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Polymers for Neural Implants

Christina Hassler,1,2 Tim Boretius,1 Thomas Stieglitz1,2

1Laboratory for Biomedical Microtechnology, Department of Microsystems Engineering-IMTEK, University of Freiburg,

Georges-Koehler-Allee 102, Freiburg, Germany

2Bernstein Center Freiburg, Hansastr. 9A, Freiburg, Germany

Correspondence to: T. Boretius (E-mail: [email protected])

Received 20 August 2010

DOI: 10.1002/polb.22169

ABSTRACT: Neural implants are technical systems that restore

sensory or motor functions after injury and modulate neural

behavior in neuronal diseases. Neural interfaces or prostheses

have lead to new therapeutic options and rehabilitation

approaches in the last 40 years. The interface between the

nervous tissue and the technical material is the place that

determines success or failure of the neural implant. Recording

of nerve signals and stimulation of nerve cells take place at

this neuro-technical interface. Polymers are the most common

material class for substrate and insulation materials in combi-

nation with metals for interconnection wires and electrode

sites. This work focuses on the neuro-technical interface and

summarizes its fundamental specifications first. The most com-

mon polymer materials are presented and described in detail.

We conclude with an overview of the different applications and

their specific designs with the accompanying manufacturing

processes from precision mechanics, laser structuring and

micromachining that are introduced in either the peripheral or

central nervous system. VC 2010 Wiley Periodicals, Inc. J Polym

Sci Part B: Polym Phys 49: 1833, 2011

KEYWORDS:biocompatibility; biomaterials; polyimides; sili-

cones; thin-films

INTRODUCTION TO NEURAL IMPLANTS Neural implants are

technical systems that are mainly used to stimulate parts

and structures of the nervous system with the aid of

implanted electrical circuitry or record the electrical activityof nerve cells. Their application in clinical practice has given

rise to the fields known as neuromodulation and neuro-

prosthetics (or neural prostheses). From the experience

gained by the early experiments in the 1960s, miniaturiza-

tion technologies, material sciences and the progress in med-

ical and especially neuroscientific knowledge evolved and

paved the way to these novel applications in therapies of

neurological diseases and rehabilitation of lost functions in

clinical practice.1,2 Neuromodulation, namely the stimulation

of central nervous system structures to modulate nerve

excitability and the release of neurotransmitters,3 alleviates

the effects of many neurological diseases. Deep brain stimu-

lation helps patients suffering from Parkinsons disease tosuppress tremor and movement disorders. It is also a treat-

ment option for severe psychiatric diseases like depression

and obsessive-compulsive disorder. Vagal nerve stimulation

has been applied first to treat epilepsy3,4 but has now

expanded to psychiatric diseases and many more applica-

tions are under development in preclinical and clinical trials.

The most commonly implanted device in the neuromodula-

tion sector is the spinal cord stimulator, used to alleviate

chronic pain and to treat incontinence.5 More than 130,000

patients have benefitted from these implants5 that derive

from cardiac pacemakers, first developed decades ago.Neural prostheses aim to restore lost functions of the body,

either sensory, motor or vegetative. An early example can be

dated back to about 1970 when Giles Brindley implanted the

first electrodes around the sacral nerves of spinal cord

injured persons to manage their bladder function.6,7 Other

implants have been developed in parallel to help patients

suffering from stroke or from spinal cord injury. Motor

implants to restore grasping,8 stance and gait9,10 as well as

ventilation11 by electrical stimulation of the diaphragm have

been developed and introduced into preclinical studies or

even as commercial products to the market. However, the

number of patients that benefit from these systems is rela-

tively low, in part due to some technical shortcomings, but

mainly as a result of the limited performance of the implants

in patients due to their individual course of injury. In combi-

nation with a limited market, it is economically quite unat-

tractive for companies to develop and approve a new device,

since the reimbursement is uncertain and the sale volume is

(too) low. Sensory implants to restore hearing, so-called

cochlear implants, are one of the main success stories of

neural prostheses. More than 150,000 patients have been

C. Hassler and T. Boretius contributed equally to this work.

VC 2010 Wiley Periodicals, Inc.

18 JOURNAL OF POLYMER SCIENCE: PART B: POLYMER PHYSICS 2011, 49, 1833

REVIEW WWW.POLYMERPHYSICS.ORG

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implanted with these technical systems, that stimulate the

nerve cells in the inner ear at several sites when the sensory

cells (hair cells) are no longer present, for example, due to

aging, diseases (meningitis or Menieres disease) or by cer-tain drug treatments.12,13 Congenitally deaf children, as well

as adults who have lost their hearing at a later point in life14

have been implanted and were able to hear and to communi-

cate via the telephone with these implants. Recently devel-

oped implants can access the brain stem15 and midbrain

auditory structures16 when tumors have destroyed the path-

ways from the ear to the cortex, to restore at least some

sound perception. In these cases, there is still room for a lot

of improvement since the speech processors are borrowed

from cochlear implants and are not yet optimized for the

neuronal target structures.

The latest technological progress in miniaturization technolo-

gies has enabled the development of retinal prostheses torestore vision through implantation of complex electrical

stimulators into the eyes of blind people.1,17 Clinical trials

have proven the feasibility of the approach, but there are still

many limitations to overcome and thus it is likely that com-

mercial products will not be available within the immediate

future.

The concept of controlling technical devices and neural pros-

theses by thoughts currently drives research in the field of

brain-machine interfaces, where a large variety of different

materials and approaches compete to become the first reli-

able solution for a clinical application.18 Unfortunately, en-

thusiasm about the technological opportunities masks the

risk and side effects that come along with implantation.

Therefore, benefits and detriments have to be carefully con-sidered in any medical and surgical treatment, and ulti-

mately the patient should give the final consent for implanta-

tion to occur.

