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Technology modules from micro- and nano-electronics for the life sciences

May 2016
Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 8(3):355-377

May 2016
8(3):355-377

DOI:10.1002/wnan.1367

Authors:

Mario Birkholz

A. Mai

Ch. Wenger

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The capabilities of modern semiconductor manufacturing offer remarkable possibilities to be applied in life science research as well as for its commercialization. In this review, the technology modules available in micro‐ and nano‐electronics are exemplarily presented for the case of 250 and 130 nm technology nodes. Preparation procedures and the different transistor types as available in complementary metal‐oxide‐silicon devices ( CMOS ) and BipolarCMOS ( BiCMOS ) technologies are introduced as key elements of comprehensive chip architectures. Techniques for circuit design and the elements of completely integrated bioelectronics systems are outlined. The possibility for life scientists to make use of these technology modules for their research and development projects via so‐called multi‐project wafer services is emphasized. Various examples from diverse fields such as (1) immobilization of biomolecules and cells on semiconductor surfaces, (2) biosensors operating by different principles such as affinity viscosimetry, impedance spectroscopy, and dielectrophoresis, (3) complete systems for human body implants and monitors for bioreactors, and (4) the combination of microelectronics with microfluidics either by chip‐in‐polymer integration as well as Si‐based microfluidics are demonstrated from joint developments with partners from biotechnology and medicine. WIREs Nanomed Nanobiotechnol 2016, 8:355–377. doi: 10.1002/wnan.1367 This article is categorized under: Diagnostic Tools > Biosensing Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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Complete List of Authors:

Birkholz, Mario; IHP,

Mai, Andreas; IHP,

Wenger, Christian; IHP,

Meliani, Chafik; IHP,

Scholz, Rene; IHP,

Keywords:

bioelectronics, semiconductor technology, biosensor, lab-on-chip,

CMOS/BiCMOS

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Technology modules from micro- and nano-electronics

for the life sciences

M. Birkholz*, A. Mai, C. Wenger, C. Meliani, R. Scholz

IHP, Im Technologiepark 25, 15236 Frankfurt (Oder), Germany

*corresponding author: birkholz@ihp-microelectronics.com

Abstract

The capabilities of modern semiconductor manufacturing offer remarkable possibilities to be applied in life

science research as well as for its commercialization. In this overview, the technology modules available in

micro- and nano-electronics are exemplarily presented for the case of 250 and 130 nm technology nodes.

Preparation procedures and the different transistor types as available in CMOS and BiCMOS technologies are

introduced as key elements of comprehensive chip architectures. Techniques for circuit design and the

elements of fully integrated bioelectronics systems are outlined. The possibility for life scientists to make use of

these technology modules for their research and development projects via so-called multi-project wafer

services is emphasized. Various examples from diverse fields like (1) immobilization of biomolecules and cells

on semiconductor surfaces, (2) biosensors operating by different principles like affinity viscosimetry,

impedance sprectroscopy and dielectrophoresis, (3) complete systems for human body implants and monitors

for bioreactors, and (4) the combination of microelectronics with microfluidics either by chip-in-polymer

integration as well as Si-based microfluidics are demonstrated from joint developments with partners from

biotechnology and medicine.

Keywords: bioelectronics, semiconductor technology, CMOS/BiCMOS, biosensor, lab-on-chip

1 Introduction

The usage of micro- and nano-electronics in the life sciences has steadily increased over the last years

1-6

. For

one reason, this development is due to the molecular nature of the mechanisms of living, for the study of

which it often suffices to manipulate only a small number of molecules. This fact established a high demand for

miniaturized systems acting as links between men and microbiology and led to medical and biotechnological

devices enabling an increased comfort for patients, the on-line monitoring of bioprocesses and various high-

throughput processes to mention only a few examples. For another reason, the demand for micro-electronics

in the life sciences derives from the fact that both disciplines increasingly stronger apply nano-technological

methods, such that they start to share a common set of technical equipment and tools.

Modern microelectronics relies on the elementary semiconductor silicon and the CMOS technology based upon

it. In the latter, electrons and missing electrons or holes may equally act as mobile charge carriers in

complementary metal-oxide-silicon devices. Since the introduction of integrated circuits (ICs) in 1958 and, in

particular, since G. Moore realized the number of devices per IC to double every 1½ - 2 years

, semiconductor

technology followed this rule like a self-fulfilling prophecy. Meanwhile, the number of transistors in computer

ICs has reached the order of magnitude of billions and their dimensions have advanced from the µm- into the

nm-range. The continuous shrinking of device dimensions and increase of IC performance is denoted as scaling

8, 9

. Its significance becomes obvious from the fact that the parameters of tomorrows ICs are already defined

today by the international semiconductor industry

Next to CMOS technology and scaling another direction of research and development has evolved denoted as

“More-than-Moore”

. It aims at introducing additional functions into integrated circuits in order to realize

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new applications in consumer electronics, sensoric devices or communication technology – to mention only a

few examples. The More-than-Approach is also motivated by cost considerations. Modern CMOS fabs have

recently reached the 32 and 22 nm node requiring investments for appropriate clean rooms on the order of

billions of Euros that lie beyond the funding options of public research institutes.

Having worked in various projects with partners from the life sciences, it seems to the authors that the

interdisciplinary dialog between both disciplines suffers from disjunctive terminology and a mutual lack of

knowledge of the techniques on the other side. This review endeavors to outline the technical apparatus avai-

lable in micro- and nano-electronics on a non-specialist, but specific level. The presentation will focus on the

capabilities of 250 and 130 nm technologies as available at the authors’ institute. It should be mentioned that

a substantial body of work has been accumulated in the field of hybrid junctions from neuronal cells and

semiconductor devices starting with the seminal work of Fromherz and co-workers in 1991

. The following

developments were reviewed in Ref.

, and important progresses on neuro-microelectronic contacts and their

perspective applications as implants and neural tissue interfaces are continuously reported, e.g. Ref.

14-16

. The

focus of this work, however, will be on the fabrication of microelectronic chips, the designs of electronic

circuits and systems and their applications in biosensors and biotechnology. The authors hope that the given

examples will make more transparent, what life scientists may expect from the presented micro- and nano-

electronics platform and how the techniques can be applied to their research and system developments.

2 Preparation technologies for microelectronic chips

2.1 Clean room processing

Microelectronic chips are produced in clean rooms categorized by the number of detectable contaminants

within certain size classes. Many of them rank between class 1 and 100, which indicates either less than 35 or

3520 particles with diameter > 0.5 µm per m

, see Figure 1A for a view into the IHP clean room, in which a 130

nm pilot line is run. Wafer processing is almost fully automated in clean rooms operating on smaller technology

nodes and staff presence is mainly restricted to maintenance.

The technical equipment or tools are adapted to the processing of silicon wafers with a specific diameter. At

the time of writing, mostly 300 mm wafers are used in modern semiconductor technology. Previous IC

generations made use of 200 mm (Figure 1B), 6”, 4” wafers etc., while the next 450 mm wafer generation is

currently under development. Silicon wafers are perfect single crystals exhibiting the highest ratio of crystalline

perfection per EUR of all materials available. Silicon atoms constituting the wafer are arranged in the diamond

crystal structure (T

) having a density of N

= 5 × 10

-3

at ambient conditions. Most wafers exhibit an

orientation with the crystallographic 〈001〉 axis being perpendicular oriented to the wafer surface.

Nevertheless, wafers with different orientations like 〈111〉 may also be processed within the same clean room;

the diameter, however, is generally fixed for the set of tools available. The thickness of a 200 mm wafer

amounts to 0.75 mm and is much larger than the microelectronic circuits exhibiting thicknesses between 10

and 20 µm according to the technology used.

