
implant. This implies extreme demands on stability
of function and set-up of the implant. Where necess-
ary, e.g. in muscle tissue or in joints, wires and sub-
strates have to be ¯exible enough to allow multiple
bending without damage of surrounding tissue and
without breaking at the end. Sharp edges which
could damage cells and tissues or rough surfaces
which allow attachment and growth of microbes
have to be avoided. No corrosion is allowed, and
insulating polymers must keep their insulating prop-
erties. The implant must remain in its implantation
site, thus a reliable ®xation must be guaranteed, e.g.
by appropriate suturing. In addition, used polymers
may not release any substances, e.g. monomers or
oligomers, modi®ers, sterilising agents like ethylene
oxide, etc. In addition to the implant itself, also ma-
terials used for the ®xation of an implant must be
biocompatible, as addressed in the perspectives of
brain implants by Mo®d et al. (1997).
The exception where release of substances is
intended are so-called drug delivery systems.
Antibiotics, hormones and growth factors could be
released in order to prevent sepsis and to improve
wound healing, tissue repair and nerve regeneration.
The materials of these systems also must be biocom-
patible, with particular emphasis on preventing pro-
tein adsorption and platelet adhesion which could
hinder the substances to be released (Park and Park,
1996).
3.2. Implant Materials
It is obvious that requirements towards implants
are very high. Nevertheless, there are many ma-
terials (metals and polymers) which meet these
requirements at least to a big portion.
Nowadays, platinum is the electrode material of
choice, because it is stable and inert. The amount of
platinum ions released into the surrounding tissue
may be neglected even after long terms of stimu-
lation. During the last years, iridium has been of
increasing importance because a stable oxide ®lm
can be formed on the surface of iridium electrodes.
This oxide ®lm has a big charge delivery capacity
and is, for this reason, well suited for stimulating
electrodes. Carbon ®bres or glassy carbon are also
used as electrode materials, and they are biocompa-
tible and stable, though they have a higher rough-
ness than metals. Platinum and iridium are
established materials in microelectronics, and also
carbon can be deposited onto microelectronic struc-
tures.
As recently reviewed by RÏõ hova (1996), polymers
are used as carrier material and for encapsulation
purposes. Most common materials are epoxy resins,
polytetra¯uoroethylene (PTFE, Te¯on1), silicone
rubbers and polyimide. These polymers are biocom-
patible, electrically insulating and stable. The bulk
properties of the polymers can be modi®ed to a cer-
tain degree, and also surface modi®cation pro-
cedures are performed in order to improve
biocompatibility.
442 P. Heiduschka and S. Thanos
3.3. Response to Implantation
When an implant is brought into the body, the
®rst event is that proteins adsorb onto the surface of
the implant. A dozen proteins can be found in bio-
logical ¯uids at concentrations higher than 1 mg/ml,
and certainly they will form major parts of layers
formed on the implant at least in the initial state of
adsorption (Andrade and Hlady, 1987). The details
of this process depend on the surface of the implant,
the composition of the biological environment and
the nature of the adsorbed proteins. Adsorption of
proteins such as collagen or ®bronectin can favour
adhesion of tissue cells (Seeger and Klingman, 1988;
Drumheller et al., 1994). An encapsulation of the
implant by autologous material (astrocytes, protein
layers, endothelial cells, ®broblasts) is desirable in
order to integrate the implant into the organism and
``mask'' it in order to avoid undesired reactions of
the immune system, thus promoting incorporation
and acceptance of the implant. On the other hand, it
was reported that ®bronectin and ®brinogen can
enhance the adhesion of di€erent bacteria, e.g.
Staphylococcus aureus, which is a common cause of
infections after implantation (Vaudaux et al., 1984,
1995). Adhesion of the uropathogen Pseudomonas
aeruginosa B4 onto polystyrene was increased when
urine-derived a-1-microglobulin was pre-adsorbed
(Wassal et al., 1995).
In¯ammatory reactions can be another conse-
quence of an implantation. In¯ammations involve
vascular, neurological, humoral and cellular re-
sponses, and the following acute-phase response is
characterised by stress-induced changes in the
neuroendocrine and immune systems (Kushner,
1982; Khansari et al., 1990). During an acute-phase
response, concentration of di€erent serum plasma
proteins increases signi®cantly, such as serum amy-
loid A, C-reactive protein, ®brinogen, a-1-antichy-
motrypsin, complement protein factor B and C3,
haptoglobin and a-1-antitrypsin, whereas concen-
tration of other proteins is decreased (albumin,
transferrin and transthyretin) (Baumann and
Gauldie, 1990). Furthermore, leukocytes adhere to
blood vessel walls and migrate into the tissue which
requires highly speci®c interactions mediated by
selectins, integrins and inmmunoglobulins (Jones et
al., 1996). Cytokines are released, e.g. IFN-g, TNF-
a, IL-1 and IL-6, which are principal mediators of
the acute-phase response (Baumann and Gauldie,
1990). High concentrations of TNF-a and IL-6, e.g.
may induce tissue damage, up-regulation of surface
adhesion molecules and enhanced production of
proteases and free radicals by macrophages.
Another issues of an in¯ammation are fever and
in®ltration of monocytes/macrophages, eosinophils,
neutrophils, lymphocytes, granulocytes, ®broblasts
and giant cells.
When an implant is brought into the brain, astro-
cytes can be observed to respond quickly to this
injury as they react to every damage (Cavanagh,
1970; Ludwin, 1985). They proliferate in the vicinity
of the implant and send their processes towards the
implant. Microglial cells are also activated and
transform from rami®ed to amoeboid type. The
implant is coated with a layer which contains col-
lagen, giant cells, nerve ®bres in di€erent states and
blood vessels (Schultz and Willey, 1976).
In order to evaluate biocompatibility of a ma-
terial, in vitro experiments play the major role
(Klein et al., 1995; Hanks et al., 1996), although
they do not re¯ect the whole complexity of the in
vivo situation. In vitro experiments are based on cell
lines and on primary cell cultures depending on the
intended site of application. After bringing the cells
in contact with the material, di€erent parameters
are evaluated, as morphological and ultrastructural
changes, cell adhesion, release of mediators, presen-
tation of molecules, changes of metabolism, etc.
One of these parameters is metabolism of arachido-
nic acid by macrophages as indicator for in¯amma-
tory processes (Charissoux et al., 1996). Release of
cytokines is also a measured parameter, e.g. of
TNF-a (Hunt et al., 1996). Although neuroprosth-
eses are not applied inside blood vessels, blood com-
patibility is also an important issue, with particular
emphasis on behaviour of blood cells, extent of
complement system activation, platelet activation
and clot formation. The ability of endothelial cells
to produce antithrombotic substances has to be
examined (Cenni et al., 1993).
There are di€erent cell surface molecules which
are important in the context of implants.
Endothelial cell cultures are preferred for biocom-
patibility studies of materials for vascular pros-
theses, and proteins important for adhesion are
expressed upon contact between the implant and the
cells. The occurrence of such proteins is studied in
biocompatibility evaluations with endothelial cells.
Examples are the platelet endothelial cell adhesion
molecule-1 (PECAM-1, CD31), the endothelial leu-
cocyte adhesion molecule-1 (ELAM-1), the intercel-
lular adhesion molecule-1 (ICAM-1, CD54), and the
vascular cell adhesion molecule-1 (VCAM-1) (Cenni
et al., 1995).
One aspect of biocompatibility for neural pros-
theses is damage by permanent charge injection.
Permanent electrical stimulation can cause damage
of neural tissue, such as gliosis, calci®cation of neur-
ons and other cells, lipid inclusions, or glycogen
granules in astrocytes, and neural tissue may be lost
®nally (see Agnew and McCreery, 1990a). The basic
parameter for stimulation intensity is the relation
between charge density and injected charge per
phase. Charge density is measured in mC/cm2 and is
determined by the frequency, the applied current
and the size of the electrode. Absence of neural
damage can be expected for the range of a charge
density of 100 mC/cm2 with 0.2 mC/phase or a charge
density of 15 mC/cm2 with 8 mC/phase (Agnew and
McCreery, 1990a, p. 229).
Agnew and McCreery (1990b) came to the con-
clusion that damage of neurons and axons has its
origin in their hyperactivity due to severe electrical
stimulation, particularly if stimulation is performed
with a high frequency. That is why frequency of
stimulation should be as low and pulse duration
should be as short as possible. Furthermore, stimu-
lation should not be performed continuously but
with cut-o€s where possible.
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
3.4. Surface Modi®cation
In order to enhance biocompatibility of implanted
materials, reduce macrophage adhesion onto the
implants and prevent in¯ammatory reactions, sur-
face modi®cations of materials intended for implan-
tation are widely studied. These investigations are
performed particularly with polymers because they
are the main material used for housing, encapsula-
tion and insulation purposes. Whereas attraction
and adhesion of macrophages and other white
blood cells to an implant can favour in¯ammations,
inhibition of such an adhesion would be an import-
ant factor of biocompatibility.
Nevertheless, it depends on the intended use of
the implant whether adhesion of proteins and cells is
desirable. The best example are vascular grafts
which require a completely di€erent cell behaviour
on their surfaces: inside the grafts minimal cellular
adhesion and ®brin formation, but extensive ad-
hesion of tissue cells and matrix formation on the
outer side. With a neuroprosthesis, also di€erent
properties are needed. Recording electrodes should
remain bare for good sensitivity, and the best would
be an intimate and stable contact between the elec-
trode and neuron cell bodies or axons. Housing and
encapsulation materials would be allowed to be
coated by tissue cells like ®broblasts in order to in-
corporate them into the body. Stimulating electrodes
are not coated if the applied currents are high
enough to cause Faradaic processes at their surface
like oxygen evolution, and processes of in¯am-
mation, gliosis and neuron damage occur not actu-
ally on the electrode surface, but nearby the
electrodes.