All neural implants have to fulfill general requirements to

become approved as a medical device: They must not harm

the body and should stay stable and functional over a certain

life-time which is in most cases in the range of decades. Her-

metic packages made of ceramics or titanium are state of the

art2 to protect the implant electronics from moisture and

ions. These packages are implanted in most cases in a place

that is quite far away from the neuronal target tissue to pre-

vent any undesired interaction or damage. The key challenge

for any neural implant is the proper design of the neuro-technical interface. Multiple electrical contact sites have to

get in close contact with neural tissue to selectively stimu-

late subsets of nerve cells. Nerves are delicate and structures

of soft tissue get easily damaged by hard materials especially

when forces due to movements occur. Polymers have been

found the optimal material class when requirements of little

response to implantation, long-term stability in a hostile

environment, low material stiffness (i.e., high material flexi-

bility), and good electrical insulation of metallic conductors

have to be combined in a single material.

Christina Hassler received the Dipl.-Ing. in microsystems engineering in 2008 from the

University of Freiburg, Germany. Later she joined the group for Biomedical Microtechnology

at the Faculty of Engineering (IMTEK), University of Freiburg as a Ph.D. student. Her interest

in research focuses on polyimide-/parylene-based intracortical microelectrodes with

biodegradable coatings.

Tim Boretiusreceived the Dipl.-Ing. in microsystems engineering in 2008 from the University

of Freiburg, Germany. Later he joined the group for Biomedical Microtechnology at the

Faculty of Engineering (IMTEK), University of Freiburg as Ph.D. student. His interest in

research focuses on polyimide based microelectrodes, active coatings and the assemblage

of the same.

Thomas Stieglitzreceived the Dipl.-Ing. in electrical engineering in 1993 (TH Karlsruhe), the

Dr.-Ing. in 1998 and qualified as a university lecturer (Habilitation) in 2002 (both from the

University of Saarland, Saarbruecken, Germany). From 1993 to 2004 he was with the

Fraunhofer-Institute for Biomedical Engineering, St. Ingbert/Germany. Since October 2004,

he is a full-time Professor for Biomedical Microtechnology at the Faculty of Engineering

(IMTEK), University of Freiburg. His research interests include biocompatible assembling

and packaging, microimplants, and neural prostheses.

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In this review, we have compiled the information that

seemed to us most valuable to enter the field of neural pros-

theses and to enable the reader to make up his own mind

about neural implants. First, we summarize the fundamental

requirements of a material-tissue interface with the nervous

system. Next, the most common polymers and their material

properties are summed up, since the most widespread mate-

rials for substrate and insulation materials of electrodes andcables are polymers. Following this, the use of polymers and

their performance in different neuro-technical interfaces

with the peripheral and central nervous system are pre-

sented for the various designs and applications. Finally, we

summarize the topic of polymers for encapsulation and pack-

aging of implantable electronics; however, a full discussion

goes beyond the scope of the current review.

FUNDAMENTAL SPECIFICATIONS OF

NEURO-TECHNICAL INTERFACES

Even though millions of people worldwide benefit from ar-

tificial joints and cardiac pacemakers, it does not mean that

the challenges to implant a technical material in the humanbody are completely solved or even fully understood. In

addition to their own special requirements, all implants

have certain fundamental specifications in common to be

stable and functional. These specifications will be explained

using the example of neuro-technical interfaces. The inter-

face of neural implants forms the boundary of technical

system and delicate soft tissue, that is nerve cells that are

surrounded by supporting cells like glial cells in the central

nervous system or fibrous tissue such as the perineurium

and the epineurium in the peripheral nervous system. The

mechanical properties of the biological tissue have to be

taken seriously into account when selecting materials for

implant manufacture as well as the anatomical constraintsand conditions of the implantation site considering space

and movement of the nerve versus muscles, skin and

bones. From the engineering point of view, proper and

detailed target specifications including the details and limi-

tations of the intended use are mandatory to make a

proper design that combines a sufficiently high robustness

with the necessary complexity of the technical system and

not the highest possible one.

Surface Biocompatibility

Any implant is designed to have a minimal impact on the

body. However, any surgical intervention is accompanied by

an inflammatory response as a normal physiological re-

sponse to this intervention. In the presence of an implant,this response tends to be increased and extended depending

on the chemical composition of the implants surface. A non-

specific foreign body reaction is initiated19 that -colloquially

spoken- tries to eat up the implant or to wall it out. Specific

immune responses with antibody mediated immune

responses hardly occur and should be prevented by the ma-

terial selection but also by the cleanness (i.e., the amount of

germs and dirt on the implant). The aspect of surface bio-

compatibility deals with all viewpoints of chemical and bio-

logical interaction of an implant with the surrounding tissue.

This biological process chain starts in any case with an

unspecific protein adsorption (also called biofouling) that

triggers the foreign body response. In the best case, it ends

up with a defined and stable encapsulation of fibrotic tissue

without harming the implant, a so-called bioinert reaction.

This encapsulation might be beneficial with respect to the

spatial fixation of the implant. However, since we deal with

implants to record electrical signals and to electrically stimu-late nerve cells, this electrically insulating encapsulation

always results in an increase of current or voltage threshold

for stimulation and in a decrease in the signal-to-noise ratios

during recording until a steady state is reached. Therefore,

substrate materials and coatings must be chosen that the

reaction after implantation is minimized and that reactive

cells are transferred into their inactivated state after the

healing reaction is terminated.20 If these specifications are

met, the material can be considered a reasonable biomate-

rial.21 One prerequisite for such a material is that it must

not cause large inflammation after surgical intervention, and

cell behavior must not be altered by toxic products that dif-

fuse out of the material itself. These basic material investiga-tions are identified in in vitro cytotoxicity tests with standar-

dized cell cultures. The international standard ISO 10993

Biological evaluation of medical devices describes test sys-

tems, procedures and evaluation schemes to classify an

implant as biocompatible or not. Cytotoxicity testing helps to

reduce animal experiments and allows assessment of differ-

ent materials due to standardized and application specific

cell lines. Alterations in cell morphology and metabolism are

good indicators for toxic chemical groups or elutes and the

surface energy of the devices under test. Polymer materials

have proven (see Polymer Materials section) their suitabil-

ity as implant materials. Their surface properties can be

even improved by chemical and bio-chemical surface modifi-

cations. In this review, however, we will focus on the inher-

ent material properties without any additional modification.