Prior to processing the electrical conductivity σ of the wafer typically amounts to 2 (Ωm)

-1

, a value which lies

between those of metals of about 10

(Ωm)

-1

and those of isolators on the order of 10

-12

(Ωm)

-1

. Type and

magnitude of conductivity may be adjusted by introducing doping elements into the Si crystal lattice. For

instance, doping with group V elements like P and As will introduce additional mobile electrons and thus

enhances the conductivity with negative charge carriers, i.e. n-type. Doping with group III elements like boron,

on the other hand, will produce a p-type conductive Si crystal due to excess and mobile positive charge carriers,

i.e. missing electrons. Smallest amounts of dopants can vary σ by orders of magnitude. The concentration of

dopants N is specified by the dimensionality of cm

-3

. While σ = 3.2 × 10

-4

(Ωm)

-1

is valid for undoped Si, the

substitution of every millionth Si by one B atom (N

= 5 × 10

-3

) causes σ to increase to 145 (Ωm)

-1

Wafer processing is started with a base doping on the order of 10

-3

, while any other doping level is

obtained by introducing higher concentrations of dopants on the order of 10

to 10

-3

within selected

areas. The tuning of conductivity in selected volume elements of the wafer compares to the situation in

biological cells, where spatially varying pH values or concentrations of electrolytes etc. are organized by

compartmenting the cell volume into cell organelles.

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In modern semiconductor technology doping is performed via ion implantation. For this purpose, doping atoms

are evaporated from a reservoir, ionized and accelerated by an electrical field towards the wafer surface. For

acceleration energies up to 900 keV an average depth of 0.6…1.5 µm below the wafer surface can be reached

depending on dopant and level of ionization. Since the Si crystal lattice is severely damaged during

implantation, a subsequent recrystallization is performed at high temperatures with huge heating and cooling

rates up to several hundred °C s

-1

in order to restrict possible diffusion effects.

For processing, a 200 mm wafer is partitioned in about 70 - 120 rectangles, so-called test fields, having a size

between 10 × 26 and 16 × 26 mm (Figure 1C). The microchips prepared on every test field are identical so that

many equal ICs are processed on one wafer. Integrated circuits are produced by a sequence of typically a few

hundred process steps belonging to the groups of coating, structuring, etching, doping and clean processes.

Coatings are applied in the form of thin films having thicknesses between a few nm and some µm. The wafer is

covered over its full size after depositing the coating and the small areas, from which device components like

the transistor gate or metal lines are prepared, still have to be excised. This is done by lithographic structuring

and subsequent etching steps.

Figure 2 displays a cross section SEM micrograph of a developed and etched photoresist layer at the resolution

limit accessible to the lithography tools used. The investigation aimed at implanting as small as possible n-

doped bars in a p-type wafer. The photoresist coating was illuminated through a mask, in which transparent

and in-transparent regions alternated in order to generate stripes of light and shadow having 130 nm width.

The micrograph was taken after implanting n-areas and prior to removal of structured photoresist and

annealing

. Doped areas were still in an amorphous state and prone to etching, which allowed achieving a

good SEM contrast. It can be seen that the intended periodicity (or pitch) of 260 nm was arrived at, albeit slight

roundings of resist edges are recognized to occur. In general, the resolution achievable by photolithography

determines the minimum feature dimensions of active devices that may be fabricated. The remarkable aspect

of semiconductor technology is not only due to the precision achievable, but also due to the reproducibility,

meaning in the example shown here that the doping bars are equably repeated more than 760,000 times along

the wafer’s diameter.

2.2 Transistor types and chip architecture

The most important devices in microelectronic circuits are metal-oxide-semiconductor field-effect transistors

or MOSFETs, which operate as amplifiers or switches. TEM micrographs of a MOSFET are given in Figure 3.

Basically they act like a valve with currents flowing from the source S to the drain D, and its magnitude being

controlled by the voltage applied to the gate G. When CMOS technology was introduced in the 1970 it was its

success to allow for the complementary preparation of both n-channel as well as p-channel MOSFETs on the

same wafer, where the latter are characterized by a channel current that is due to missing electrons or holes.

The preparation of MOS devices requires several thin film depositions, e.g. gate oxide, polycrystalline silicon

gate and source/drain spacer material and contact electrodes.

The geometrical distance between source and drain is denoted as channel length L. It represents a key

parameter for the performance of the technology used, since it is a measure for the speed of switches that may

be designed with the underlying MOSFETs. The smaller L is the earlier D is reached by charge carriers starting

from S. Between 1975 and 2012 the channel length L was reduced from 3 µm to about 22 nm in modern CMOS

fabs, while the clock frequency of processors increased from a few MHz into the GHz range.

An important role in semiconductor manufacturing is played by the tools for thin film deposition. The applied

processes are often denoted as vapor deposition, since they are usually performed via condensation from the

gas phase. Two different groups may essentially be distinguished with the first one encompassing physical

processes like evaporation or sputtering, while the processes from the second group are of basically chemical

nature. Depending on whether a process belongs to either the first or the second group, it is either denoted a

PVD or a CVD process.

For instance, the MOSFET gate from polycrystalline silicon depicted in Figure 3B, is prepared by a CVD process,

in which gaseous silane SiH

is introduced into the deposition chamber to decompose into Si and H

. The wafer

temperature lies between 500-600°C causing a thermal decomposition of SiH

. While H

returns to the gas

phase, the remaining Si atoms condensate on the surface to form the layer. Typical growth rates are on the

order of nm s

-1

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Next to field-effect transistors FETs, where the charge carrier transport is regulated via a voltage applied to the

gate, another type is represented by hetero-junction bipolar transistors HBTs. They differ from FETs by the

direction of current, which is mainly oriented perpendicular to the wafer surface instead of being parallel. In

addition, start and end point of the current to be amplified are named emitter and collector, with the two of

them being separated by the so-called base (Figure 3C). Most importantly, however, the emitter-collector

current is not adjusted by a voltage but by another current that is introduced laterally into the base.

While only one charge carrier type n or p is flowing from source to drain of a MOSFET, the charge transport in

HBTs is related to both electron and holes that are transported in the active state and from which the notion of

a bipolar device derives. Extreme high cutoff frequencies above 200 GHz may be obtained with the HBT

configuration, with the base region acting as key element. It is formed from the solid binary phase Ge

0.2

0.8

containing about 20% germanium, with Ge atoms distributed randomly over Si crystal lattice sites. The

preparation is performed as a thin layer by CVD from SiH

and GeH

by the technique of epitaxial growth,

where the crystal structure of the growing film is imposed from the underlying crystal lattice. Figure 5 displays

the TEM micrograph of a HBT configuration.

A focus of HBT research was to increase the maximum frequency of operation f

max

, by which the device may be

operated. The approach to achieve this goal was to stabilize the boron doping of the SiGe base by adding small

amounts of carbon to reduce the out-diffusion of B atoms during subsequent annealing steps

. This measure

allowed to substantially increasing the steepness of B doping profile, which turned out as a key for high-

frequency performance and, for the time of writing, HBT limiting frequencies f

max

of up to 500 GHz have already

been achieved

Figure 4A displays the schematic architecture of a microelectronic chip fabricated by a 0.25 µm technology that

allows for the preparation of MOSFETs having L = 0.25 µm. Various horizontal metal layers and vertical

connections between them can be recognized that are embedded into electrically isolating glass, SiO

indicated by blue color. At the lower edge of the figure, active devices like MOSFETs and HBTs can be seen that

are prepared directly upon the silicon wafer. The process part used for the fabrication of active transistors is

denoted as Frontend-of-Line (FEoL) and distinguished from the subsequent process parts that are named as

Backend-of-Line (BEoL).

For the technologies considered horizontal metal layers are essentially made up from aluminum alloyed with a

few percent of copper (Al:3%Cu). They are deposited by a magnetron sputtering process at 0.27 Pa and 200°C.