3.4.1. Surface Roughening
First kind of surface modi®cation which can be
done is the preparation of smooth or rough surfaces.
If minimal cell adhesion is intended, surfaces are
made as smooth as possible. If cell adhesion is
wished in order to achieve good incorporation into
the body, rough surfaces are advantageous.
Roughening is performed by particular production
techniques, where roughness is an intrinsic property
of the material, or it can be done by micromachining
techniques, where particular patterns are applied to
the smooth material, e.g. by photolithographic or
micromechanical procedures. In many cases, V-
shaped grooves are milled or etched into the ma-
terial in order to align growth of ®broblasts and to
®x the implant within the tissue. One important
example are dental prostheses, where reliable attach-
ment is essential for long-term clinical success. Long
grooves running perpendicularly to direction of
insertion of dental implants could impede down-
growth of epithelial cells on the implant, which
allows connective tissue to adhere and leads to a bet-
ter ®xation of the implant (Chehroudi et al., 1991).
For many years, carbon has been used for di€er-
ent kinds of implants, such as dental implants, per-
cutaneous devices, tendon and tracheal substitutions
and heart valves (Haubold et al., 1979; Iumashev et
al., 1983; Alberktsson et al., 1986; Tian et al., 1993).
Carbon is known for its excellent biocompatibility,
and it is also used for coating of polymeric materials
443
to improve properties of the latter (Pizzoferrato et
al., 1993; Cenni et al., 1995). Main modi®cations of
carbon used for implantation purposes are pyrolitic
carbon and glassy carbon. Both modi®cations have
a turbostratic structure which leads to a microscopi-
cally heterogeneous surface distribution of electron
density and a microscopic roughness (Jenkins et al.,
1972; Wege, 1984; Oberlin, 1989). One possible
reason for the observed good cell adhesion proper-
ties is the combination of hydrophobic surface
which favours protein adsorption and roughness
which gives cells good ``points of attack'' for ad-
hesion.
3.4.2. Chemical Modi®cation
Another kind of surface modi®cation is to change
the chemical composition. Ratner (1997) divides
these surface modi®cation procedures into biological
and non-biological methods depending on the kind
of molecules bound to the surface:
. non-biological modi®cation: functional groups
(amine, hydroxy, carboxy), sulphonates, n-alkyl
chains, hydrogels, polymers such as poly(ethylene
oxide), poly(2-hydroxyethyl methacrylate), poly(n-
vinyl pyrrolidone), polyacrylamide, and
. biological modi®cation: coating with heparin,
hyaluronic acid, sugars, peptides, lipids, enzymes
or growth factors.
Naturally, layers created by di€erent methods must
be stable unless not being intended for biodegrada-
tion. After their fabrication, no reactivity may
retain, for example by non-saturated binding sites,
e.g. sites activated with carbodiimide) or reactive
double bonds (e.g. after cross-linking with alde-
hydes).
The well-known statement that ``water is the most
biocompatible substance we know'' would lead to
the conclusion that hydrophilic and therefore wetta-
ble surfaces should be advantageous. Several sub-
stances are hydrophilic per se, e.g. glass or silicon
dioxide. In other cases, hydrophilic surfaces can be
obtained by polar or ionic groups. Such functional
groups can be placed on the surface by chemical
modi®cation of surfaces or by coating with appro-
priate molecules, e.g. with proteins or sugars. With
a polymer, monomers can be applied for the prep-
aration which carry ionic or polar groups, or co-
polymers can be prepared in order to combine
di€erent properties for desired mechanical proper-
ties and surface chemistry (see, for example, Kishida
et al., 1991; Arshady, 1993). A surface which has to
become hydrophilic can have anionic properties by
introduction of negatively charged groups, particu-
larly carboxy (0COOÿ) groups. Neutral hydrophilic
surfaces can be obtained by hydroxy (0OH) or
amide (0CONH) groups, and cationic hydrophilic
surfaces are made by introduction of di€erent
amino groups (0NH2, 0NHR0, or NR3).
Yun et al. (1995) modi®ed PTFE surfaces with
di€erent functional groups and found that cell ad-
hesion and cytokine release were inhibited at best
when modi®cation was performed with amide
groups to obtain neutral hydrophilic surfaces.
Coating of hydrophilic surfaces with polysacchar-
ides, e.g. dextrans, has been recognised to be advan-
444 P. Heiduschka and S. Thanos
tageous because each monomer within the chain car-
ries up to three hydroxy groups. Indeed, non-speci®c
protein adsorption can be reduced (OÈsterberg et al.,
1993; Marchant et al., 1994).
In order to prepare hydrophilic surfaces and to
prevent undesired protein adsorption, surfaces were
coated with poly(ethylene oxide), heparin and albu-
min, and a reduced thrombogenicity accompanied
with a reduced plasma protein adsorption and plate-
let adhesion was found (Amiji and Park, 1993). The
authors explain these e€ects by a steric repulsion
mechanism because the surface molecules can be
regarded as entropic ``springs'' (Milner, 1991). A
special technique for the deposition of protein mol-
ecules is cross-linking using glutaraldehyde or carbo-
diimide as shown for arterial prostheses coated with
cross-linked gelatine (Drury et al., 1987; Bordenave
et al., 1989; Marois et al., 1995), albumin (Guidoin
et al., 1984; Cziperle et al., 1992; Marois et al.,
1996) or collagen (Noishiki and Chvapil, 1987;
Guidoin et al., 1989). Another possibility for cross-
linking is derivatisation of molecules to be deposited
with photodimerisable groups, such as thymine, cin-
namate or coumarin. Upon irradiation with UV
light, these groups bind, and derivatised molecules
are deposited onto the surface, as demonstrated for
the deposition of chondroitin sulphate, hyaluronic
acid and gelatine onto Dacron or polyurethane
(Kito and Matsuda, 1996).
A di€erent kind of introducing hydrophilic
groups into a surface is treatment with plasma in a
glow-discharge apparatus (Yasuda, 1985; Moroso€,
1990; Piskin, 1992). The plasma can be made of
di€erent substances, e.g. from oxygen, ammonia or
water, but also from organic molecules such as
methacrylates or siloxanes, and a big variety of ma-
terials can be treated, even materials which are nor-
mally inert, such as polystyrene or PTFE. On such
inert materials, plasma treatment is also used in
order to form reactive groups for further binding of
other molecules. Bigger molecules like polyethylene
glycols can also be deposited, and resulting layers
resist protein adsorption and cellular attachment, as
could be shown for tetraethylene glycol dimethyl
ether (LoÂpez et al., 1991). Plasma polymerised silox-
anes were shown to provide an anti-thrombogenic
surface which is important for vascular grafts and
oxygenator devices (Hu et al., 1997).
3.4.3. Speci®c Modi®cations
It has been said already that adsorption of pro-
teins onto implant materials is desirable in those
cases where tissue cells may adhere in order to facili-
tate wound healing and incorporation of the
implant. Adhering proteins serve as a kind of ``tem-
plate'' to recruit healthy cells from intact tissue
around the site of damage. If the electrodes are
implanted into nerves, their appropriately designed
surfaces should incite the neurons to adhere to the
electrodes and to regenerate their axons along the
electrodes. First investigations for the purpose of
peripheral nerve regeneration were performed with
biodegradable polymers derived, e.g. from extracts
of the extracellular matrix (Yannas et al., 1987;
Aebischer, 1988; Chang et al., 1989).
For a rational design of regeneration-promoting
surfaces, it is necessary to ®nd out the key structures
which give rise to the desired behaviour of cells, e.g.
neuron adhesion and axonal regeneration. One
example of such a key structure is the tripeptide
sequence RGD (Arg-Gly-Asp) which is present in
®bronectin, a protein of the extracellular matrix
(ECM), and to which many types of cells bind
(Ruoslahti and Piersbacher, 1987; Hynes, 1990).
Besides the big variety of binding cells, the import-
ance of the RGD sequence is also underlined by the
fact that it occurs in other adhesive proteins too,
e.g. laminin (Grant et al., 1989), collagens, ®brino-
gen, vitronectin, von Willebrand factor (Hynes,
1987), entactin (Chakravarti et al., 1990), albolabrin,
rhodostomin and other viper venom proteins listed
in Soszka et al. (1991) and Chiang et al. (1996),
tenascin (Sriramarao et al., 1993), and a zinc protein
(Takagaki et al., 1994). Thus, it has been possible to
reduce the big protein molecule (molecular weight
of 500,000) to a small tripeptide (molecular weight
of 292) with the relevant function. Various materials
were modi®ed by di€erent methods with the RGD
peptide, as shown for glass, polyethylene terephthal-
ate (PET) and PTFE by Massia and Hubbell (1990,
1991), for polyacrylamide by Brandley and Schnar
(1989), for poly(ethylene acrylate) by Hirano et al.
(1993), for poly(g-methyl L-glutamate) by Kugo et
al. (1994), for cross-linked polymer networks by
Drumheller and Hubbell (1994), and for poly(vinyl
alcohol) by Sugawara and Matsuda (1995). Whereas
the non-modi®ed materials showed only poor cell
adhesion, it could be observed in a high degree after
coating with RGD peptides, and also cell spreading
and migration were observed in some cases. This in-
dicates that modi®cation of implant surfaces with
``biologically inspired'' synthetic molecules would be
able to promote incorporation of the implants into
the tissue.