Structural Biocompatibility

Surface biocompatibility is necessary but depicts only one

aspect of biocompatibility. Structural biocompatibility refers

to mechanical interaction between the implant and the sur-

rounding tissue and includes weight, shape and flexibility

(Youngs modulus). For a long time, mechanical mismatch

has been assigned to cell and tissue damage and the follow-

ing release of mediators as a result of the implantation event

initiating the inflammatory cascade. Therefore, a lot of

research has been conducted to reduce insertion damage

especially in the central nervous system (for a review, seeref. 22) but also in the peripheral nervous system to prevent

collateral damage of the nervous tissue by movements of the

implant. The mismatch of mechanical properties of the tech-

nical material and target tissue leads to cellular reactions

that attack and eventually encapsulate the implant23 and

results in a less effective electrical performance as already

described in Surface Biocompatibility section. Recently,22 it

has been shown in central nervous system implants that

micromovements due to mechanical mismatch also lead to a

chronic inflammation that results in glial scars around



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electrode carriers and finally electrode failure. These investi-

gations on how the organism reacts to a certain material,

shape and texture have to be performed in chronic in vivo

experiments in animals before any device is allowed to enter

a clinical trial according to the ISO 10993 and other direc-

tives, for example, the medical device directive and the active

implantable device directive (AIMD) in the EU. Polymers

with their large variability in stiffness and their ability to es-

tablish multilayer substrates with gradients in Youngs mod-

uli are excellent candidates with respect to structural bio-

compatibility in neural implant applications.

Biostability

Most of the chronic implants stay within the human body for

decades. Even if the battery powered electronics have to be

exchanged every 5 to 10 years, the neuro-technical interface,that is the electrode, usually remains implanted. The techni-

cal term biostability summarizes different chemical aspects

with respect to material stability and system integrity.23 Met-

als should not corrode, and substrate and insulation layers

should not delaminate or degrade. In polymers, hydrolytic,

oxidative and enzymatic degradation may occur and can be

accelerated by pH changes and voltages on integrated inter-

connect lines. In vitro soaking tests, for example, in physio-

logic saline, Ringers solution or cell culture media allow a

first approximation of the biostability of the materials and

are often performed at higher temperatures to accelerate the

diffusion processes and thereby their influence on aging and

the mean time to failure. General aspects on testing proce-

dures are also described in the ISO 10993. Care has to be

taken in the models of accelerated aging to predict the mean

time to failure. Failure mechanisms in polymers do not

always follow diffusion processes but depend on tempera-

ture initiated processes in some cases that are not described

by the Arrhenius equations that are commonly used in the

field of implant manufacturing.24 However, the results must

be validated by in vivo tests for the most promising material

candidates to exclude additional enzyme or foreign body

reactions that could not have been foreseen in in vitro mod-

els. Again, the ISO 10993 guides the applicant through the

necessary experiments that have to be done before a medical

device approval can be passed.

Changes in Implant Performance due

to the Intended Use

Neural implants should not interfere with the mechanical,

chemical and physiological properties of nerves (e.g., trauma

caused by surgical intervention) as already discussed earlier.

In active medical devices, the official regulatory term for

any recording and stimulation interface to the nervous sys-

tem, the presence of electronic systems and their use must

not alter nerve behavior either. Design measures have to be

TABLE 1 List of the Electrical, Mechanical, and Thermal Properties of Chosen Polymers

Properties of Polymers Polyimidea Parylene Cb PDMSc SU8d LCPe

Precursor BPDA/PPD DPXC N/A N/A N/A

Possible thicknesses (lm) 115 1100 10100 for

spin coating

1300 253000

Density (g/cm3) 1.101.11 1.289 1.08 1.0751.238 1.4

Viscosity (Pa s) 5 6 1 0.01400 0.0615

Moisture absorption (%) 0.81.4 0.06 550 250 300315

Glass transition temperature (C) 200210

Thermal conductivity (W/cm K) 0.29 8.2 1525 0.0020.003

Thermal coefficient of

expansion (ppm/K)

12 35 52 438

Specific heat (107 cm2/s2 K) 1.13

Specific resistivity (Xcm) > 1016 >1016 1015 7.8 1014 1 1013

Disruptive strength (V/cm) 1.510s 2.6106 2000 >4 105 4.7 106

Dieletric coefficient er 3.5 (at 1 kHz) 3.1 (at 1 kHz) 2.63.8 (at 50 Hz) 3.2 (at 10 MHz) 3 (at 1MHz)

Loss factor tan d 0.0013 (at 1 kHz) 0.019 (at 1 kHz) 0.0020.02 (at 50 Hz) 0.02 (at 1 MHz)

Tensile strength (MPa) 392 69 6.2 60 182

Tensile module (MPa) 8830 20 0.10.5 20 10,600

Elongation (%) 30 200 600 4.86.5 3.4

USP class VI VI VI

a UBE UVarnishS.31

b PCS Parylene C.32

c NuSil MED1000.33

d MicroChem SU8 2000 & 3000 Series.34,35

e Vectra MT1300.36



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electrical insulation but also handling properties and manu-

facturing technologies to obtain the desired feature sizes,

thicknesses and mechanical performance, which is often a

compromise between strength to withstand the implantation

process and the flexibility to prevent damage of the target

tissue. This section presents those polymer materials that

have been already established in many clinical applications

or in research developments and serve as carrier or as insu-lation material for neural implants.

Polyimide

Polyimides are a branch of commercial available polymers

most widely used in various aspects of microelectronics and

also, within the last 30 years, in biomedical applications.