Five to seven metal layers are prepared in IHP’s technology flows with the precise number depending on the

technology used. The top-most layers TM1 and TM2 exhibit thicknesses of 2 and 3 µm being significantly

thicker than the underlying metal layers of only 0.58 to 0.72 µm denoted by M1..M3.

The latter are shown in a cross section micrograph in Figure 4B. Also, vertical tungsten plugs may be recognized

that are introduced into previously etched holes in the inter-layer dielectric (ILD). The W plug preparation is

performed with a CVD process using W(CO)

as a precursor to assure a continuous hole filling starting from the

bottom and the side walls. Such conformal deposition may not be achieved by PVD processes. The tungsten

plugs have no direct contact with Al:Cu metal layers, since the latter are covered on top and at the bottom by

titanium nitride TiN, an electrically conducting ceramic acting as a diffusion barrier.

From the materials science point of view, TiN is a remarkable solid that behaves in mechanical respect like a

ceramic and, concomitantly, disposes of an electrical conductivity of 5 x 10

-1

comparable to those of metals

. TiN layers in CMOS architectures obey only a few nm thicknesses and are usually deposited by the PVD

technique of magnetron sputtering. TiN remains practically un-corroded when brought in contact with biogenic

fluids. Altogether, metal layers and W plugs act as lateral and vertical electrical connections. They are

electrically isolated by embedding them in ILD. The latter are essentially formed from SiO

deposited by CVD

techniques with SiH

, O

or other gaseous precursors that are introduced into the deposition chamber and

reacted at temperatures of up to 400°C on the wafer surface.

Another group of processes used in microelectronic clean rooms are etching processes. They mainly apply to

selected areas of thin films deposited over the full wafer that are not required for the circuit to be configured.

On the one hand, etching may be based on wet-chemical processing, where the wafer is dived into an etching

solution. Well known, for instance, is the HF dip, by which the wafer is submerged for a few minutes in 2% HF

in order to dissolve the native oxide SiO

layer that covers every elemental Si surface under ambient conditions

with a thickness of 1..2 nm.

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On the other hand, plasma etching techniques are moreover applied operating with ions accelerated towards

the wafer in order to sputter unwanted layers off the surface. These processes may only be performed in

vacuum chambers, since plasma may only be ignited under low-pressure conditions. Etching processes can be

performed selectively by covering the surface with dedicated layers as e.g. photoresist and opening only over

areas intended for etching. However, the protection layer has to be chosen such that a high selectivity of the

process is given, i.e. that the protection is more resistant to etching than the layer to be etched off.

Essentially, all processes have now been presented for fabricating microchip architectures as shown in Figure 4.

Several of the structures mentioned like irradiated photoresist or etched-off layers are measured during wafer

processing by SEM and other inspection techniques. Special control structures are designated for this purpose

on every test field, by which, for instance, the critical dimensions of MOSFET gate lengths L, widths W and

other parameters are controlled.

In addition, various test devices are subjected to electrical control. They are denoted as process control

monitors PCMs and encompass e.g. MOSFETs and HBTs, devices for determination of sheet resistances or

capacitors. A full measurement of a wafer thus yields between some thousand measurement points that are

automatically valued, the results of which decide on releasing the wafer to the customer.

3 Surface conditioning

An important presupposition to be fulfilled relates to the state of the particular surface that interacts with the

bio-milieu

21, 22

. In most cases the interaction has to act through defined material windows, because of the high

corrosivity of electrolyte solutions versus semiconductors.

An illustrative example is given in Figure 6 showing an optical microscope view of the surface and a SEM cross

section view of a microelectronic chip, where a defect in the surface passivation has allowed the surrounding

electrolyte solution to reach the TM1 level. It may be recognized that the metal line made of Al:Cu has been

damaged along a path of many µm causing a total failure of the sensor chip. Such defects have to be avoided

without restraints and various measures can be taken for this purpose like planarization of the surface

usage of particular nitrogen-rich silicon nitride

3.1 Metallic electrodes

In most bioelectronics devices a set of metallic electrodes has to interact electrically with the bio-milieu. This is

a particular challenging task, since the presence of electrical fields was often observed to intensify corrosion

effects. In these situations titanium nitride may be the material of choice, since it turned out remarkably

corrosion-resistant. Its corrosion-resistance in biotechnological applications is expressed by negligible redox

rates in cyclic voltammograms when TiN was used as working electrodes

, compare Figure 6C. Accordingly,

TiN electrodes are applied in biomedical applications like the artificial retina implant

or IHP’s glucose sensor

chip

26, 27

. TiN should always be considered as the top-most electrode material, when the electrodes are

intended to interact with bio-milieus.

Introducing other metals into the clean room than those already processed is not an easy task. This is due to

the fact that various metal atoms in semiconductors act as deep recombination centers for free charge carriers.

The associated reduction of current densities is detrimental to many devices and may cause their failure.

Additional materials thus have to pass an extensive qualification procedure, before releasing them for

preparation processes in the clean room.

The usage of some materials, however, is excluded from the outset. This holds, for instance, for gold acting as

efficient recombination center in silicon. On the other hand, gold is multiply used for the immobilization of

organic molecules on technical surfaces by forming a covalent bonding via sulfur atoms

28, 29

. Post-CMOS

processes have thus been developed that allow for the deposition of gold electrodes on otherwise fully

processed microelectronic chips

. For this purpose, the wafer is covered with photoresist, exposed and

developed and finally discharged from the clean room to receive a full-covering gold deposition outside. In a

subsequent lift-off process the wafer is bathed in resist-dissolving solution leaving only the areas with an Au

layer that were not covered by resist.

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3.2 Nano-structured surfaces for immobilization

Alternative protocols may apply for the covalent immobilization of biomolecules that were initially developed

for glassware, since the native SiO

surface layer exposes hydroxide groups Si-OH into aqueous media. Here,

the well-known cross-linking techniques based on organosilanes like aminopropyl-triethoxy-silane (APTS)

should be considered or double cross-linking that additionally make use of glutaraldehyde (GD)

31, 32

It appears more elegant to immobilize biomolecules on semiconductor surfaces by other methods like physical

adsorption. In particular, the interesting perspective arises for microelectronics to make use of electrical fields

generated within the chip itself. In principle, this approach will enable to map the structures inscribed into the

silicon surface to the immobilized molecular layer

. A first approach for electrically-assisted immobilization is

offered by the structuring of a silicon surface by alternating p- and n-doped stripes. Due to the diffusion of

electrons and holes, a built-in electric field is formed – as well-known from the pn junction, with the electrical

field lines will not confine to the silicon volume, but also extend above the wafer surface.

Figure 6 A/B shows the results as obtained from a finite-element simulation (FEM) of a line lattice of n-doped

stripes that were implanted into a p-doped wafer having a base doping N

of some 10

-3

. The width of the

stripes amounted to 130 nm, while the depth of n-doped areas was adjusted by the implantation energy to

20 nm. Electrical fields are seen to extend up to 100 nm into the space above the surface

, where they can

cause the orientation and attraction of dipolar molecules like amino acids, proteins etc. It has to be mentioned,

however, that electrical fields in aqueous solutions will cause the formation of a Helmholtz layer and thereby

reducing the range of surface fields compared to the vacuum case

. An intermediate state during the

preparation of a doping line lattice is displayed in Figure 2C

17, 36

Such doping lattices may not only have an orienting effect on biological macromolecules, but also on complete

cells. The intentional orientation of cells is essential for biomechanics, cell biology, tissue engineering and

regenerative medicine applications

. The orienting effect of a surface doping lattice has been investigated in a

model system for the case of human cancer cells. Figure 6C demonstrates the successful orientation of MG-63

osteoblasts along a doping lattice with a width of p- and n-doped stripes of 180 nm each

Various other methods for the structuring of semiconductor surfaces are possible, which all offer the

advantages of semiconductor processing, i.e. to operate at the lowest level of the length scale accessible by

technical means today and to be reproducible in large sample numbers. One variant of particular interest

makes use of nanometer sized or micrometer sized electrodes that are embedded in an isolator. This may, for

instance, be realized by configuring the tungsten vias in regularly ordered arrays. The preparation scheme and

micrographs of such an array are shown in Figure 7 with W electrodes of 500 nm diameter and 2 µm distance

. Such arrays may effectively be used to pursue an electrical immobilization of small objects by

dielectrophoresis (DEP) as shown in the next section.