Other peptide sequences in proteins had been also
identi®ed to be important for cell attachment. In
®bronectin, six additional adhesion sequences have
been found besides RGD which are listed in
Mooradian et al. (1993). In thrombospondin-1, the
sequences RFYVVMWK and IRVVM were found
to support attachment of cells (Kosfeld and Frazier,
1993). In the C-reactive protein, the adhesive
sequence FTVCL was found (Mullenix et al., 1994).
However, there are only few cases of utilisation of
these peptides. The ®bronectin-derived sequence
WQPPRARI was immobilised on polystyrene and
PET, and enhanced adhesion and spreading of en-
dothelial cells was found on the resulting surfaces
(Huebsch et al., 1996).
Laminin is probably the most investigated ECM
protein. It is particularly interesting because it is an
abundant component of the basement membranes
during development of the embryonic nervous sys-
tem, but also present in the mature nervous system
with apparently important functions not only
restricted to guidance or adhesion. In the developing
and maturing central nervous system (CNS), lami-
nin plays a crucial role, e.g. in cell migration, di€er-
entiation and axonal growth (Martin and Timpl,
1987; Kleinman et al., 1987; Martin et al., 1988).
Besides the characterisation in vivo, it has been
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
extensively used as a substrate for studies of the
growth of neurons in vitro. Laminin is a big, multi-
domain protein (Beck et al., 1990) with many bind-
ing sites for di€erent cell receptors (Castronovo,
1993; Mercurio, 1995; Gullberg and Ekblom, 1996;
Wei et al., 1997). Amino acid sequences of laminin
which have been identi®ed to be important to cell
adhesion or growth are, e.g. CDPGYIGSR (Graf
et al., 1987), RYVVLPRPVCFEKGMNYTVR
(Charonis et al., 1988), SIKVAV (Tashiro et al.,
1989), SRARKQAASIKVAVSADR (Sephel et al.,
1989), RNIAEIIKDI (Liesi et al., 1989), PDSGR
(Kleinman et al., 1989), CQAGTFALRGDNPQG
(Tashiro et al., 1991), KQNCLSSRASFRGCVR-
NLRLSR (Gehlsen et al., 1992), YFQRYLI
(Tashiro et al., 1994), SIYITRF, IAFQRN and
LQVQLSIR (Nomizu et al., 1995).
However, only few of these peptides have been
used for the modi®cation of surfaces until now. The
peptides used in most cases are YIGSR and IKVAV
or longer versions of these sequences. Massia and
Hubbell immobilised GYIGSR onto glass (1990)
and PET and PTFE (1991) and obtained adhesion
and spreading of human ®broblasts. Hirano et al.
(1993) coupled YIGSR and YIGSR-NH2 to poly(-
ethylene acrylate) and obtained slightly enhanced
attachment of di€erent cell lines. In these cases,
e€ects of YIGSR sequence were slightly lower than
those of RGD. GYIGSRY was coupled to poly(-
ethylene glycol) in a cross-linked network, and good
®broblast adhesion was achieved vs. no adhesion on
bare polymer (Drumheller and Hubbell, 1994).
Fluorinated poly(ethylene propylene) was modi®ed
with YIGSR and an IKVAV peptide with 19 amino
acids (19-mer IKVAV), and attachment of neuro-
blastoma and PC12 cells was evaluated (Ranieri et
al., 1995). In most of these cases, it was reported
that albumin pre-adsorption was necessary for e-
cacy of immobilised peptides, probably because
adsorbed albumin helped the bound peptide to
achieve a relatively natural conformation on the
hydrophobic surfaces.
O€enhaÈusser et al. (1997) coupled the 19-mer
IKVAV peptide onto amine-modi®ed glass, silicon
wafers or microelectronic surfaces. Embryonic rat
hippocampal neurons attached to the modi®ed sur-
face and developed processes. It could be shown by
the patch-clamp technique that these neurons were
able to produce action potentials. Another laminin
peptide, RNIAEIIKDI, was used by Matsuzawa et
al. (1996) to modify glass substrates. Again, embryo-
nic rat hippocampal neurons attached to the modi-
®ed surface and developed a mature morphology
with outgrowing axons similar to that of neurons
growing on laminin. In both cases, a chemically
de®ned medium without serum was used. This may
be possible because the surface is hydrophilic due to
its prior modi®cation with amino groups.
In our laboratory, we investigate possibilities of
modi®cation of electrode surfaces in order to
achieve a stable contact between neurons and elec-
trodes. For this purpose, we tested di€erent laminin
peptides (SRARKQAASIKVAVSADR and SIK-
VAV, RNIAEIIKDA, YFQRYLI, CDPGYIGSR,
PDSGR, GTFALRGDNPQ) which were prepared
by Kienle (1997). The immobilisation method
445
should be quick and simple, and, furthermore,
should modify only the electrodes, but not the sub-
strate without expensive photolithographic tech-
niques. These requirements directly lead to the
technique of electrochemical polymerisation. The
peptides were modi®ed with a polymerisable group,
3-hydroxyphenylacetic acid. Immobilisation of pep-
tides by this technique could be demonstrated
already for antigenic peptides (Heiduschka et al.,
1996, 1997). After immobilisation of the peptides
listed above onto glassy carbon, enhanced adhesion
of embryonic chicken neurons was found, and neur-
ite outgrowth from both adhered neurons and
stripes of retina tissue could be observed (Huber et
al., 1998). These e€ects di€ered depending on the
peptide, and laminin as whole protein molecule
showed better ecacy when immobilised, particu-
larly for the outgrowth of axons out of retina tissue.
Best results with synthetic peptides were obtained
with the 18-mer IKVAV peptide. It further could be
shown that electrochemically polymerised peptide
layers on recording electrodes which provide an inti-
mate contact between neurons and electrodes would
not insulate the electrode. After polymerisation of 3-
hydroxyphenylacetic acid, the impedance of micro-
electrodes did not change signi®cantly (Valderrama
et al., 1995).
For future developments, it would be desirable to
®nd special peptide sequences to which each type of
cell responds speci®cally upon contact with the
modi®ed surface. In this case, attachment and repul-
sion, activation or deactivation of each type of cell
could be directed in the desired way as sketched in
Fig. 6.
4. AUDITORY IMPLANTS
The cochlea implant is one of the ®rst implants
which have been developed for practical use, and it
has been working well since more than ten years in
patients su€ering from auditory impairment. It will
be therefore discussed as an example of successful
development of a neuroprosthetic implant.
Fig. 6. Summary of optimum surface behaviour of an
implanted neuroprosthesis: encapsulation surface (left),
recording electrodes (left bottom) and stimulating electro-
des (right bottom).
446 P. Heiduschka and S. Thanos
In a healthy ear, the sound vibrations are col-
lected by the outer ear and sent down the ear canal
to the eardrum which vibrates the three small bones
of the middle ear. Subsequently, the ¯uid in the
snail-shaped cochlea vibrates, and these vibrations
stimulate the approx. 30,000 tiny hair cells which
are located in the organ of Corti inside the cochlea.
The electrical signals produced by the hair cells
stimulate the bipolar cells of the spiral ganglion,
which central ®bres form the auditory nerve which
leads the signals into the brain where they are inter-
preted as sound. The sound is tonotopically rep-
resented in the cochlea: high frequencies (up to 20
kHz) are sensed in the basal region, whereas low fre-
quencies (down to 16 Hz) are sensed in the highest
part of the cochlea, the apex. This distribution has
its origin in a 104:1 gradient of the sti€ness of the
basilar membrane and is the prerequisite of the
tonotopic organisation of the auditory system.
Besides this site-dependent principle of frequency
discrimination which is called spectral analysis,
there is another mechanism called periodicity analy-
sis. Here the frequency is ``calculated'' in the brain
based on the time period of incoming action poten-
tials.
In case of a disease or a trauma, the hair cells
may be diminished or damaged. The same may hap-
pen at increasing age. A widespread reason for
acquired hearing impairment or even deafness is
meningitis, where the site of damage is almost
always the cochlea with loss of the organ of Corti.
As a consequence of hair cell loss, the auditory
nerve may not be stimulated, and even the loudest
sounds may not be heard. That is why hearing aids
which only amplify loudness of sound do not help
in inner ear diseases. When the auditory nerve itself
still is intact, it may be stimulated arti®cially by elec-
trodes implanted in the cochlea, and this is what is
done with the so-called cochlea implant which is
applied now for approx. 20 years. The success varies
due to heterogeneity of diseases and the di€erent
degree of destruction. When the auditory nerve itself
is destroyed in addition to hair cells, e.g. due to sur-
gical removal of bilateral tumours of the acoustic
canal, a cochlea implant does not make sense any
more. In such cases, direct stimulation of the brain
areas may be tried in order to elicit acoustic sen-
sations.
4.1. Brain Stem Implants
Such a stimulation can be performed by the audi-
tory brain stem implant (ABI), which electrically
stimulates the auditory pathway at the level of the
cochlear nucleus. For this purpose, it could be
shown that penetrating electrodes are more e€ective
than surface electrodes, and their necessary stimu-
lation threshold was considerably lower (67.5 vs
11.4 mA), their dynamic range was bigger (13.1 vs
24.5 dB), and metabolic activity of some CNS
regions was higher as could be shown by higher
uptake of [14C]2-deoxyglucose (El Kashlan, 1991).
The correct placement of an ABI may be aided by
recording of brain stem responses which are
recorded during the implantation (Waring, 1995,
1996). The evoked response generally had 2 or 3
waves, and peak latencies of these waves were
approx. 0.3, 1.3, and 2.2 msec (Waring, 1995).