Generally used as an insulation or passivation layer, poly-

imides provide protection for underlying circuitry and metals

from effects such as moisture absorption, corrosion, ion

transport, and physical damage. Furthermore, it acts as an

effective absorber for alpha particles that can be emitted by

ceramics, and as a mechanical stress buffer.30 Key properties

are: thermoxidative stability, high mechanical strength, high

modulus, excellent insulating properties, and superior chemi-

cal resistance (for values see Table 1). Typically, polyimides

are available as photo-definable and nonphoto-definable ver-

sions whereas photo-definable polyimides tend to have a

higher moisture uptake that limits their use in vivo; the lat-

ter will therefore not be discussed further.37 Synthesis of

polyimides is achieved by adding a dianhydride and a dia-

mine into a dipolar aprotic solvent (like N,N-dimethylaceta-

mide or N-methylpyrrolidinone) which rapidly forms poly

(amic acid) at room temperatures. This precursor of polyi-

mide can be easily stored, shipped or used to form thin

films, coatings and fibers. Conversion of poly(amic acid)s to

the designated polyimides is most commonly performed by

thermal imidization. For wafer level manufacturing, thisinvolves spin-coating of the precursor onto the wafer, which

specifies the thickness of the layer, a prebake at modest tem-

perature (120 C) to drive the solvent partly out of the

layer, which makes it more sticky, and a curing step at high

temperature (350 C) in nitrogen atmosphere.38 Metal can

be deposited afterwards onto the polyimide by various

means, for example, vapor deposition or sputtering, and

encapsulated by a second layer of polyimide. Using reactive

ion etching (RIE) with oxygen, the polyimide-metal-poly-

imide stack can be patterned and electrodes and/or inter-

connection sites opened. The resulting devices can be peeled

off the wafer using tweezers. Overall, processing polyimides

is similar to conventional microelectronic processes, yieldinglow production costs, high pattern accuracy and high

repeatability.

Although polyimide, especially the BPDA/PPD type [see Fig.

1(b)] which is most often used as biomaterial and commer-

cially available under the trademark of DuPonts PI2611 or

UBEs U-Varnish-S, is not certified according to the aforemen-

tioned ISO 10993, various groups have proven its biocompat-

ibility, low cytotoxicity and low hemolytic capacity, both for

bulk materials39 and long-term implanted electrodes.40 Exist-

ing applications are manifold and include peripheral nervous

system (PNS) and central nervous system (CNS) implementa-

tions, such as cuff and intrafascicular electrodes or shaft and

ECoG electrodes, respectively (see Classification of Neural

Interfaces and PNS Interfaces section). Devices made of

polyimide have elicited only mild foreign body reactions in

several applications in the peripheral and central nervous

system showing good surface and structural biocompa-

tibility.4144 They have proven to be biostable and functionalfor months in chronic in vitro and in vivo studies.24,45

PDMS

Since Kipping in 1904 assigned the name silicone to the

group of synthetic polymers whose backbone is made of

repeating silicon to oxygen bonds and methyl groups, this

material and its applications have flourished. It is probably

the most widely used material among the synthetic polymers

for biomedical applications today. Later, a more specific no-

menclature was developed and the basic repeating unit

became known as siloxane and the most common silicone is

polydimethylsiloxane or PDMS [see Fig. 1(c)]. Since the

methyl groups can be substituted by a variety of othergroups, for example, phenyl, vinyl or trifluoropropyl, ena-

bling the linkage of organic groups to an inorganic backbone,

silicones can be prepared with combinations of unique prop-

erties. They are used for example, as insulators in electron-

ics, as moulds in semiconductor manufacture, as sealants or

adhesives in the construction industry, as well as in numer-

ous pharmaceutical and medical device applications.46 Their

key-features for use in biomedical applications include physi-

ological indifference, excellent resistance to biodegradation

and ageing, and high biocompatibility (for values see Table

1). A further significant property is the high permeability to

gases and vapors that is about 10-fold when compared to

natural rubber, while acting as ion barriers. A previous bio-

durability study showed no changes in the material pro-

perties after 2 years of implantation in test and control

specimens, and no evidence of biodegradation could be

detected.47 Furthermore, implants utilizing silicone encapsu-

lation such as the Brindley bladder stimulator have already

been in clinical use since the 1970s and proved to be stable

over a period of about 25 years in vivo, after which the sili-

cone rubber was reported to become more brittle.7,48 Sili-

cones can be processed either by spin-coating, resulting in

thinner film thicknesses, or by molding techniques, which

enable their use in a variety of applications. In biomedicine,

PDMS is usually used as encapsulation and/or as substrate

material. When encapsulating a device for use in vivo, special

attention should be paid to a number of aspects such as theadhesion of silicone to bulk material and void free deposi-

tion and curing of the silicone rubber, since these will signifi-

cantly contribute to osmotic reactions occurring when sili-

cone is immersed into ionized water (e.g., the body

environment).4952 As substrate material, PDMS is often

spin-coated to achieve a defined and uniform layer. In a next

step, a patterned metal foil is placed onto the uncured sili-

cone rubber and a second PDMS layer is spin-coated on top.

After curing, the polymer-metal-polymer stack can be pat-

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have their specific pros and cons.5355 Photo-definable PDMS

is also available but not in implantable grades.

Common biomedical applications include cardiac pace-

makers, cuff and book electrodes in the PNS, and cochlear

implants, bladder and pain controllers, and planar electrode

arrays in the CNS. Many of these systems are commercially

available and found in common clinical settings (for an over-

view see e.g., ref. 2). PDMS is one of the most successful

polymers since it results in only mild foreign body reactions

(as cured material in active implants), is extremely stable

and keeps its flexibility. It is an excellent insulator and has

clinical approval according to USP class VI for unrestricted

use in chronic implants. Process technology is well estab-

lished for various manufacturing technologies.

Parylene

Parylene is the common name for polyparaxylylene (PPX),

a group of linear, noncross-linked and semicrystalline poly-

mers, which belong to the thermoplasts. Since the discov-

ery of the manufacturing process in the mid 20th century,

more and more parylene types have been developed, that

differ only slightly in their properties. Parylene layers are

deposited in a vapor deposition polymerization56 process,

using the dimer of the adequate parylene type as starting

substance. This dimer is heated up until it vaporizes and

later on splits into a monomeric gas. When the gas reaches

the deposition chamber, it cools down and polymerizes on

the target. This deposition process allows a conformal coat-

ing of the target from all sides and even sharp edges and

crevices under components are covered.5759 Typical layer

thicknesses reach from a few hundred nanometers until

several micrometers, depending on the coating machine.

The deposited layers are compatible to MEMS processing

and can be structured by reactive ion etching.