4 Biosensor modules

Sensor technology represents the main field of applications, to which microelectronics currently delivers the

most relevant contributions to biotechnology. Firstly, this relates to the miniaturization enabled by the use of

microchips for the measurement of physico-chemical quantities like temperature, pressure, conductivity, ion

density, pH or viscosity etc. Secondly, micro-sensors are multiply applied for the detection and measurement of

concentrations of biochemical analytes in samples of serum, pure bred or cell culture media etc. The

miniaturization of biosensors is of particular interest, since it paves the way for integrating it close to the point

of interest or point of care and to monitor the analyte concentration regularly. The obtained transients of

metabolites or other small biomolecules may be of great interest to medical research, the individual health of a

patient or the understanding of a bioprocess.

4.1 Microelectromechanical systems (MEMS)

Also micro-electromechanical systems (MEMS), which combine microelectronics with mechanically excitable

parts, have been developed for this purpose

40, 41

. A microviscosimeter may serve as an example that operates

by affinity sensorics to determine low-molecular weight analytes. The detection scheme relies on an assay

containing a receptor and a polymer formed from analyte monomers and being spatially separated by a

semipermeable membrane from the test solution. The receptor is acting as a weak antibody with a highly

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specific paratop for the target molecule. However, its dissociation constant K

is only on the order of 10

-5

and the receptor-analyte binding then is of reversible nature.

The plant lectin Concanavalin A (ConA) has been used in many investigations for glucose detection due to its

specific binding pocket for glycosyl and mannosyl residues. The protein is isolated from Canavalia ensiformis,

which was one of the first, purely isolated proteins

and encompasses 235 amino acids with 26.5 kDa

. The

formation of the active tertiary structure requires the inclusion of Mn

and Ca

into the functional center and

for physiological pH values ConA configures into a homo-tetramer with sugar binding sites being exposed at its

periphery.

Mixing ConA with glucose polymers like dextran causes the formation of a macromolecular network between

lectin tetramers and polymer molecules exhibiting a gel-like character. Mixtures with high viscosities on the

order of a few 100 mPa⋅s may be prepared by varying the size of dextran molecules, the ConA or dextran

concentration

. The usage of such mixtures for the determination of glucose concentrations appears of having

been investigated for the first time by Schultz et al. in 1978

. Various approaches to measure glucose by

affinity assays have been tested since then, which initially relied on fluorescence detection

46-49

, to later

encompass impedance-based

50-52

and viscosimetric techniques

53-57

The variation of viscosity due to glucose variation is made use of in a recently developed variant. A BioMEMS

has been developed for this purpose, in which a bendable beam is moved through the ConA-dextran-glucose

assay and from the velocity of which the viscosity is deduced, s. Figure 8A. The beam is bend in a quasi-

electrostatic operation mode, i.e. a high-frequency voltage to attract the beam to the ground plate. The

frequency amounts to 3.2 GHz and is situated between the absorption maximum of water at about 17 GHz and

of protein solutions at some 100 MHz

During the measurement the beam is moved towards the ground plate and from the time t

it takes to reach a

defined position the viscosity is derived. Figure 8B-D show one of the measuring chambers realized (without

the assay) and a four-fold clamped beam exhibiting a thickness of only 50 nm. The restoring mechanical

element in the middle of the beam is designed in the form of a double-U. Beam and ground plate are made

from TiN due to its demonstrated in vitro and in vivo stability

23, 25

. Glucose may continuously be monitored

with this BioMEMS in the relevant physiological range between 0.3 and 30 mM L

-1

with a precision of a few

percent

(Figure 11D).

4.2 Label-free immunoassays

Microelectronics may also be applied for the classical approach of immuno-assays with very small dissociation

constants K

of the receptor-analyte complex in order to realize the detection with a miniaturized system.

Again, the success is decided about by the performance of the interface, i.e. by the immobilization of

antibodies on the semiconductor surface and its biocompatible design. Various sensoric techniques have been

investigated for the microelectronic transformation of the binding event into an electrical quantity.

One approach makes use of dielectrophoresis

and the tungsten arrays presented in the previous section. It

was shown in Ref.

that the functionality of anti-bodies could be conserved after their dielectrophoretic

immobilization. An array as displayed in Figure 7 was applied for this purpose with all tungsten nano-cylinders

being subjected to the same alternating voltage by connecting them via a bottom metal layer. DEP with such an

array appears particularly suited for molecules compared to cells, because their small dimensions and

curvature (30 nm in the case considered here) allow for the generation of sufficiently strong electrical field

gradients. Frequencies in the 10..100 kHz range turned out as optimal with respect to avoiding thermally

induced effects and formation of gas bubbles. These frequencies were successfully applied for investigations

carried out with intrinsically fluorescing protein R-phycoerythrin RPE that was brought in contact with mouse

anti-RPE-IgG1 anti-bodies. The array was positioned under a fluorescence microscope and covered with ITO-

coated glass serving as a counter electrode. Anti-bodies were first immobilized on W electrodes by applying a

100 kHz voltage with 18 V

rms

, which was followed by a rinsing step. Finally, REP was introduced and its binding

to immobilized anti-bodies can clearly be recognized by inspecting the fluorescence micrograph (Figure 9B)

4.3 FET-derived sensors

In addition to BioMEMS, SAWs and MRRs the classical bio-analytical devices of microelectronics have to be

mentioned, which are ion-selective field effect transistors ISFETs. Various derivatives were developed from

them

like ChemFET, EnzymeFETs etc., which all operate by the same principle: instead of using the gate

voltage V

to tune the source-drain current of a MOSFET, an ion-sensitive or analyte-sensitve layer above the

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FET channel is used to modulate the channel current I

. Molecular receptors have to be immobilized upon the

gate that interact with the analyte via diffusion or chemical bonding to vary I

, and from the variation of which

the concentration may be deduced. ISFETs have found their main field of application for pH measurements

for which the largest variation I

/pH of 59 mV/pH has been observed for Ta

layers covering the channel

The ISFET became largely acquainted to biotechnology in 2011, when IonTorrent presented their next

generation sequencing tool for DNA sequencing

Spatio-temporal variations in various fields of biotechnology may be investigated by a recently developed ion

camera that also operates with an ISFET array and achieving resolutions of 66 µs and 70 ms in space and time

. ISFETs have been adopted for the detection of alkali metal ions, penicillin in combination with pH and

functional hybrid systems with living cells for both fundamental studies and biosensoric applications to

mention only a few examples

66-68

4.4 Impedimetric sensors

Next to classical biosensors that operate via aptamers, lectins or enzymes by the principle of steric comple-

mentarity, the detection may also be performed by electromagnetic procedures taking a kind of finger print

from the target molecules. Rather promising appears the extension of impedance spectroscopy or dielectric

spectroscopy from kHz and MHz into the GHz range. Appropriate sensor structures may be prepared by

semiconductor technology in a comparatively simple manner, since oscillator circuits only have to supply their

output signals to interdigitated electrodes (IDE)

69-71

or microstrip lines

in the vicinity of the biomilieu to let

them interact with the biochemical assay under investigation. The dependence on angular frequency ω = 2πf is

accounted for by the dielectric function ε(ω), for which the real and imaginary parts ε‘ and ε“ for water are

shown in Figure 11A. The course of the dielectric function of a typical protein solution is overlaid to the Figure

showing an additional resonance peak at about 100 MHz, i.e. at lower frequencies due to the higher mass of

proteins compared to H

The analysis of impedance spectra always requires a dielectric modelling for interpreting the measured data,

which recursively allows for deducing the molecules and their concentration. Compared to an enzyme test, the

technique is of limited specificity and requires thorough pre-investigations with respect to the assignment of

possibly occurring spectral patterns. Advantageously, impedance spectroscopy also allows for the monitoring

of full cells and cell ensembles

As in the case of SAW sensors, the geometry parameters of interdigitated electrodes have to be adapted to the

frequency range used in impedance spectroscopy. They accordingly shrink with increasing frequency. For a

frequency of 12 GHz, for instance, the penetration depths of electrical fields maximally amounts to a few mm

into a water solution for an optimally designed IDE geometry. This aspect has to be considered, whenever

spatial inhomogeneities of molecules or cell densities may be expected within the solution under investigation.