McCreery et al. (1992) also utilised evoked poten-
tials to optimise the position of stimulation micro-
electrodes in the cochlear nucleus in experiments
with cats. They used 75 mm iridium wires for stimu-
lation, and neurons and neurophil adjacent to the
microelectrodes appeared to remain undamaged
except for some small gliotic scars. However, a cer-
tain depression of neuronal excitability was found
which implies the necessity to ®nd the lowest poss-
ible excitation threshold by careful monitoring of
both the psychophysical threshold for auditory per-
cepts and the electrically evoked auditory brain stem
response.
Brackmann et al. (1993) described implantation of
a single-electrode ABI into the auditory brainstem
of patients who were totally deaf due to removal of
their bilateral acoustic neuromas. Correct position-
ing of the electrode in the lateral recess of the fourth
ventricle is very important for maximised auditory
sensation and minimised activation of other nerves.
Shannon et al. (1993) reported that these implanted
electrodes were stable for more than 10 years, and
that the auditory sensations produced by the
implant were similar to the results achieved by
single-electrode cochlea implants. Patients could dis-
criminate sound when it was combined with lip-
reading. By this implant, tinnitus reduction could be
achieved in several patients (Soussi and Otto, 1994).
Later on, also implants with eight electrodes have
been applied (Otto and Staller, 1995). Twelve
patients received such an implant, and eleven of
them received useful auditory sensations.
4.2. Cochlea Implants
Though there are slightly di€erent views about
who is a candidate for cochlear implantation, it is
widely accepted that recipients of such an implant
should be at least 2 years old, have a severe or a
profound bilateral hearing loss and receive little or
no bene®t from conventional hearing aids.
Successful application of a cochlea implant requires
proper training, thus the recipients must have a high
motivation. An appropriately working device is
expected to allow the patient to detect speech and
environmental sounds, to use the telephone, to
improve lip-reading abilities, to distinguish between
di€erent kinds of environmental sounds and, in case
of children, to improve speech and language learn-
ing.
How does the cochlear implant work? As outlined
before, it by-passes damaged parts of the ear and
directly stimulates nerve ®bres of the auditory nerve.
These signals may be interpreted in the brain as a
sound after a period of rehabilitation. The whole
device consists of two parts, one situated outside the
head (microphone, speech processor, power supply,
transmitter) and one implanted into the ear (recei-
ver, stimulating electrodes). The sound recorded by
the microphone is converted in a series of electrical
signals by the speech processor which is then trans-
mitted through the skin to the receiver (Fig. 7). The
signals are led to the electrodes, which apply the sig-
nal to the auditory nerve ®bres. The right program-
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
Fig. 7. (A) Scheme of a cochlea implant with arrows indi-
cating informatiom ¯ow. Sound is recorded by a micro-
phone and converted into a series of electrical signals by
the speech processor. The electrical signals are transmitted
through the skin to the receiver which converts them into
stimulating pulses applied by the stimulator to the neurons
of the auditory nerve. 1Ðear canal, 2Ðeardrum mem-
brane, 3Ðthree little bones (hammer, anvil, stirrup), 4Ð
cochlea, 5Ðauditory nerve. (B) Detailed view of the
cochlea with the inserted stimulator. The electrodes are dis-
tributed along the implant thus providing spatially di€eren-
tiated stimulation. 1Ðscala tympani, 2Ðscala vestibuli, 3Ð
basilar membrane with the organ of Corti which contains
hair cells and sensory nerve endings, 4Ðganglion spirale,
5Ðauditory nerve.
ming of the speech processor starts 4±6 weeks after
implantation, and this may take several weeks to
months. The whole procedure of programming is
tightly connected with adaptation processes in the
brain which may require synaptic plasticity in order
to rebuild the auditory system.
Although there are 30,000±40,000 nerve ®bres in
the auditory nerve, stimulation can be performed
for technical reasons by only few electrodes.
Commercial devices usually have 6±22 electrodes.
Based on the tonotopic organisation of the auditory
system described above, it would be straightforward
to arrange stimulation microelectrodes along the
windings of the cochlea and apply distinct electrical
stimulation pulses according to the occurrence of
distinct frequencies in the environmental sound
recorded by the microphone. The speech processor
would analyse the recorded sound with respect to
distinct frequency ranges and generate an appropri-
ate series of electrical pulses for every single stimu-
lation electrode. Indeed, this approach is performed
with a variety of commercial multi-channel systems
and there has been good success upon implantation
of such devices. The number of stimulating electro-
des mentioned above should be increased in order to
achieve a higher quality of stimulation and thus a
better acoustic sensation by the patient. However, if
447
the number of electrodes is increased, their distance
gets smaller, and considerable interference and
cross-talk between the channels occur (Hartmann
and Klinke, 1990). One way to resolve this problem
and to minimise interference was development of
new signal processing schemes where only one elec-
trode is activated at a given time. This method is
called ``sequential stimulation'' in di€erence to sim-
ultaneous stimulation. However, spatial resolution
of electrical stimulation cannot be enhanced as it
would be desirable.
As described already for the brain stem implants,
also with cochlear implants measurement of evoked
potentials is used to evaluate e€ects of electrical
stimulation. Whereas most information can be
gained by recording of responses of individual cells
or ®bres (Merzenich et al., 1973; Glass, 1983;
Hartmann et al., 1984; van den Honert and
Stypulkowski, 1984), measurement of evoked poten-
tials is much more convenient, can be performed in
alert animals and can be used for the investigation
of long-term changes. Among the evoked potentials,
recording of the middle latency responses seems to
be useful (Kileny and Kemink, 1987; Burton et al.,
1989), and extended investigations have been per-
formed, e.g. by PopelaÂrÆ et al. (1993, 1995). The
auditory brainstem response (ABR) is often used to
evaluate the residual hearing of patients as well as
the performance of cochlear implants. In most clini-
cal cases, click-evoked ABRs are recorded. Of
course, measurement of evoked potentials is not a
hearing test per se.
In the ®rst implants, only a single electrode has
been used, and provided therefore limited success.
Cochlear implants gained higher acceptance since
MEAs have been applied which allow multi-channel
stimulation. The electrodes are arranged on a whorl-
shaped carrier which is introduced into the cochlea
so that the single stimulating sites are placed near to
the appropriate sites of the organ of Corti and the
surface of the cochlear nucleus. However, it must be
taken into account that damage of components of
the cochlea can occur by the surgical process of
insertion of the long electrodes applied for multielec-
trode stimulation. The spiral ligament is ®rst site of
damage in these cases, and also the basilar mem-
brane could be disrupted which would lead to a
lesion of remaining dendrites and subsequent de-
generation of the spiral ganglion cells. This means
that potentially existing residual hearing may be
destroyed. On the contrary, there are reports that
inserted implants caused minimal damage and are
well tolerated (Burton et al., 1996). In order to over-
come the problem of cochlea damage, several ``soft''
surgical strategies have been developed (e.g. use of
lubricating liquids for better insertion, Rogowski et
al., 1995) which will not be further discussed here.
Cohen (1997) critically contemplates the concept of
``soft surgery'' and states that success of the cochlea
implant mainly depends on full electrode insertion,
the right stimulation strategy and the survival of a
sucient number of ganglion cells.
The problem of full electrode insertion mentioned
above arises particularly in the case of cochlea ossi®-
cation which often happens. The implant cannot be
inserted into the cochlea any more. Drilling is only a
448 P. Heiduschka and S. Thanos
partial solution because the drilled out portion is
limited to the ®rst part of the basal turn, and stimu-
lation results are poor. One possibility is not to
insert the multi-electrode carrier into the cochlea at
all, but to drill small holes into the cochlea at cer-
tain sites and insert small single electrodes through
these holes (Chouard, 1994). Although this pro-
cedure appears to be delicate and time-consuming, it
looks more advantageous, particularly because pos-
itions of the electrodes may be set very exactly
which favours tonotopic excitation. Another way is
the development of an implant consisting of two
arrays (Lenarz et al., 1997). Whereas the ®rst array
is inserted into the drilled out basal turn, the second
array is inserted into the second turn which has to
be opened for this purpose. The authors reported
that an improved performance of the implant could
be achieved.
In this context, it was argued that the tonotopic
theory for cochlear implants is not valid because
dendrites of the spiral ganglion cells may retract or
degenerate after loss of the hair cells (which is dis-
cussed later), and therefore multi-electrode implants
would not be useful. It thus may be concluded that
selective stimulation of the spiral ganglion cells
would not be possible, and consequently only one
electrode with an electrical ®eld penetrating the
whole cochlea would be enough. However, it is well
established that a tonotopic organisation occurs
both in the healthy auditory system and in the case
of deafness. Naturally, quality of the tonotopy
strongly depends on the time of onset and duration
of deafness. In any case, the performance of patients
with multichannel cochlear implants is anticipated
to be maybe better than the performance of patients
with single-channel devices (Gantz et al., 1987;
Tyler, 1987). Experiments with deafened cats
showed variations in parameters of auditory evoked
potentials recorded in individual tonotopical cortical
places when the auditory nerve was stimulated with
di€erent con®gurations of electrodes through a
multi-electrode implant (PopelaÂrÆ et al., 1995).
Stimulation with monopolar electrodes yielded
results with much greater variability among individ-
ual cats and induced profound functional alterations
in the CNS (Leake et al., 1995). For this reason, the
authors stated that application of monopolar
devices should be contra-indicated for at least young
children. Comparative studies in humans showed
that the outcome of an implant is better with a
higher number of active electrodes (Amadori et al.,
1996).