Parylene C [poly(dichloro-p-xylylene), Fig. 1(a)] is the most

popular parylene type for the use in biomedical applications,

due to the well suited combination of electrical and barrier

properties. It is used as substrate6062 or encapsulation6367

material for many kinds of biomedical microdevices. Its good

biocompatibility68 (FDA approved, USP class VI), chemically

and biologically inertness, good barrier properties, slippery

surface and its functionality as an electrical insulator predes-

tines parylene C for the use as substrate or encapsulation

material for implanted neural prostheses.

In recent years another parylene type called parylene HT

arose, which has similar properties, but can withstand highertemperatures. The first electrode arrays using parylene HT

as substrate material, have already been produced.69

Parylene C has been established as one of the encapsulation

materials for chronic implants due to the aforementioned

properties and due to its approval as material for unre-

stricted use in implants. However, due to our own experi-

ence, the handling properties of thin sheets of parylene C

are not as good as those of polyimide in comparable thick-

ness. The material is more fragile and is not as strong and

robust, for example, in substrate integrated microelectrode

arrays. Its advantage, however, is the deposition technology

at room temperature that does not interfere with connection

and assembling technologies.

LCP

Liquid crystal polymers (LCPs) represent a separate material

class among the polymers. They are built up of rigid and

flexible monomers which are linked to each other, and hence

they can organize in aligned molecule chains with a crystal-

like spatial regularity. The main properties of LCPs are high

mechanical strength at high temperatures, extreme chemical

resistance, low moisture absorption and permeability, and

good barrier properties for other gases.

Originally, LCP was used as a high-performance thermoplas-

tic material for high-density printed circuit boards fabrica-

tion and semiconductor packaging. Today, many different

types of LCPs are available, including LCPs which are spe-

cially designed for use in medical engineering (FDA

approved, USP class VI). Commercial LCP material is sup-

plied in sheets with predefined thickness from 25 lm to 3

mm. These sheets are melt-processible and can be structured

by laser machining and reactive ion etching. LCPs are not yet

widely-used in biomedical applications, but some first

approaches to use LCPs for the fabrication of flexible elec-

trode arrays have been developed.70

LCPs were promised to become the new shooting star in

neural interfaces due to the low water uptake and the manu-

facturing technology. However, the enthusiasm of the first

scientific presentations has not been transferred to many

groups. Results from chronic in vivo studies have to show

first, if the promised performance can be achieved and if the

results are better than with already established materials.

SU-8

SU-8 is a multicomponent photoresist, based on epoxy SU-8

resin including a photo-acid generator (PAG) compound and

FIGURE 2 A general classification of electrodes to interface

with the peripheral and central nervous system regarding inva-

sivity and selectivity. The actual selectivity depends on the ana-

tomical and physiological environment and their respective

applications.



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incorporated solvent. It has interesting properties, which

make it a very attractive material for a wide range of appli-

cations including micromachining, micro-optics, microfluidics,

and packaging. SU-8 is highly transparent for wavelengths

>400 nm and is chemically and mechanically stable (see Ta-

ble 1).71 The photoresist is commonly exposed with conven-

tional UV radiation, although i-line (365 nm) is the recom-

mended wavelength. Upon exposure, cross-linking proceedsin two steps: first, formation of a strong acid during the ex-

posure step, followed by a second, an acid-catalyzed, ther-

mally driven epoxy cross-linking during the postexposure

bake.34,35 The oligomer is depicted in Figure 1(d), the eight

functional groups allow for high degrees of cross-linking af-

ter photo-activation.72 An additional hard bake can further

cross-link the imaged SU-8 structures and therefore improve

the sidewall smoothness and mechanical stability.73

Biocompatibility tests were performed by different groups

using a baseline battery of ISO 10993 physiochemical and

biocompatibility tests and found minimal irritation after one-

and 12-week implantation periods in rabbit muscles, as well

as after a 54 week implantation in rats. Cytotoxicity showed

a reactivity less than grade 2 (mild reactivity) and no steam

or gamma sterilization-induced damage was observed.74,75

However, due to the complex nature of biocompatibility, it

cannot be concluded that SU-8 meets all specifications neces-

sary to meet the full ISO 10993 requirements for implants.

In biomedical applications, SU-8 is commonly used as a sub-

strate material, for example, in shaft electrodes for CNS

interfaces due to its improved flexibility compared to sili-

con,76 as a guiding structure for regenerating axons in sieve

electrodes,77 as a wave-guiding core in electrodes for optical

stimulation,78 and as a microfluidic channel in multimodal

electrodes that have the capacity to deliver for example,

pharmaceuticals next to electrical stimulation or recording.79

SU-8 might be an alternative material to silicon. It is biocom-

patible and the processing costs are cheaper compared to

the relatively expensive silicon micromachining. However,

since no microelectronic circuitry can be integrated, it has to

prove superior performance at the material-tissue interface

to become a real competitor to already established silicon

shaft electrodes.

INTERFACES

Classification of Neural Interfaces

Neural interfaces and implants are used for many applica-

tions in the human body and can be manufactured frommany different materials. Although there are a huge variety

of types of implants and interfaces, they can be divided up

into various categories, with some similarities and differen-

ces between them. One immediate feature that many have in

common is design of cables of packages for electronics and

batteries. In this section, we will focus on the neuro-techni-

cal interface itself. One system for classifying implants, intro-

duced earlier in this review, is whether the implants are

used to target the central nervous system (CNS) or periph-

eral nervous system (PNS). In general, approaches for CNS

and PNS are different since brain structures need different

access methods than nerve bundles in the periphery. How-

ever, there is a general tendency in both:43 greater spatial se-

lectivity requires a higher level of invasiveness (Fig. 2). The

question to select an adequate interface always should be:

Which selectivity do I need for the intended use of my target

specification and which degree of invasivity is adequate? In

other words: Is the benefit of the implant large enough thatI can justify the risk of possible damage due to the implanta-

tion? Detailed solutions to interface technical devices with

the CNS and PNS at different levels of invasivity will be dis-

played in the following sections.