The frequency range above 1 THz increasingly comes into focus of bio-analytics, but comparatively few

spectroscopic studies were performed. In general, the penetration depth up to which THz sensors may gain

information from biological samples is in the sub-mm range. The investigations performed pointed to

characteristic peak patterns of nucleosides, nucleotides, saccharides and proteins that compare to the

detection specificity in UV-VIS spectroscopy

73, 74

. At the moment, Si-based microelectronic circuits are still

unavailable for such high frequencies and investigations have to be executed with III-V semiconductor wave

generators

73, 75

. This field of application may offer interesting perspectives for BiCMOS technologies including

high-frequency HBTs. So far, first studies with sub-THz radiation generated by SiGe:C HBT circuits were carried

out for gas sensorics

5 Microchips for molecule sensors and cytometry

Next to the sensor modules, that are in direct contact with the bio-milieu, a microelectronic chip encompasses

additional devices and modules, which serve for the generation of excitation signals or the processing of

measurement data.

Figure 10A schematically depicts the central elements of the electrical circuits of the affinity sensor chip

introduced in the previous section. A nearly mirror symmetry can be recognized to divide the upper and the

lower part, which stands for the division of the circuit into a measuring MEMS (top) and a reference MEMS

(bottom). The cavities of both microelectromechanical systems are blue shaded and their properties are

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modelled in this equivalent circuit by parallel operating capacitors (C) and resistors (R). Both devices are

marked by an arrow to indicate that their absolute values are varying during beam bending. This holds,

however, only for the measuring MEMS and not for the reference one, since the latter is mechanically rigid and

does not bend, although it is subjected to the same voltage.

A high-frequency (HF) voltage of 3.2 GHz is applied to the beam, while the chip is powered with a DC voltage of

3 V. The required HF voltage thus has to be generated on-chip, for the purpose of which three inverters are

used forming a ring-oscillator circuit. An inverter is simply build up from a p- and an n-transistor. Electrical

circuits composed of an uneven number of inverters have the remarkable property to convert a DC supply into

an oscillating resonance state with resonance frequency f

depending on the design parameters of the

transistors. The capabilities of the sensor-chip with a foot print of ½ mm

only (Figure 10B) have already been

demonstrated for in vitro glucose measurements (Figure 10C).

An important step on the way to realize a microelectronic biochip is the design of the circuit layout. Here, the

design essentially is the partition of lithography masks into dark and transparent areas. Various software

techniques have been developed for this purpose that all run under the title of Electronic Design Automation

(EDA). The design of circuit layouts takes place in a modular fashion with modern EDA tools, i.e. in a particular

technology usable elements like C, R, MOSFETs, HBTs etc. are stored in libraries as so-called parameter cells.

Figure 12B shows the micrograph of an impedance measurement chip operating in the frequency range around

28 GHz

. Its key element is an open microstrip line probing the solution above the chip, the dielectric function

of which is measured by affecting the electrical capacitance of an oscillator circuit. Such high-frequency

impedance chips may advantageously be applied for monitoring the density of biomolecules or microorganisms

in culture solutions. Parameter cells from SiGe:C HBTs, MOSFETs, pc-Si resistors and MIM capacitors as well as

dedicated device developments have to be combined for the circuit design and optimized with respect to the

intended application

69, 70, 72

. The chip footprint still is on the order of mm to allow for a sufficient spatial

separation of sensor functionality in the middle of the chip and bond pads at the periphery.

The function of the designed integrated circuits is examined by simulation runs in order to recognize possible

errors prior to chip production and cost-intensive usage of clean room resources. Simulations and design

optimization are often iteratively performed, until the circuit exhibits the intended behavior. Various

constraints have to be considered during circuit design with respect to minimum distances between devices or

vias or between devices and metal lines, which have been set-up to facilitate optimum chip operation. The set

of geometrical constraints is denoted as design rules and a so-called design rule check (DRC) is consequently

performed for every submitted chip design. Chip preparation is generally rejected by foundries for designs

failing the DRC.

Designed and simulated circuits are finally submitted to the foundry for production. After successful DRC they

are included, for instance, in a full test field of an MPW shuttle. A recently processed test field in an IHP 0.25

µm MPW run is exemplarily displayed in Figure 11C.

6 System integration

An essential development step is related to the integration of the microchip into an operative system, which

must be preceded by a technical and electronic design. Also a user scenario must be defined that has to include

specifications of electronic components and the system integration and has to include the important question

of sterilization.

The challenges to be expected can be illustrated by the system integration of the affinity BioMEMS presented

above into a medical implant intended for a continuous monitoring of glucose levels in human tissue. The

sensor is scheduled by the operation scenario to determine one glucose concentration value c

every 5 min and

to transmit the measured data five times per day. An operating time of at least half a year is planned for the

sensor system. Figure 13A schematically depicts the implant architecture

The control of measurement cycles and intermediate data storage is usually performed by a microcontroller

µC. This is a minicomputer integrated into single chip disposing of all computer components in miniaturized

form, with micro-signal processors TI MSP 430 having found the broadest dissemination. In case of a wireless

data transmission the appropriate frequency band and the transmission protocol have to be chosen, by which

the sensor communicates with the base station. For medical implants the 403-405 MHz frequency range has

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been approved by regulatory bodies

78, 79

, which is denoted as Medical Implant Communication Service (MICS)

and used by some 10.000 cardio implants worldwide.

System components are configured and electrically connected on a printed circuit board (PCB), which is made

of highly isolating materials and exhibits only little absorption. Figure 12B shows the PCB developed for the

glucose sensor implant. Electrical connections are usually implemented from copper or – for life science

applications – frequently from gold. In the Figure, the upper part of the PCB is seen to carry the JTAG port for

µC programming, which may be cut off afterwards in order to reduce the form factor.

A battery as used in cardio implants is scheduled for the power supply

that has to encompass a few 100 mAh

in order to enable the number of 288 measurements and 5 data transmissions per day. The battery then

becomes the form-factor-determining component of the implant. Data transmission requires an antenna and

the sensor chip will be connected via a so-called zero-insertion-force connector.

The BioMEMS chip was integrated into a cooling body that also allowed for the integration of the

semipermeable membrane at very small distance (ca. 150 µm) above the surface of the sensor chip. It also

offered sufficient space for the reception of the affinity assay encompassing Con A and dextran in an

electrolyte solution. All sensor components were integrated into a full sensor system by a silicone casting

see Figure 12. This system offers a platform to investigate the sensor function and stability under in vitro and in

vivo conditions.