In 1995, more than 12,000 people world-wide
used cochlear implants (for an overview, see, for
example, NIH Statement, 1995). A majority of them
is able to understand up to 80% of high-context sen-
tences, recognises environmental sounds and can lis-
ten to music. In spite of good experience with these
devices, there are also limitations. Noisy environ-
ment remains a problem. Cochlear implants may
not provide the dynamics of sound, i.e. the range of
amplitude, like normal hearing does. While normal
hearing provides loudness di€erences of 4 orders of
magnitude, only a factor of 10 may be heard by
such an implant. Another problem is that success of
implantation and rehabilitation cannot be predicted
very exactly. Several deaf people still cannot use the
telephone and depend on lip-reading, and some of
them are helped only slightly by these implants.
Failure to surgically recover auditory function is
particularly observed when individuals were born
with deafness. Poorer results were also achieved in
children with pre- or peri-lingual onset of deafness
compared to children with post-lingual onset of
deafness. However, the di€erence between these two
groups appears to lessen with time (NIH Statement,
1995). The reason for this failure is most probably
absence of the appropriate synaptic connections in
the brain which would allow to interpret the incom-
ing nerve signals as sound. For acoustic sensations,
especially with patients who are deaf from birth, a
lot of connections have to be established in the
brain. This task is certainly easier to accomplish in a
developing brain than in an adult one. This may
explain the observation that implantation at an age
of 2 years ultimately results in a better auditory per-
formance than implantation at the age of 3 years or
later (NIH Statement, 1995). Special problems of
the application of cochlea implants in children are
reviewed by Langman et al. (1996).
The observation that individuals with shorter
auditory deprivation achieve better results than
people with a longer deaf period can be seen in the
same context as the ability of the brain to process
signals incoming from the auditory nerve. It has
been known for a longer time, that sensory depri-
vation leads to plastic changes in the corresponding
areas of central nervous system, particularly in the
cortex. In case of removal of sensory input, the
deprived area of the somatosensory cortex becomes
responsive to neighbouring regions (Kaas et al.,
1983; Kaas, 1991).
Another problem is that often not only hair cells
but also neurons of the spiral ganglia are a€ected by
the disease or trauma which lowers the prospects of
a good auditory performance of a cochlea implant.
There are hints that hair cells in the vestibule may
be regenerated (Forge et al., 1993; Warchol et al.,
1993), but these ®ndings are controversial (Rubel et
al., 1995). Moreover, hair cells in the cochlea are
much more di€erentiated, and regeneration of lost
hair cells in the mammalian cochlea appears not to
be possible at the moment. First e€ect after loss of
hair cells is retraction and degeneration of the den-
drites of the bipolar spiral ganglion cells. It is gener-
ally known about the nervous system that neurites
may retract when the target cells are lost because
neurotransmitters and other factors are not supplied
any longer. In the cochlea, BNDF and NT-3 are
produced by the developing organ of Corti, and
NT-3 is produced by the inner hair cells also in the
adult stage (Ylikosi et al., 1993; Schecterson and
Bothwell, 1994). Moreover, transcripts for trkB and
trkC which are speci®c receptors for BDNF and
NT-3, respectively, were found on the auditory
neurones (Ylikosi et al., 1993). Recently it was
found that NT-3 can elicit a tropic response on out-
growing auditory neuronal processes in vitro
(Malgrange et al., 1996). In the guinea pig cochlea,
auditory neurones underwent apoptotic cell death
after destruction of associated hair cells, and per-
fusion of BDNF and/or NT-3 onto the scala tym-
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
pani almost completely rescued the auditory neur-
ones from this apoptosis (Staecker et al., 1996;
Ernfors et al., 1996). In addition, infused neurotro-
phins can also have tropic e€ects on the dendrites of
the auditory neurones (Staecker et al., 1996).
One supplementing measure to improve success of
cochlea implants would therefore be to continuously
deliver NT-3, at least during the ®rst time after im-
plantation. This could be done by coating the
implant with a permeable polymer ®lled with the
neurotrophin which then would be released over a
certain period of time. On the other hand, exper-
iments with young deafened cats showed that
ganglion cell survival can be improved with electri-
cal stimulation mediated by such an implant (Leake
et al., 1991), and this neuroprotective e€ect was
found to be restricted to the area of stimulation
(Leake et al., 1992). However, if the site of implan-
tation and the stimulation pattern are not appropri-
ate, spiral ganglion cell rescue is less e€ective, and
functional organisation of the central auditory sys-
tem may be modi®ed as could be shown in young
cats (Leake et al, 1995).
Under permanent discussion is which kind of con-
tact between the external electronics and the
implanted electrode would be most suitable. Most
of the systems apply transcutaneous connection, i.e.
the skin remains intact, and the stimulation infor-
mation is passed through the skin by electromag-
netic coupling. This requires a transmitter outside
the head and a receiving antenna beneath the skin
which gives the information to the electrodes. The
other possibility is to let the leads pass directly
through the skin. Such a percutaneous system allows
an easier troubleshooting and a more ¯exible con-
nection between speech processor and the electrodes.
Moreover, they are compatible to magnetic reson-
ance imaging (MRI), whereas transcutaneous con-
nectors utilise a magnet and ferrous materials which
are incompatible with the high magnetic ®elds pro-
duced by an MRI device.
5. VISUAL IMPLANTS
Blindness can be caused by a variety of ocular dis-
eases and systemic disorders. Among them, retinal
diseases possess a prominent position as they fre-
quently reduce visual acuity and result in non-cur-
able blindness. Age-related macular degeneration
(ARMD) and retinis pigmentosa (RP) are well-
known diseases with high incidence. Approximately
1.2 million people are a€ected by RP which is a her-
editary disease and more than 5 million individuals
su€er world-wide from ARMD. The result of RP is
a progressive degeneration of photoreceptor cells
within the retina. Whereas macular degeneration
leads to a central loss of vision, patients su€ering
from RP ®rst lose peripheral vision which is then ac-
companied by loss of central vision.
With the contemporary technologies, electronic
devices will not be able to replace the function of
the eye completely. The human retina contains
approx. 120 million rods and 6 million cones which
converge their signals to about 1 million ganglion
cells. For an arti®cial electronic device, a resolution
449
of several hundreds of pixels (picture elements,
points) can be estimated to be the absolute mini-
mum for a useful optical image which would allow
rough orientation, i.e. recognition of doors, stairs,
cars, etc. The problem is not to record a picture
with a high resolution, but to transmit this infor-
mation in a meaningful way to the appropriate
site(s) within the brain. A huge number of single sti-
mulating electrodes is needed, and di€erent levels of
pre-processing of the optical information are
required depending on the place of implantation.
For this purpose, it is inevitable to understand how
the optical information is encoded within the retina
and how it is transmitted to the brain to create inge-
nious mental imagination.
The possibilities of application of visual pros-
theses are illustrated in Fig. 8. Two main types are
in development, retinal and cortical prostheses.
Retinal prostheses can be applied if the retinal
ganglion cells (RGCs) and hence the optic nerve are
still intact, and they are thought to replace function
of lost photoreceptor cells. If the RGCs are lost, the
optic nerve degenerates, and cortical prostheses
which electrically stimulate the visual cortex may be
developed in these cases. In the following, both
kinds of prostheses shall be discussed.
5.1. Retinal Prostheses
As outlined above, retinal prostheses are intended
to mimic the function of lost photoreceptor cells.
The photoreceptor cells are the ®rst in the excitation
chain which follows the optical stimulus. Their
membrane potential EM is decreased (absolute
value, i.e. the amplitude, increases) depending upon
extent of light irradiation by decreasing membrane
conductivity for Na+ ions gNa, whereas EM is
increased by increasing gNa in the case of darkness
up to ÿ30 mV. The potential is then synaptically
transmitted to the next layers of the retina, i.e. the
horizontal cells, the bipolar cells, the amacrine cells,
and ®nally the ganglion cells. The RGCs are organ-
ised into cells with so-called receptive ®elds of ON±
OFF characteristics. The sophisticated signal proces-
sing like divergence and convergence within the ret-
ina makes it possible to enhance contrast, detect
motion, to adapt to di€erent light intensities and
match the images into a topographic fashion which
is then the basis for binocular vision.
In the concept of retinal prostheses, an implanted
MEA applies light-dependent electrical pulses to the
RGCs which are then transmitted as a series of
action potentials to the brain to result there in a
meaningful image. There are two di€erent ways to
implant such a MEA: (i) ``on top'' of the retina
(epiretinal implant), i.e. between the ganglion cell
layer and the vitreous (Wyatt and Rizzo, 1996;
Rizzo et al., 1996; Humayun et al., 1996; Eckmiller,
1997) or (ii) ``beneath'' the retina (subretinal
implant), i.e. directly at the place of the lost photo-
receptor cells (Chow and Chow, 1997; Zrenner et
al., 1997). With an epiretinal implant, the distance
between electrodes and RGCs is smaller, and hence
RGCs can be stimulated more directly. In addition,
also the axons traversing from more peripheral sites
than the location of the implant may come under
450 P. Heiduschka and S. Thanos

Fig. 8. Examples of investigated possibilities to (partial) restoration of vision by the application of

microelectrode arrays (MEAs). If the retinal ganglion cells (RGC) are still intact, then the stimulating
MEA could be implanted into the eye, either onto the RGC layer (epiretinal implant) or by replacing
photoreceptor cells (subretinal implant), and nerve signals of stimulated RGC are forwarded into the
brain. Otherwise, the MEA is put on the surface of the visual cortex (epicortical implant). Alternatively,
the cortical implant can also consist of an array of needles which are inserted into the cortex.