Since we like to focus on materials that are flexible instead

of stiff, to better match the mechanical properties of nerv-

ous tissue, we do not describe wire or silicon based neuro-

technical interfaces (for an overview, see e.g., ref. 80) but

focus on polymer materials. These polymer materials have

been selected in a way that they adapt to the shape of the

neuronal target tissue as well in the PNS as in the CNS and

follow motions of the tissue in the micro as well as in the

macro scale. They are the enabling materials to manufacture

electrode arrays, either in small or large scale. All of the

applications that are presented below have shown that the

interfaces are only little reactive due to material and shape,

that is only mild foreign body reactions could be observed

and are stable over the implantation periods. A lot of care

has been taken in all designs and developments to find the

optimal shape of the implantable nerve interfaces to

reduce the risk of device failure due to tethering forces as

well as the damage of the target tissue due to clumsy

designs. However, this expert knowledge cannot be trans-

ferred in simple design rules but is a long process of

continuous exchange and communication with the end user

in experimental neuroscience and clinical research andapplications.

PNS Interfaces

In the following, a brief overview of interfaces to contact

with the peripheral nervous system is given. To stay consist-

ent with Figure 2, the different interfaces will be explained

in order of increasing invasiveness, from low to high. Since a

large variety of approaches emerged over the last few deca-

des, it is not the intention of the authors to provide a com-

plete list of interfaces, but rather to present the key

approaches and concepts underlying electrode design and

manufacture. For more details see references 8184.

Extraneural cuff electrodes are commonly made out of PDMS[Fig. 3(a)] or polyimide, and encircle the nerve com-

pletely.86,87 Hence, the invasiveness is limited to the prepara-

tion of the nerve, which itself stays untouched. Cuff electro-

des contain a number of electrode sites on the inner surface

facing the nerve and have been investigated over decades

and have finally been transferred into clinical applica-

tions.88,89 Despite their advantages of simplicity of handling

and the ability to stimulate and record general activity from

the outer parts of the nerve, they still have a number of limi-

tations. Firstly, their selectivity is limited to subgroups and



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superficial fibers in the nerve. Secondly, the nerve can be

damaged due to micromotion of the electrode array, espe-

cially in peripheral nerves of the limbs.83 To achieve a better

selectivity Tyler and Durand designed a variation of the cuff

electrode that slowly penetrated the epineurium, loose con-

nective tissue that is placed between and around nerve bun-

dles, without compromising the perineurium. Thus, the elec-

trode sites are placed within the nerve trunk but outside the

nerve fascicles. The slowly penetrating interfascicular nerve

electrode (SPINE) achieves this aim through blunt elements

extending radially into the lumen of a PDMS tube that enclo-

ses the nerve.90 However, after histological evaluation it was

shown that the shape of the nerve was actually deformed

from an elliptical shape into a flatter ribbon like shape giving

access to deeper fascicles, that is nerve bundles that are sur-

rounded by the perineurium of the nerve. From these

results, a new electrode design was extracted, the flat inter-

face nerve electrode (FINE), which reshapes the nerve into a

more electrically favorable geometry [Fig. 3(b)]. Since this

reshaping requires the slow application of a relatively high

force, only moderate flattening of the nerve is possible with-

out inducing nerve damage.91,92 Recently, Schiefer et al.

implanted a multicontact FINE in the femoral nerve of

humans and showed high selectivity in restoring knee

FIGURE 3 PNS interfaces. (a) Tripolar cuff electrode made of PDMS;85 (b) flat-interface nerve electrode (FINE) From Tyler et al.,

IEEE Trans Neural Syst Rehabil Eng, 2002, Vol. 10, 294303, VC 2010 IEEE; (c) polyimide based longitudinal intrafascicular electrode

(LIFE) From Farina and coworkers, Am Physiol Soc, 2008, Vol. 104, 821827, reproduced by permission; and (d) transversal intra-

fascicular multichannel electrode (TIME).



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extension and hip flexion by functional electrical stimulation

at least in an acute experiment.93

Penetrating electrodes comprise the next level of invasive-

ness. Intrafascicular electrodes are placed within a distinct

fascicle in the nerve and have direct contact to the targeted

fibers and are, hence, more invasive than extraneural electro-

des. The placement of the contact sites increases the signal-

to-noise ratio (SNR) of recordings and enhances stimulation

and recording selectivity. Stimulation of targeted fascicles

can be achieved with little cross-talk to adjacent fascicles

while complete recruitment of the nerve fascicle is possible

with low stimulation intensities. The longitudinal intrafascic-

ular electrode (LIFE) and the transversal intrafascicular mul-

tichannel electrode (TIME) are the most recent examples

[Fig. 3(c,d)]. Both designs implement polyimide substrates

and platinum metal tracks and active sites. As the names

suggest, LIFEs are implanted longitudinally within individual

nerve fascicles whereas TIMEs are implanted transversally

through the designated nerve and fascicles.44,94 Since TIMEs

penetrate the whole nerve and, thus, contact more fascicles

on its way, they are expected to have a higher selectivity

than LIFEs but comparative studies are not available yet.

FIGURE 4 CNS interfaces. (a) FLEXeas cochlear electrode by MED-EL VC MED-EL Elektromedizinische Gera te GmbH; (b) parylene

based retina electrode array From Rodger et al., Sens Actuators B: Chem, 2008, Vol. 132, 449460, VC Elsevier, reproduced by per-

mission; (c) silicone based book electrode;85 (d) polyimide based 252-channel epicortical array (by courtesy of B. Rubehn); (e) poly-

imide based shaft electrode From Mercanzini et al., Sens Actuators A: Phys, 2008, Vol. 143, 9096, VC Elsevier, reproduced by

permission.



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Rossini et al. implanted LIFEs for 4 weeks in the median and

ulnar nerves of humans and reported reproducible and local-

ized hand/finger sensation while stimulating and stable

selective recordings.95

If the nerve is already severed, for example, after an amputa-

tion trauma, regenerative electrodes can be applied. Sieve

like electrodes made of polyimide incorporate multiple via-holes and electrodes through which regenerating axons are

coaxed to grow through. These electrodes have shown good

long term in vivo stabilities and a decent regeneration of

axons.40,96 Recent approaches facilitate a three-dimensional

electrode that has a guidance structure, made out of SU-8 or

polyimide, through which regenerating axons should grow.