Another example relates to an autonomous sensor capsule for algae bioreactors. Goal of the project was to

follow the transients of pH, electrolyte and glucose in a photo-bioreactor build up from some 100 m of

translucent tubes with an inner diameter of 5 cm. It is still unresolved, which inhomogeneities occur in such

reactors and how they affect growth and yield of the algae culture

. Mobile capsules being transported with

the fluid stream appear to be the system of choice. In this case, wireless data transmission must not obey the

strict regulations of medical implants, but may follow usual industry standards

The outer diameter of the sensor capsule was set to 44 mm, which is a little smaller than the inner diameter of

the reactor tubes

. The system PCB is mounted in the equatorial plane of the capsule with its upper layer

exposing the sensor surfaces, while the other components of the electrical circuit were installed on the

opposite side. The upper sphere of the capsule is permeable to the algae medium, while the lower part is

hermetically sealed as is the PCB such that the liquid medium cannot enter the electronics-carrying side.

Potentiometric sensors were scheduled for measuring pH and Na

, while glucose was intended to be monitored

by an amperometric sensor. Figure 13 schematically depicts the PCB layout, where also the electrode surface

for conductivity measurements can be recognized. In this example, the transceiver CC1101 is used as radio chip

operating in the 433 MHz band

7 Microfluidics and lab-on-chip systems

Microfluidic techniques developed in the last decades offer a suitable platform for the application of

microelectronics in the life sciences

. In principle, they may be realized from polymeric solids, while silicon

was of less importance, because the access to semiconductor technology was not simple and associated with

higher costs

. However, the perspective appears attractive to perform biotechnological experiments on

combined microelectronic-microfluidic platforms and – concomitantly – the first steps of data accumulation

and “intelligent” processing. In general, the combination of both micro-techniques is a central approach to lab-

on-chip technologies.

Remarkably, the first microfluidic channels were introduced in silicon wafers for chromatographic applications

. Today, the decisive technological process makes use of deep reactive ion etching (DRIE) and is also known as

Bosch process. It can be applied for introducing the channels for fluid transport into the Si wafer and operates

by a plasma-assisted etching from the gas phase. The process is capable to produce some 100 µm deep holes

and ditches

. The common integration of fluidics and sensor elements is of particular importance for

impedance spectroscopy at high frequencies, since the damping of electromagnetic radiation severely

increases with increasing frequency. In particular, the objects of interest have to be very close to the sensor

chip, when frequencies in the GHz range and in the THz range shall be applied for the investigation, i.e. the

distance must be less than about 100 µm, with the precise value depending upon the chosen frequency, the

electrode geometry and the amount of heat tolerable during the investigation.

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A two wafer approach as already developed

may be applied to position the microfluidics in close proximity to

the sensor elements of the integrated circuit

90, 91

. The wafer carrying the BiCMOS circuit is thereby designated

as BiCMOS wafer or top wafer, whereas the bottom wafer supplies the fluid inlet and outlet that are prepared

as cylindrical holes by the DRIE process. In addition, the top wafer encompasses another microfluidic channel,

which is positioned directly below the integrated circuit, by which the fluid is probed. An alignment technology

for backside integration was to develop in advance to allow for DRIE of the wafer backside to align the micro-

channel under the sensor circuit with a precision in the 1-2 µm range

It can be seen from Figure 14 that the silicon below the sensor area is completely etched off, facilitating the

fluid to stream along the bottom side of the electronic circuit. The Figure also displays the stacking of top and

bottom wafer in the area of the active circuit. Critical parameters are the fracture toughness of the BEoL stack

and the Reynolds number of the flow in the top wafer. It is outlined in Ref.

that flow rates of some 100 µL s

-1

might be realized with the two-wafer configuration, even for channel heights of only 50 µm in the BiCMOS

wafer.

Various projects have thus demonstrated the feasibility to integrate microelectronic circuits into microfluidic

platforms. Life scientists may formulate their experimental constrains and intention to configure in cooperation

with semiconductor technologists the appropriate lab-on-a-chip devices with combined components.

8 Multi-project-wafer service

In order to enable access to its technology for external users so-called multi-project wafer MPW shuttles are

regularly processed at IHP (in general, such a service is offered by various semiconductor fabs). The ICs of

several customers are prepared in these runs for one of the offered technologies that differ with respect to the

performance parameters of MOSFETs and HBTs. Table 1 gives an overview of the technologies offered by IHP’s

MPW service and device characteristics.

For participation the MPW service, a potential user has to login and upload his layout data for a chosen

technology run via the IHP webserver. After a formal procedure, the design rules as well the parameter cells for

the most important devices will be supplied allowing for the design of customer-specific circuits. Generally,

these tools have to be applied by scientists and developers from the electronic disciplines. Life scientists with

interest in biochips are thus recommended to cooperate with circuit designers.

Submitted designs are combined into a common test field, which also comprises several hundred test

structures and alignment markers, see Figure 11C. After this the set of lithography masks may be prepared.

Prior to clean room processing the appropriate wafer type has to be selected, whereas for product flows

typically wafers with 2 Sm

-1

und 〈001〉 orientation are chosen. Wafers are collected into a lot that usually

comprises of 24 pieces, see Figure 1B. Processing starts with the labelling of each wafer, which is followed by

various cleaning steps. Subsequently, the essential set-up of the integrated circuit begins. It is divided into

different modules like TRENCH, TRCHFI, BLAYER etc., which stands for the separation of active areas,

preparation of buried layers and so on.

Wafer processing is finished for 0.25 and 0.13 µm technologies about 2½ - 3 month after starting the lot and

after a few 100 process steps. Chips then have to be separated, which is usually performed by automated

circular-blade saws. Beforehand, the wafer is subjected to thinning to reduce its original thickness to 300 µm or

another customer-specified value. Next to conventional sawing the technique of laser dicing may be applied for

chip separation

, which practically avoids any particle generation. Finally, the separated microchips are

delivered for experimentation or system integration.

9 Conclusions

Next to micro- and nano-electronics no other technology exists that operates on length scales so close to the

molecular structures of living. New bio-analytical and bio-sensor principles are enabled by them that may

directly be integrated into microelectronic chips allowing for the detection, transduction, analysis and

otherwise intelligent processing of measured data within smallest regions of space. Various semiconductor fabs

offer their assistance to life scientists for the fabrication of BioASICs by usage of multi-project wafer services.

The pilot line of IHP disposes of a set of 0.25 and 0.13 µm CMOS/BiCMOS enabling, for instance, the

preparation of MEMS devices with mechanical membranes from bio-stable TiN, di-electrophoretic electrode

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arrays, impedimetric measurement chips in the GHz range, HBTs with transient frequencies in the few 100 GHz

range and Si-integrated microfluidics to mention only a few technology modules, from which full bio-systems

might be configured. The usage of microelectronic techniques is expected to pave the way for substantial

progress in various fields of life science research and development. It still suffers from the so-far disjunctive

terminology between both disciplines, but the authors hope that the presented review might foster a broader

utilization of microelectronics by life scientists.

Acknowledgement

We thank our colleagues from IHP that helped during the collection of this overview and which enabled to offer

the technology modules presented above to external customers. We likewise thank our partners that

participated in project translation and the German Federal Ministry of Research and Technology (grant

numbers 0313862B and 16SV3934), German Federal Ministry of Economics (KF 0653901 UL8), the European

Regional Development Fund and the German state Brandenburg (TeraSens project) for funding cooperation

projects, the results of which were presented here. We particularly thank Aktionszentrum BioTOP, the

diagnostic network Berlin-Brandenburg, IGE from TU Berlin and the center for molecular diagnostics and

biotechnology ZMDB for long-standing and manifold support in transferring microelectronics to the life

sciences, and last, but not least, the Chair of Bioprocess Engineering of TU Berlin, with which the Joint Lab

Bioelectronics IHP/TUB was founded in 2012.

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References

1. Cumming DRS. ISFET technology for multi-sensor technology: from lab-in-a-pill to massively parallel

measurements. Electronics Letters 2011. Available at: http://digital-

library.theiet.org/content/journals/10.1049/el.2011.2891.