the in¯uence of the stimulating electric ®elds. Thus,
excitation of these axons markedly lowers local
speci®city of stimulation at the site of implantation.
With a subretinal implant, the electrodes could per-
form directly the function of photoreceptor cells by
giving a stimulus upon irradiation. Subsequent in-
formation processing would be performed by the
other neuron layers of the retina. This would not be
possible with an epiretinal implant, and therefore
the latter would require a highly sophisticated
encoding of visual information into stimulating sig-
nals.
Numerous experiments have been performed to
achieve excitation of RGC cell bodies rather than
axons. This task is complicated because the detailed
position of stimulating electrodes relative to the cell
bodies cannot be controlled. One possibility is to
utilise di€erent excitation thresholds of cell bodies
and axons upon cathodic or anodic stimulation, and
it seems that preferred excitation of cell bodies can
be achieved by anodic stimulation. Another
approach is application of non-radial electrode con-
®gurations. When the lines of the electrical ®eld of
linear electrodes arranged in parallel run perpendi-
cularly to the axons, a minimal potential di€erence
is built up within the axon, and in the other case,
with the electrical ®eld longitudinal with the axon,
the potential di€erence would be higher thus lower-
ing threshold for excitation. Currently, geometries
of MEAs are under investigation with non-sym-
metrical electrodes in order to improve selectivity of
ganglion cell stimulation.
With subretinal implants, stimulation is supposed
to be more similar to the natural way because
incoming light would be applied as an electrical sig-
nal directly at the place where it hits the retina, and
the same is done by the photoreceptor cells.
Consequently, the concept of most subretinal
implants consists of an array of photodiodes which
directly supply an electrical pulse upon light ex-
posure. Further processing of these signals would
then be carried out by the neuronal layers of the ret-
ina, and RGCs would ®nally transmit the visual in-
formation to the brain. Naturally, neuronal layers
beneath the ganglion cell layer are necessary for this
concept. However, it must be expected that they
degenerate step by step because photoreceptors
which supply stimulating signals are lost. In fact,
such a degeneration has been observed in all retinal
layers, but it is claimed that remaining neurons
should be sucient for the application of a visual
prosthesis (Santos et al., 1997). Retinal implants are
inserted through the anterior part of the eye, and
animal experiments are performed mainly with rab-
bits. The whole surgery is very delicate because the
retina is very thin and soft. For epiretinal implants,
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
it is crucial to remove the vitreous completely at the
place of implant attachment because otherwise ®rm
adhesion cannot be achieved. For this purposes, it is
advantageous that the vitreous of the rabbit quickly
contracts and forms strands upon trauma, and
therefore it can be grasped and removed. The epiret-
inal implant can now be placed onto the retina. For
subretinal implants, the retina is incised, e.g. with a
sharply edged canule, and then the inner retina may
be separated from the pigment epithelium. The sub-
retinal implant can be inserted now between the
inner retina and the epithelium. Finally, the
detached parts of the inner retina must be attached.
As every neural implant, also a retinal implant
must meet very high requirements with respect to its
biocompatibility and long-term stability. Moreover,
an implant within the eye must be especially compa-
tible and stable because in such a delicate organ an
in¯ammation or extensive scar formation would
have fatal consequences, and surgical interventions
cannot be repeated for several times. It is clear that
a retinal implant should be soft, tiny and without
sharp edges, particularly when implanted beneath
the retina. The shape of the implant must ®t the
round eyeball which can be achieved by a ¯exible
substrate. Nevertheless, it will certainly be of favour
to produce the MEA with a vaulted shape.
One aspect already mentioned in the biocompat-
ibility section is the charge density of electrical
stimulation signals. Humayun et al. (1994) per-
formed bipolar stimulation of di€erent retinae using
platinum wires. They found that surface electrical
stimulation could be performed in bullfrog eyes
(13 mC/cm2), normal rabbit eyes (19 mC/cm2), and
rabbit eyes with outer retinal degenerations
(112 mC/cm2). These threshold values are within the
range denoted in the biocompatibility section, and
the authors conclude that electrical stimulation may
be a suitable approach for restoration of vision.
Until now, implantation experiments with retinal
implants have been performed only with animals.
The purpose of these experiments was to evaluate
biocompatibility and long-term stability of the
implants. Currently, several rabbits with subretinal
implants measuring 3 mm in diameter and 50±
100 mm thick are being kept for observation, and it
seems that they are well tolerated by the ocular tis-
sue (Zrenner et al., 1997). However, there are only
few reports about application of active electrodes in
such an implant. The means to evaluate function of
implanted electrodes is recording of cortical visually
evoked potentials (VEPs). They should appear in a
similar manner as if the stimulus would be given by
an equivalent optical signal. Humayun et al. (1995)
reported that electrical cortical responses could be
elicited by stimulating electrodes which were placed
in the lens of the eye in rabbits after chemically
induced photoreceptor degeneration. Rizzo et al.
(1996) also could record VEPs upon electrical stimu-
lation of the rabbit retina. Chow and Chow (1997)
implanted bipolar strip electrodes into the subretinal
space of adult rabbits. The electrodes were driven
by external photodiodes. When the photodiodes
were ¯ashed in a remote position, cortical responses
were obtained similar to the normal light-induced
VEPs produced by the pre-implanted eye. Humayun
451
et al. (1996) inserted small electrodes into the sclera
of blind patients. Spots of light, so-called phos-
phenes, could be elicited upon application of short
biphasic pulses. Patients who previously had been
able to see were able to localise the position of the
phosphenes accurately according to the retinal area
stimulated, which indicates a certain conservation of
the visual map. Two subjects were able to recognise
movement of electrodes by detecting movement of
the phosphenes, and they also could see two phos-
phenes when two electrodes were active. This is not
surprising since phosphenes can also be produced by
irritation of horizontal cells, whose localisation is
determined within the retina. Phosphenes are rather
``tactile'' signals, but may be well used as orientation
guides upon blindness.
One problem is delivery of adequate quanta of
energy needed for stimulation. Photodiodes used for
retina implants are still too weak, that means vol-
tage produced by them upon irradiation with day-
light is still insucient. Therefore, it is tried to
overcome this problem by installation of a small in-
frared laser device which is worn by the patient on
glasses. The laser beam directed onto the photo-
diodes is controlled by a computer-assisted video
camera. In one possible design, the photodiodes are
situated directly on the MEA, and the most straight-
forward concept is to combine one photodiode with
one electrode. In order to avoid damage to retinal
neurons by the laser beam, this design is applicable
only for epiretinal implants. In another design, the
receiving photodiodes are placed at the edge of the
retina, and thin wires lead to the stimulating MEA
underneath or above the retina. For the epiretinal
implant, di€erent concepts for the encoding of the
optic information are developed, e.g. by the group
of Eckmiller (1997), particularly trying to consider
receptive ®elds of the retina. Finally, a subretinal
implant may not disrupt supply of oxygen and
nutrients to the retina. Therefore, MEAs have been
designed with holes in order to allow exchange of
substances (Zrenner et al., 1997).
5.2. Cortical Prostheses
When the optic nerve is damaged, no information
can be conducted from the eye to the brain.
Therefore, reconstruction of visual abilities by direct
stimulation of the visual cortex has been supposed
(Hambrecht, 1995). Cortical implants consist of a
MEA placed under the skull directly on the appro-
priate side of the visual cortex, and the electrodes
stimulate cortical neurons to elicit visual sensations.
In fact, patients with such implanted electrodes
reported to ``see'' phosphenes. There have been nu-
merous investigations about necessary properties of
such an electrode array, and, on the other hand,
useful information about the organisation of the
visual cortex, i.e. the retinocortical map, could be
gained by electrical stimulation experiments. Several
experiments were performed to correlate the pos-
ition of the electrodes with the spatial positioning of
the phosphenes in the visual ®eld (e.g. Dobelle et al.,
1979). In order to enable the patients to recognise
more complex structures, e.g. letters, a matrix of
phosphenes must be created by simultaneous stimu-
452 P. Heiduschka and S. Thanos
lation by many electrodes. Such a matrix was simu-
lated by a monitor covered with an opaque perfo-
rated mask, and from the experiments was
concluded that a MEA consisting of 25  25 electro-
des on an area of 1  1 cm2 should produce a phos-
phene image on a visual acuity of approximately 20/
30 provided that the MEA is implanted near the
foveal representation of the visual cortex (Cha et al.,
1992).
Schmidt et al. (1996) implanted 38 microelec-
trodes in the right visual cortex of a 42-year-old
woman who had been blind over 22 years. 34 micro-
electrodes were able to produce phosphenes, and
most of the microelectrodes had stimulation
thresholds below 25 mA. Brightness and size of the
phosphenes could be in¯uenced by stimulation par-
ameters, and separate phosphenes could be detected
by the patient when stimulating electrodes had a
spacing of 500 mm. Moreover, the authors reported
that six phosphenes could be elicited simultaneously,
and they all moved simultaneously with eye move-
ments.
The task to provide vision by cortical stimulation
appears to be much more complicated because cur-
rent knowledge about vision is far away from a
detailed understanding. Although implantation and
maintenance of MEAs in the cortex seems to be
easier than in the eye, the questions of appropriate
image processing and creation of spike trains for
stimulation are highly complicated, particularly for
moving images and colours.