These guidance structures are in principal channels that can

be filled with nerve growth factor or other bioactive solu-

tions and can even incorporate electric active sites which

enable additional recordings.97,98 Although a high degree of

selectivity can be achieved, sieve electrodes require the

transection and regeneration of nerves, and thus can only be

ethically applied in already transected nerves. Moreover,time is needed for the regenerating axons to grow through

the structure, thus, precluding acute experiments.

Summarizing the results of different PNS nerve interfaces,

we can conclude that PDMS with embedded metal tracks

and electrodes is superior when low integration density and

medium size implants have to be developed that need to be

robust in first place. Microsystem technologies using poly-

imide as substrate material is only advantageous and benefi-

cial if extremely small structures and large scale integration

is required. In these cases the approach is mandatory and

justifies the longer development time and the higher devel-

opment and manufacturing costs.

CNS Interfaces

Neural interfaces to the central nervous system have a vari-

ety of applications. Depending on function and implantation

site, implant requirements and properties are different, and

thus many different electrode designs exist. However, two

general concepts developed over the last decades: precision

mechanics implants with metal sites and wires encapsulated

in PDMS and micromachined approaches with silicon as bulk

material to manufacture multiple shafts in a single device

that look like a brush or a nail bed. Depending on implanta-

tion site and application these implants have different shapes

and numbers of electrode sites. The most common known

and well established neural implant is the cochlear implant

(CI). These systems are commercial available (MED-EL,

Vienna, Austria; Cochlear, Lane Cove, Australia; Advanced

Bionics, Valencia, California; Neuroelec, Vallauris, France) and

are now implanted for about 30 years. The neural interface

of such a system is a multichannel electrode [Fig. 4(a)] that

is inserted into the scala tympani of the cochlea. Due to

the special shape and the fragile structure of the cochlea,

the electrodes have to be flexible, and hence they are

made of soft materials such as silicone rubber99101 or

polyimide.102,103 Todays research mainly focuses on achiev-

ing a higher selectivity and hence better hearing

quality.13,104,105

Another well known application for interfacing with the CNS,

despite still being in the research and development phase, is

the restoration of vision. Experiments in the late 1960s and

early 70s demonstrated that blind humans can perceive elec-

trically elicited phosphenes in response to ocular stimula-

tion, with a contact lens as a stimulating electrode,106 sev-

eral groups worldwide work on the development of either

epiretinal prostheses17,69,107114 with implantation of the de-

vice into the vitreous cavity on the retinal surface or subreti-

nal prostheses115120 with implantation of the prosthesis in

the potential space between the neurosensory retina and the

retinal pigment epithelium. It is obvious that for a retina

implant no stiff and bulky substrate or housing materials

can be used, due to the limited space and the shape of the

implantation site. The use of polymers for the stimulating

electrode arrays is more or less obligatory. Generally they

are made of silicone,108 polyimide,17 parylene C110 or a com-

bination of them. Figure 4(b) shows a parylene-based micro-

electrode array with 1024 stimulating sites (60 of them con-nected), developed by Rodger et al.,69 that was chronically

implanted for 6 month onto the retina of canines. The pre-

ceding array with 16 stimulation sites, embedded into sili-

cone rubber, was already implanted up to 18 month into

three patients with retinitis pigmentosa,111 which were able

to perform simple visual tasks better than before

implantation.

Interfacing the optical nerve is the most invasive approach to

restore sight. There, silicone cuff electrodes are used,121123

which are similar to those, which are used to interface the PNS

(see PNS section). But due to the high risk during surgery and

the poor resolution, interfacing the optical nerve is not the

first choice to restore vision. The visual cortex is also used asinterface for vision prostheses either using polymer coated

wires or silicon microneedles as implants (for a review, see

ref. 1). Since we like to focus on flexible polymer based neural

implants, we do not describe this exciting research here.

Another site of the CNS that is possible to interface is the

spinal cord. In the 1980s, Brindley introduced a sacral ante-

rior root stimulator for bladder control in paraplegia, with

book electrodes [Fig. 4(c)] as neural interface.124 These elec-

trodes entrap the sacral roots and are made of silicone rub-

ber. Until 1994, 500 patients received this implant system.125

Silicone rubber electrodes are used until today to interface

the spinal cord, but researchers also developed electrodes,

using other polymer materials like parylene as substrate ma-

terial.69 However, clinicians have learned to handle the sili-

cone based electrodes in the spinal canal and implants have

shown excellent performance with respect to long-term sta-

bility. Therefore, evolutionary developments seem to have a

higher success rate to get transferred into clinical practice

than new revolutionary designs in which stability, perform-

ance and side effects are not clear.

A much wider field of applications offers the direct contact-

ing of brain tissue. To interface the brain, two completely



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different electrode designs are possible. The first and less

invasive possibility is the use of epicortical electrode arrays.

These are two-dimensional electrode arrays which can be

placed epidurally or subdurally on the cortex. They have to

adapt to the anatomical structure of the cortex, making poly-

mers necessary as substrate material. The first arrays were

made of silicone rubber and were used for stimulating the

visual cortex126 or recording for localizing epileptogenic

foci.127 Today silicone rubber arrays are commercial avail-

able (e.g., Ad-Tech Medical Instrument Corporation, Racine,

WI) for the use in clinical practice to locate the seizure focus

during the presurgical diagnosis of epilepsy.128 To obtain a

higher spatial resolution, researchers try to scale down the

electrode diameters and pitches and to scale up the amount

of recording/stimulating sites. This is feasible with MEMS

technology using polyimide as substrate material.129134 Fig-

ure 4(d) shows a 252-channel polyimide-based electrode

array, which was implanted onto the visual cortex of a mon-

key,134 and was after 4.5 month still able to record signals.