2. Graham AHD, Robbins J, Bowen CR, Taylor J. Commercialisation of CMOS Integrated Circuit

Technology in Multi-Electrode Arrays for Neuroscience and Cell-Based Biosensors. Sensors 2011,

11:4943-4971.

3. Rothe J, Lewandowska MK, Heer F, Frey O, Hierlemann A. Multi-target electrochemical biosensing

enabled by integrated CMOS electronics. J. Micromech. Microeng. 2011, 21:054010.

4. Pan T, Wang W. From Cleanroom to Desktop: Emerging Micro-Nanofabrication Technology for

Biomedical Applications. Annals of Biomedical Engineering 2011, 39:600-620.

5. Kumar S, Prakash R, Chouhan S, Salhan AK. CMOS sensors for microscopy, spectrophotometry and as a

transducer in biosensors. In: Point-of-Care Healthcare Technologies (PHT): IEEE; 2013.

6. Ghallab YH, Ismail Y. CMOS Based Lab-on-a-Chip: Applications, Challenges and Future Trends. Circuits

and Systems Magazine, IEEE 2014, 14:27-47.

7. Moore GE. Cramming more components onto integrated circuits. Electronics 1965, 38:114-117.

8. Dennard RH, Gaensslen FH, Yu H-N, Rideout VL, Bassous E, LeBlanc A. Design of Ion-Implanted

MOSFETs with Very Small Physical Dimensions. IEEE J. Solid-State Circuits 1974, 9:256-268.

9. Bohr M. A 30 Years Retrospective on Dennard's MOSFET Scaling Paper. IEEE Solid State Circuits Society

News 2007, 12:11-13.

10. ITRS EC. 2013 Edition - Executive Summary. International Technology Roadmap for Semiconductors

2013. Available at: http://www.itrs.net/Links/2013ITRS/2013Chapters/2013ExecutiveSummary.pdf.

11. Arden W, Brillouët M, Cogez P, Graef M, Huizing B, Mahnkopf R. More-than-Moore - White Paper.

2011.

12. Fromherz P, Offenhausser A, Vetter T, Weis J. A neuron-silicon junction: a Retzius cell of the leech on

an insulated-gate field-effect transistor. Science 1991, 252:1290-1293.

13. Fromherz P. Joining microelectronics and microionics: Nerve cells and brain tissue on semiconductor

chips. Solid-State Electronics 2008, 52:1364-1373.

14. Panaitov G, Thiery S, Hofmann B, Offenhäusser A. Fabrication of gold micro-spine structures for

improvement of cell/device adhesion. Microelectronic Engineering 2011, 88:1840-1844.

15. Schuettler M, Donaldson N, Seetohul V, Taylor J. Fibre-selective recording from the peripheral nerves

of frogs using a multi-electrode cuff. Journal of Neural Engineering 2013, 10:036016.

16. Ballini M, Muller J, Livi P, Yihui C, Frey U, Stettler A, Shadmani A, Viswam V, Lloyd Jones I, Jackel D, et

al. A 1024-Channel CMOS Microelectrode Array With 26,400 Electrodes for Recording and Stimulation

of Electrogenic Cells In Vitro. Solid-State Circuits, IEEE Journal of 2014, 49:2705-2719.

17. Birkholz M, Zaumseil P, Bauer J, Bolze D, Weidner G. Small-Angle X-ray Reciprocal Space Mapping of

Surface Relief Gratings. Mater. Sci. Eng. C 2007, 27:1154-1157.

18. Osten HJ, Lippert G, Knoll D, Barth R, Heinemann B, Rucker H, Schley P. The effect of carbon

incorporation on SiGe heterobipolar transistor performance and process margin. In: Electron Devices

Meeting, 1997. IEDM '97. Technical Digest., International; 1997.

19. Heinemann B, Barth R, Bolze D, Drews J, Fischer GG, Fox A, Fursenko O, Grabolla T, Haak U, Knoll D, et

al. SiGe HBT Technology with fT/fmax of 300 GHz/500 GHz and 2.0 ps CML, Gate Delay. In:

International Electron Devices Meeting (IEDM); 2010.

20. Martienssen W, Warlimont H, eds. Handbook of Condensed Matter and Materials Data. Berlin:

Springer; 2005, 1120.

21. Hämmerle H, Kobuch K, Kohler K, Nisch W, Sachs H, Stelzle M. Biostability of micro-photodiode arrays

for subretinal implantation. Biomat. 2002, 23:797-804.

22. Graham AHD, Bowen CR, Taylor J, Robbins J. Neuronal cell biocompatibility and adhesion to modified

CMOS electrodes. Biomed. Microdev. 2009, 11:1091-1101.

23. Fröhlich M, Birkholz M, Ehwald K-E, Kulse P, Fursenko O, Katzer J. Biostability of an implantable

glucose sensor chip. IOP Conference Series: Materials Science and Engineering 2012, 41:012022.

24. Lisker M, Trusch A, Krüger A, Fraschke M, Tillack B, Weimann N, Ostermay I, Krüger O. Silicon Nitride

Stop Layer in Back-End-of-Line Planarization for Wafer Bonding Application. International Conference

on Planarization/CMP Technology (ICPT) 2014.

Page 13 of 39

John Wiley & Sons

Wiley Interdisciplinary Reviews: Nanomedicine

For Peer Review

Birkholz et al.: Technology modules … 14

25. Birkholz M, Ehwald K-E, Wolansky D, Costina I, Baristiran-Kaynak C, Fröhlich M, Beyer H, Kapp A, Lisdat

F. Corrosion-resistant metal layers from a CMOS process for bioelectronic applications. Surf. Coat.

Technol. 2010, 204:2055-2059.

26. Birkholz M, Ehwald K-E, Kulse P, Drews J, Fröhlich M, Haak U, Kaynak M, Matthus E, Schulz K,

Wolansky D. Ultrathin TiN membranes as a technology platform for CMOS-integrated MEMS and

BioMEMS devices. Adv. Func. Mat. 2011, 21:1652-1656.

27. Kulse P, Birkholz M, Ehwald K-E, Bauer J, Drews J, Haak U, Höppner W, Katzer J, Schulz K, Wolansky D.

Fabrication of MEMS actuators from the BEOL of a 0.25 µm BiCMOS technology platform. Microelectr.

Eng. 2012, 97:276-279.

28. Hrapovic S, Liu Y, Enright G, Bensebaa F, Luong JHT. New Strategy for Preparing Thin Gold Films on

Modified Glass Surfaces by Electroless Deposition. Langmuir 2003, 19:3958-3965.

29. Lee JM, Park HK, Jung Y, Kim JK, Jung SO, Chung BH. Direct Immobilization of Protein G Variants with

Various Numbers of Cysteine Residues on a Gold Surface. Anal. Chem. 2007, 79:2680-2687.

30. Kitzmann J. Strukturierte Goldabscheidung mittels Galvanik und PVD. 2011.

31. Schnyder B, Kötz R, Alliata D, Facci P. Comparison of the self-chemisorption of azurin on gold and on

functionalized oxide surfaces. Surf. Interface Anal. 2002, 34:40-44.

32. Birkholz M, Zaumseil P, Kittler M, Wallat I, Heyn MP. Structure of biomembrane-on-silicon hybrids

derived from X-ray Reflectometry. Mater. Sci. Eng. B 2006, 134:125-129.

33. Birkholz M. A thin film approach to protein crystallography. Nucl. Instr. Meth. Phys. B 2009, 268:414-

419.

34. Ratzke M. Kraftmikroskopie als Werkzeug zur Charakterisierung elektrischer

Oberflächeneigenschaften. Physik 2011. Vol. Doktor.

35. Israelachvili J. Intermolecular and Surface Forces. 2nd ed. Amsterdam: Academic Press; 1991.

36. Zaumseil P, Birkholz M, Weidner G. X-ray Characterization of Periodic Sub-nm Surface Relief Gratings.

phys. stat. sol. a 2007, 204:2657-2661.