6. OTHER NEUROPROSTHETIC IMPLANTS
The principal idea of replacing nerve function
with implants can be drawn back to the work of
Sarno€ et al. (1950), who performed respiration by
electrical stimulation of the phrenic nerve. However,
it took another two decades till development of bio-
materials, electrodes and electronics allowed to
make completely implantable devices for functional
electrical stimulation (FES). FES is applied for per-
ipheral nerves, and there is a broad ®eld of di€erent
clinical applications which will be mentioned in this
chapter.
Respiratory pacing in case of ventilatory insu-
ciency is performed by electrical stimulation of the
phrenic nerve in the thorax using a platinum ribbon
electrode which is placed behind the nerve (Creasey
et al., 1996), or by stimulation of the phrenic nerve
with silastic cu€ electrodes or ``half cu€s'' (Glenn
and Phelps, 1985). Energy necessary for stimulation
is provided by an attached subcutaneously
implanted radio frequency (RF) receiver inductively
coupled to an external RF transmitter. Phrenic
nerve stimulation was also reported to be performed
in children (Girsch et al., 1996). It is a widely
applied technique despite some occasional problems,
e.g. diaphragm fatigue. There are also devices with
an internal energy supply via a battery, where only
programming is performed with a computer and a
radio transmitter (Mayr et al., 1993).
Peripheral nerve stimulation is also used for
chronic pain reduction (for a review, see Stanton-
Hicks and Salamon, 1997). Nashold et al. (1982)
reported on the implantation of electrodes into
upper or lower extremities. Pain relief was achieved
in a half of cases in the arms and in a third of cases
in the legs. Pain caused by trigeminal neuropathy
could be reduced by electrodes stimulating the tri-
geminal ganglion and rootlets (Meyerson and
Hakanson, 1986). Waidhauser and Steude (1994)
described electrical stimulation of the trigeminal
nerve in the case of so-called atypical trigeminal
neuralgia which is characterised by long-lasting
burning pain sensations without any pain attacks.
Peripheral nerves of the hand were stimulated in
order to reduce chronic somatic peripheral nerve
pain (Strege et al., 1994). Pain management by
stimulation of central areas is discussed below.
Another important ®eld is assistance of muscle
movement of lower or upper extremities, i.e. legs
(Cybulski et al., 1984) or arms. The peroneal nerve
was stimulated in order to improve walking abilities
of hemiplegic patients, particularly to manage the
so-called ``drop-foot'' (Teng et al., 1976; McNeal et
al., 1977; Waters et al., 1984; Strojnik et al., 1987).
The nervus femoralis and the nervus gluteus inferior
were also stimulated by implanted electrodes, and
paraplegic patients were reported to obtain ability
to stand up from the wheel-chair and even ``walk''
several steps with crutches (Kern et al., 1985). A
partial restoration of hand function was achieved in
tetraplegic patients by stimulation of the median
nerve (Kiwerski et al., 1983). Nevertheless, the large
®eld of neurostimulation for restoration of move-
ment of paralysed patients will not be treated in this
paper.
Finally, treatment of epileptic seizures has to be
mentioned. For this purpose, the vagal nerve is
stimulated electrically. Uthman et al. (1990) could
achieve reduction of the seizure frequency or
decreased duration or intensity of seizures. As side
e€ects, they reported a tingling sensation in the
throat and hoarseness during stimulation. The
stimulation was performed with two spiral electro-
des wound around the vagal nerve. In a subsequent
report, good e€ects of the electrical stimulation were
reported, and the authors state that the patients tol-
erated the implantation and stimulation well with-
out pain, discomfort, or important changes in their
daily activities (Wilder et al., 1991).
6.1. Bladder Stimulation
In a healthy organism, micturition is achieved by
complex interactions of the somatic, sympathetic
and parasympathetic innervation of bladder and
urethral muscles (Hoyle et al., 1994). The bladder
detrusor smooth muscle is controlled mainly by
parasympathetic motor neurons located in the sacral
spinal cord segment S3 which are excited by des-
cending preganglionic ®bres. During bladder ®lling,
the urethral sphincter contracts to maintain conti-
nence. At this stage the parasympathetic signalling
pathways and the detrusor are inhibited by sym-
pathetic nerves, and the sphincter muscle is con-
tracted by somato-motoric nerves. During
micturition, the detrusor muscle contracts followed
instantly by sphincter muscle relaxation. A€erent
®bres ascending from the detrusor muscle provide
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
information about the stretching state and therefore
about the ®lling of the bladder, and a€erents from
the urinary tract contribute to a positive feed-back
during voiding.
In cases of serious neuropathic voiding disorders,
e.g. caused by a spinal cord injury, bladder function
is disturbed. In many patients with spinal cord
injury, re¯ex pathways responsible for continence
still work, but micturition cannot be initiated in a
normal way. During the ®rst time after injury, no
re¯ectory voiding occurs, and the bladder is weak
and atonical. Later on, a stage of low bladder
volumes and frequent voidings follows. The most
common form of micturition malfunction is detru-
sor-sphincter dyssernergia, i.e. the detrusor and the
sphincter are activated simultaneously instead of
alternately (Mahoney et al., 1980), which leads to an
incomplete voiding of the bladder and a high risk of
infection of the urinary tract. Other abnormal dis-
orders can be too weak contraction of the detrusor
leading to incomplete emptying of the bladder due
to sphincter muscle convulsion or lesion of detrusor
muscle as a consequence of in¯ammations, trau-
matic nerve damage or surgical transfer of the urin-
ary tract. Multiple sclerosis or arteriosclerosis of
brain vessels also can lead to incontinence.
Patients with spinal cord injury can control their
micturition by re¯ectory initiation of detrusor con-
traction by tapping or pressing their abdomen. In
other cases, catheterisation is necessary. Particularly
the latter method is an awkward and inconvenient
one. At least partial restoration of the bladder func-
tion can be performed by FES of di€erent nerves or
muscles. Electrical stimulation to restore normal
micturition has been investigated since several dec-
ades (for reviews, see Schmidt, 1986; Talalla, 1986;
Talalla et al., 1987; Tanagho, 1990). It can be
applied directly in the spinal cord (Grimes and
Nashold, 1974; Jonas and Tanagho, 1975), the
sacral nerve roots (Brindley et al., 1986; Tanagho et
al., 1989), the pelvic nerves (Holmquist, 1968;
Kaekenbeck, 1979), or the detrusor muscle (Boyce
et al., 1964; Halverstadt and Parry, 1975; Magasi
and Simon, 1986). Among these possibilities, sacral
nerve root stimulation has been the most successful
in case of intact e€erent innervation of the detrusor
muscle. Stimulation of the sacral root can be per-
formed by surface electrodes (Walter et al., 1989) or
by implanted intradural (Brindley et al., 1986; van
Kerrebroeck et al., 1991) or extradural (Tanagho et
al., 1989) electrodes.
Most of the e€erent ®bres for the bladder are
located in the ventral branch of the sacral nerve
root. However, electrical stimulation of the ventral
branch with cu€ electrodes also leads to contraction
of the urethral sphincter which leads to hindering of
bladder evacuation. Moreover, legs also are moved
by the stimulation, or penile erection, sweating and
piloerection can occur (Nashold, 1974). The reason
for this e€ect is the composition of the ventral sacral
roots which contain nerve ®bres innervating several
muscles of the legs, the pelvic ¯oor, the urethral and
anal sphincter, and preganglionic parasympathetic
e€erents innervating the detrusor muscle. Small
nerve ®bres need a higher stimulus for their exci-
tation than large ®bres, and that is why excitation
453
of small e€erents for the detrusor is always ac-
companied by the excitation of large ®bres for the
sphincter and leg muscles.
There are several attempts to overcome this pro-
blem, which are reviewed, e.g. by Rijkho€ et al.
(1994). Such an attempt is the post-stimulus voiding
technique described by Jonas and Tanagho (1975)
which takes advantage of di€erent relaxation times
of the striated sphincter muscle (0.4 sec) and the
smooth detrusor muscle (13 sec), and a commer-
cially available system based on this principle has
been developed by Brindley et al. (1982, 1986).
Schmidt et al. (1979) achieved reduction of urethral
resistance caused by sacral root stimulation by sec-
tion or blocking of the pudendal nerve, which, how-
ever, is a severe and irreversible procedure. Sweeney
et al. (1990) tried to avoid this nerve section by re-
versible blocking of signal transmission through the
pudendal nerve by simultaneous stimulation of the
pudendal nerve at a more distal site and subsequent
mutual annihilation of the two action potentials
upon their collision. This procedure is a sophisti-
cated one and requires implantation of additional
electrodes. In experiments with dogs, ThuÈro€ et al.
(1982) used di€erent excitation thresholds of large
®bres for the sphincter and small ®bres of the detru-
sor. A high frequency pulse train with an amplitude
sucient for excitation of the large sphincter ®bres
was applied to fatigue the sphincter muscle, and a
stronger stimulus was then given to activate the
detrusor. The principle of sphincter fatigue was also
applied by Sawan et al. (1996) who developed an
implantable computerised electrical stimulation sys-
tem for bladder evacuation in animal models (dogs)
after spinal cord transection.
However, several problems remain with all these
methods. Unwanted movement of the legs is not
avoided. In general, stimulation of the sacral root
can be applied only in patients with a complete
spinal cord transection or in patients without pelvic
pain sensation. Otherwise, electrical stimulation can
cause pain because a€erent ®bres of the ventral
roots may also be excited (Schalow, 1989).
Therefore, the so-called anodal block technique
became more and more attractive which is expected
to solve the above-mentioned problems (Accornero
et al., 1977; Brindley and Craggs, 1980; Fang and
Mortimer, 1991). Nerve ®bre membranes near an
anode are hyperpolarised, and action potentials can-
not pass this zone with a sucient anodic current.