In all epicortical electrode arrays the flexibility of the mate-rial and the interface is the most important property. Me-

chanical strength of the implant is important only during the

implantation procedure. Afterwards, supporting substrate

structures could be dissolved, for example bioresorbable silk

fibroin, as recently proposed by Kim et al.135

Generally, epicortical electrodes record local field potentials,

but depending on the application, a higher selectivity is

required. This is possible with a more invasive approach,

more precisely the use of penetrating electrodes, which are

directly inserted into the cortex. To be able to penetrate the

brain tissue, a certain stiffness of the electrode shaft is

required. Therefore, iridium wires, tungsten wires or silicon

shafts were used over a long time period and polymers likeparylene C or polyimide served as insulating material.65,136139

But stiff silicon shafts cannot adapt to the mechanical condi-

tions of the brain tissue and, hence, micromotion of the

brain, due to breathing and the heart beat, constantly injures

the brain tissue. For this reason, researchers are currently

trying to develop penetrating electrodes using more flexible

materials like polyimide [Fig. 4(e)], parylene C, SU-8 or benzo-

cyclobutene (BCB).6062,139147 However, the use of flexible

substrate materials is accompanied by further challenges. It

is difficult to insert flexible probes into the cortex and hence

several approaches to overcome this problem were devel-

oped, like bending the electrode shafts,148 coating or filling

the shafts with degradable/dissolvable materials,

61

partlyattaching a silicon backbone layer,142,143 or using an inser-

tion shuttle149 to make the shafts stiff enough for insertion

and flexible enough to decrease the tissue damage.

The discussion with its accompanying hypotheses how stiff

electrodes should be for intracortical implantation to elicit

minimum tissue reaction in chronic implantation is still not

finished. Implants need either certain stiffness or adequate

tools to get inserted into the brain. Coating might be benefi-

cial but should be either stable over time or resorbable with-

out eliciting additional adverse reactions. Nowadays, there

are not yet enough data acquired to take the final decision

which path has to be followed to get the best intracortical

interface. More research has to be done before these intra-

cortical microstructures are mature enough to be transferred

into clinical applications.

From Interfaces Towards Active Implants

Neural implants interconnect a neuro-technical interface (theelectrode array) with electronics and energy supply. Reliable

implants with market approval for chronic implantation ei-

ther place the electronics and battery in a hermetic package

or consist of hermetically sealed components that are encap-

sulated in a nonhermetic coating.150 Even though neural

implants have different designs on the interface part, the

concepts and paradigms for hermetic packages are very simi-

lar. Most packages consist of metal (titanium) or ceramic

(alumina) packages with a very limited number of hermetic

feedthroughs that interconnect the electronic circuitry

inside the package with the electrodes and sometimes a coil

for energy supply and data transmission outside the package.

Polymer materials are widely used as final encapsulation

and material-tissue interface but they are not applicable as

hermetic encapsulation since all polymers are NOT hermetic

according to the definitions in international standards. The

established and proven technologies are sufficient for the

established neural implant applications. Nevertheless, more

sophisticated feedthroughs and packaging techniques to-

gether with reliable hybrid assembly techniques have to be

developed to accept the challenges of high channel implants

for vision prostheses or brain-machine interfaces with antici-

pated 1000 channels and the biological space restrictions in

the eye and the brain. Furthermore, much time, effort and fi-

nancial resources are necessary to transfer a device from the

actual proof of concept to an approved and certified biomed-

ical product, which is accepted by physicians and patientsalike. In the case of the cochlear implant, there was a period

of 15 years between the first clinical trial and the accep-

tance according to NIH guidelines.151

CONCLUDING REMARKS

Polymers have been the enabling material to develop and

produce the vast majority of neural-technical interfaces that

exist today. The ability of certain polymers to adapt to the

conditions of the surrounding tissue is crucial to manufac-

ture stable interfaces that can work reliably over many years

without harming the body. The success stories of cochlear

implants, bladder management systems or epicortical elec-

trode arrays for epilepsy management, which are all com-mercial available systems and are already used in clinical

practice, show that polymers can fulfill these requirements.

PDMS is the most successful material and proved to combine

only little tissue reactivity with excellent long term stability

and reliability. In combination with precision mechanics for

packages, cables and electrode sites, neural implants have

predicted lifetimes close to the life expectancy of humans.

Unfortunately, the technology has reached its limit of com-

plexity and further miniaturization and integration density is

hard to overcome with existing concepts and philosophies.



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Fabrication technologies for polymers to produce interfaces

with high counts of electrodes within limited space (and

thus high selectivity) are available. The materials, however,

have never been in a chronic implantation in a large number

of patients, so far. The main challenge is still to avoid the

hydrolytic, oxidative and enzymatic degradation due to the

harsh environment of the human body or at least to slow it

down to a minimum which enables the interface to workover a long time period, before it finally has to be exchanged.

Therefore, it is mandatory to carefully select the appropriate

materials, keeping in mind that each application has its own

specific requirements. Materials like polyimide show promis-

ing results but no company is on the market that is currently

willing to deliver materials with the certificates that are rec-

ommended from the national authorities for its use in medi-

cal devices. Without this approval according to national or

international standards, the most adequate materials from

a technical and practical standpoint are precluded due to

legal and economic reasons. In addition, micromachining

technologies that allow large scale integration of electrodes

often use much thinner layers as clinically establishedimplants. The stability of polymer insulation materials as

well as on electrical interconnects and electrodes -aspects

that have been intentionally neglected in this review- have

to fulfill higher standards to survive the same implantation

time; degradation as well as corrosion rates must be orders

of magnitudes lower than in precision mechanics implants

since we start with material thicknesses in the nanometer

and micrometer range. Nevertheless, since the list of appro-

priate polymers is constantly increasing and possibilities to

manufacture tailor-made surfaces that further enhance the

materials behavior become more suitable, it seems feasible

that long lasting polymer interfaces beyond PDMS will be

available in the near future.

ACKNOWLEDGMENTS

Part of the work has been funded by the German Federal Minis-

try of Education and Research (BMBF) in the Bernstein Focus

Neurotechnology Freiburg/Tubingen: The Hybrid Brain

(grant no. 01GQ0830) and by the European Union in the 7th

Framework Program (grant CP-FP-INFSO 224012/TIME) for

the TIME project (Transverse, Intrafascicular Multichannel

Electrode system for induction of sensation and treatment of

phantom limb pain in amputees). The authors thank Ben Town-

send and Martin Schuettler for their constructive criticism

regarding this manuscript.

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