Larger ®bres are blocked earlier than smaller ones,
and a selective ®bre blockade can be achieved.
Tripolar cu€ electrodes were shown to be useful for
both excitation and anodal block.
For a systematic and successful development far
from rules-of-thumb and empirical animal or clinical
trials, the behaviour of the system cu€ electrode-
axon has to be evaluated. A ®rst simple model was
presented by Altman and Plonsey (1986). A more
detailed study of the volume conductor was pre-
sented by Ferguson et al. (1987). Rijkho€ et al.
(1994) developed a three-dimensional rotationally
symmetrical model and calculated geometric and
electrical parameters for an asymmetric tripolar cu€
which would allow selective activation of the detru-
sor without excitation of the sphincter and the a€er-
454 P. Heiduschka and S. Thanos
ent nerves. The authors state that, however, dorsal
sacral roots still would be transected in order to
abolish autonomic re¯ex contractions of the bladder
and to avoid re¯ex incontinence. Nevertheless, elec-
trodes and stimulation protocols have been applied
successfully in patients (Rijkho€ et al., 1997a,b).
A di€erent technique to achieve selective stimu-
lation of the bladder is the application of microelec-
trodes within the sacral spinal cord. Carter et al.
(1995) demonstrated that sustained elevation of
bladder lumenal pressure without simultaneous acti-
vation of the urethral sphincter or leg muscles is
possible in the cat by electrical stimulation with four
50 mm iridium microelectrodes. The e€ects of stimu-
lation could be varied by changing the positions of
the four electrodes and the stimulus parameters.
These experiments were continued in order to evalu-
ate histopathologic and physiologic e€ects of im-
plantation and stimulation (Woodford et al., 1996).
Electrodes were implanted into the S2 segment of
the sacral spinal cord of a cat in order to excite
preganglionic parasympathetic neurons, and bladder
detrusor muscle contraction could be achieved upon
stimulation. Interestingly, this e€ect was not
restricted to the stimulation site of the S2 segment.
One problem that still has to be solved was move-
ment of implanted electrodes inside the spinal cord,
whereas neuronal damage caused by electrical stimu-
lation was less pronounced.
6.2. Stimulation of Spinal Cord and Brain
Electrical stimulation in the area of the spinal
cord and the brain, i.e. the CNS, is particularly deli-
cate due to the high complexity of the central ner-
vous tissue leading to the enhanced risk of
unwanted damage of nerve function in the course of
implantation and stimulation mode and to more
complicated patterns of responses which may be eli-
cited by stimulation. Only few examples of stimu-
lation in the CNS have to be presented here, and
auditory and optical neuroprostheses have been dis-
cussed already.
Stimulation of the spinal cord is intended for a
big variety of applications, mainly in the case of
spinal cord injury, where failure of descending ®bres
has to be compensated by stimulation of (pre-)
ganglionic neurons. One important application is
the control of bladder function by stimulation in the
sacral area, and di€erent possibilities of bladder
stimulation were described in the text above.
Another important application is the reduction of
pain sensations (Burton, 1975; Kumar et al., 1991;
Broggi et al., 1994; Stanton-Hicks and Salamon,
1997), originating, e.g. from diabetic peripheral neu-
ropathy (Tesfaye et al., 1996), arachnoiditis, peri-
neural ®brosis following surgeries, multiple sclerosis,
ischemic pain in the extremities from peripheral vas-
cular disease and angina pectoris (Augustinsson et
al., 1995), or loss of limbs by accident or amputa-
tion. A ®rst preliminary report on pain inhibition
was published by Shealy et al. (1967). The treatment
is based on the ``gate control'' theory (Melzack and
Wall, 1965) which has its origin in the observation
that pain in the skin can often be toned down by
gently stimulating the skin around the site of hurt
by soft tickling, brushing or massaging. By these
tactile stimulants, inhibitory interneurons within the
dorsal horn can be activated, thus suppressing trans-
mission of pain. Moreover, these interneurons are
in¯uenced by descending ®bres from the brain too,
and lateral inhibition can occur via the large diam-
eter a€erents. The advantage is that these ®bres
have a low stimulation threshold and can be easily
activated due to their large diameter.
Upon stimulation, a sensation is produced in the
corresponding skin area called paresthesiae which
includes tingling and numb feelings. Usually, stimu-
lating electrode arrays are implanted epidurally, and
several anode-cathode combinations can be realised
at various spinal levels. As complications, wound
infection, electrode displacement or fracturing, and
®brosis at the stimulating tip of the electrode can
occur. For this reason, high sterility during surgery
and prophylactic antibiotics to prevent infections
are required. Nevertheless, implantation of a stimu-
lation system is a safe and quick operation in gen-
eral which can be performed under general or local
anaesthesia and is well tolerated by most patients.
For an e€ective pain management, the area of
hurt must be covered by paresthesiae (Law and
Miller, 1982; Barolat et al., 1991). However, Struijk
et al. (1993) showed that not only dorsal column
®bres but also dorsal root ®bres may be activated,
which was con®rmed by Barolat et al. (1993) who
showed that dorsal roots, dorsal root entry zone,
dorsal horn, and dorsal columns are involved in
stimulation. Another problem is that motor re-
sponses and unpleasant sensations can be caused by
stimulus amplitudes which are 40±60% above per-
ception threshold (Jobling et al., 1980; Law, 1987;
Tulgar et al., 1993), and thus only a small amplitude
window is available for stimulation. If it would be
possible to activate selectively only dorsal column
®bres with higher amplitudes, a better pain treat-
ment could be achieved. In order to achieve prefer-
ential stimulation of dorsal column ®bres, electrode
geometries and electrode combinations were varied.
Extended theoretical considerations were performed,
e.g. by Struijk and Holsheimer (1996), and they
could be correlated with clinical observations
(Holsheimer, 1997).
In order to reduce pain, also brain areas are
stimulated. Brain stimulation is usually taken into
consideration for patients in whom other forms of
pain treatment have failed. Electrical stimulation in
the thalamic nuclei VPL and VPM inhibits the acti-
vation of spinal dorsal horn neurons by noxious
stimuli, and considerable relief of pain can be
achieved at the major portion of patients with very
few permanent complications (Young, 1990).
Unfortunately, not all patients receive e€ective pain
relief, and other stimulation targets such as the K-F
nucleus in the parabrachial region of the brain stem
have been explored in order to provide pain relief to
more patients. Ebel et al. (1996) performed stimu-
lation of the motor cortex. However, the bene®cial
e€ects decreased in some of the patients after a
good initial phase.
Multiple e€orts are undertaken in order to restore
normal abilities, e.g. free standing or movement of
legs, in case of paraplegia. Rushton et al. (1997)
 Implantable Bioelectronic Interfaces for Lost Nerve Functions
achieved movement of parts of legs by electrical
stimulation in the lumbar root.
7. FINAL CONCLUSIONS
Replacement of damaged or lost nerves by arti®-
cial implants with recording and/or stimulating elec-
trodes has been a goal of many e€orts since several
decades. The construction and application of a neu-
roprosthesis is a common matter of di€erent ®elds
of research, such as neurobiology, medicine, compu-
ter science, microelectronics, microtechnology, sur-
face science, electrophysiology and electrochemistry.
The high complexity of both structure and function
of the nervous system is, however, a real obstacle on
the way to apply simple neuroprostheses, whereas
really functioning, easy-to-handle and long-term
stable neuroprostheses are still not available yet.
Nevertheless, implants are applied successfully in a
few particular cases, which means that a partial res-
toration of the natural function can be achieved
over a longer time period. These special cases are
the cochlea implant and implants for bladder stimu-
lation. However, both prostheses are not real neuro-
prostheses. Other applications, as pain management
or stimulation of the limbs, are still not in the state
as broad applicability and reliability could be
claimed.
In the ®eld of replacement of sensory functions
besides hearing by cochlear implants, visual pros-
theses are the target of ongoing e€orts. Since the
visual system is the most complicated sensory one,
the natural impediments are particularly large. A
satisfactory prosthetic replacement of visual func-
tion and microelectronic improvements which will
allow parallel processing of detectable photic stim-
uli.
Although the loss of other sensory functions
seems on the ®rst view to be of less importance, in-
dividuals su€ering from either sensory weakness or
loss feel it as a devastating event. Whereas photic
detection can be performed by a camera and hearing
by a microphone, the problem arises with taste and
olfaction with no appropriate sensors until now.
The molecular and neuronal mechanisms of taste
and olfaction are still not completely understood,
and mimicking of such processes by arti®cial sensors
was realised in part by only a few laboratory set-
ups.
Two problems which were not touched in this
review are technical realisation of the ready-to-
implant device and data processing. In the past,
many approaches failed because problems of encap-
sulation, connection and stability towards leaking
and corrosion. Nevertheless, realisation of an appro-
priate data transmission and processing is still a big
challenge, particularly for sensory neuroprostheses
where multi-channel stimulation is required. On-
chip electronics, multi-plexing and parallel proces-
sing are key features to manage the huge amount of
data necessary for a useful stimulation. In order to
recognise and classify neural signal patterns, di€er-
ent architectures of computer programs called arti®-
cial neural nets (ANN) have been created. They are
also needed to produce arti®cial spike trains for
455
stimulation purposes. The goal of current research
of computer science is to choose the best kind of
ANN for the single task and to make the ANN as
reliable and fast as possible. As the next step, e€orts
are performed to make neural processors with
adaptable neural net circuits.
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