37. Li Y, Huang G, Zhang X, Wang L, Du Y, Lu TJ, Xu F. Engineering cell alignment in vitro. Biotechnology

Advances 2014, 32:347-365.

38. Körtge A, Stählke S, Lange R, Birkholz M, Fraschke M, Schulz K, Nebe B, Elter P. Alignment of MG-63

Osteoblasts on Fibronectin-Coated Phosphorous Doping Lattices in Silicon. World Academy of Science,

Engineering and Technology 2013, 73:801-804.

39. Otto S, Kaletta UC, Bier F, Wenger C, Hölzel R. Dielectrophoretic Immobilisation of Antibodies on

Microelectrode Arrays. Lab on a Chip 2014, 14:998-1004.

40. Bashir R. BioMEMS: state-of-the-art in detection, opportunities and prospects. Adv. Drug Delivery Rev.

2004, 56:1565-1586.

41. Grayson ACR, Shawgo RS, Johnson AM, Flynn NT, Li Y, Cima MJ, Langer RS. A BioMEMS Review: MEMS

Technology for Physiologically Integrated Devices. Proc. IEEE 2004, 92:6-21.

42. Sumner JB, Gralén N, Eriksson-Quensel I-B. The molecular weights of Concanavalin, Concanavalin A

and Concanavalin B. J. Biol. Chem. 1938:45-48.

43. Bouckaert J, Dewallef Y, Poortmans F, Wyns L, Loris R. The Structural Features of Concanavalin A

Governing Non-proline Peptide Isomerization. J. Biol. Chem. 2000, 275:19778-19787.

44. Ehwald R, Ballerstadt R, Dautzenberg H. Viscosimetric Affinity Assay. Anal. Biochemistry 1996, 234:1-8.

45. Schultz JS, Sims G. Affinity Sensors for Individual Metabolites. Biotechnol. Bioeng. Sympos. 1979. Vol.

9, Pages 65-71.

46. Schultz JS, Mansouri S, Goldstein IJ. Affinity sensor: a new technique for developing implantable

sensors for glucose and other metabolites. Diabetes Care 1982, 5:245-253.

47. Ballerstadt R, Evans C, Gowda A, McNichols R. Fiber-Coupled Fluorescence Affinity Sensor for 3-Day in

Vivo Glucose Sensing. J. Diabetes Sci. Technol. 2007, 1:218-227.

48. Nielsen JK, Christiansen JS, Kristensen JS, Toft HO, Hansen LL, Aasmul S, Gregorius K. Clinical Evaluation

of a Transcutaneous Interrogated Fluorescence Lifetime-Based Microsensor for Continuous Glucose

Reading. J. Diabetes Sci. Technol. 2009, 3:98-109.

49. Dutt-Ballerstadt R, Evans C, Pillai AP, Orzeck E, Drabek R, Gowda A, McNichols R. A human pilot study

of the fluorescence affinity sensor for continuous glucose monitoring in diabetes. J Diabetes Sci

Technol. 2012, 6:362-370.

50. Huang X, Siqi L, Schultz J, Qian W, Lin Q. A Capacitive MEMS Viscometric Sensor for Affinity Detection

of Glucose. Microelectromechanical Systems, Journal of 2009, 18:1246-1254.

51. Huang X, Li S, Schultz JS, Wang Q, Lin Q. A dielectric affinity microbiosensor. Applied Physics Letters

2010, 96:033701.

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52. Xian H, Siqi L, Davis E, Dachao L, Qian W, Qiao L. A MEMS Dielectric Affinity Glucose Biosensor.

Microelectromechanical Systems, Journal of 2014, 23:14-20.

53. Ballerstädt R, Ehwald R. Suitability of aqueous dispersions of dextran and Concanavalin A for glucose

sensing in different variants of the affinity sensor. Biosens. Bioelectr. 1994, 9:557-567.

54. Beyer U, Schäfer D, Thomas A, Aulich H, Haueter U, Reihl B, Ehwald R. Recording of subcutaneous

glucose dynamics by a viscosimetric affinity sensor. Diabetol. 2001, 44:416-423.

55. Zhao Y, Li S, Davidson A, Yang B, Wang Q, Lin Q. A MEMS viscosimetric sensor for continuous glucose

monitoring. J. Micromech. Microeng. 2007, 17:2528-2537.

56. Birkholz M, Ehwald K-E, Ehwald R, Kaynak M, Borngräber J, Drews J, Haak U, Klatt J, Matthus E, Schoof

G, et al. Mikroviskosimeter zur kontinuierlichen Glucosemessung bei Diabetes mellitus.

Mikrosystemtechnik Kongress 2009 2009:124-125.

57. Birkholz M, Ehwald K-E, Basmer T, Reich C, Kulse P, Drews J, Genschow D, Haak U, Marschmeyer S,

Matthus E, et al. Sensing glucose concentrations at GHz frequencies with a fully embedded BioMEMS.

J. Appl. Phys. 2013, 113:244904.

58. Gabriel G, Gabriel S, Grant EH, Halstead BSJ, Mingos DMP. Dielectric parameters relevant to

microwave dielectric loss. Chem. Soc. Rev. 1998, 27:213-223.

59. Pethig R. Review Article—Dielectrophoresis: Status of the theory, technology, and applications.

Biomicrofluidics 2010, 4:022811.

60. Laux EM, Wenger C, Kaletta UC, Bier FF, Hoelzel R. Functionality of Dielectrophoretically Immobilized

Enzyme Molecules. Electrophoresis 2014, 35:459.

61. Schöning MJ, Poghossian A. Bio FEDs (Field-Effect Devices): State-of-the-Art and New Directions.

Electroanalysis 2006, 18:1893-1900.

62. Hammond PA, Ali D, Cumming DRS. Design of a single-chip pH sensor using a conventional 0.6-μm

CMOS process. Sensors Journal, IEEE 2004, 4:706-712.

63. Grattarola M, Massobrio G. Bioelectronics Handbook: MOSFETs, biosensors, and neurons. New York:

McGraw-Hill; 1998.

64. Rothberg JM, Hinz W, Rearick TM, Schultz J, Mileski W, Davey M, Leamon JH, Johnson K, Milgrew MJ,

Edwards M, et al. An integrated semiconductor device enabling non-optical genome sequencing.

Nature 2011, 475:348-352.

65. Nemeth B, Symes MD, Boulay AG, Busche C, Cooper GJT, Cumming DRS, Cronin L. Real-Time Ion-Flux

Imaging in the Growth of Micrometer-Scale Structures and Membranes. Advanced Materials 2012,

24:1238-1242.

66. Schöning MJ, Sauke M, Steffen A, Marso M, Kordos P, Lüth H, Kauffmann F, Erbach R, Hoffmann B. Ion-

sensitive field-effect transistors with ultrathin Langmuir-Blodgett membranes. Sensors and Actuators

B: Chemical 1995, 27:325-328.

67. Poghossian A, Schöning MJ. Chapter 14 ‘High-order’ hybrid FET module for (bio)chemical and physical

sensing. In: Alegret S, ed. Comprehensive Analytical Chemistry. Vol. Volume 39: Elsevier; 2003, 587-

623.

68. Poghossian A, Ingebrandt S, Offenhäusser A, Schöning MJ. Field-effect devices for detecting cellular

signals. Seminars in Cell & Developmental Biology 2009, 20:41-48.

69. Guha S, Jamal FI, Schmalz K, Wenger C, Meliani C. CMOS lab on a chip device for dielectric

characterization of cell suspensions based on a 6 GHz Oscillator. In: European Microwave Conference,

European Microwave Week 2013, (EuMW 2013). Nürnberg; 2013.

70. Guha S, Jamal FI, Schmalz K, Wenger C, Meliani C. An 8 GHz CMOS Near Field Bio-sensor Array for

Imaging Spatial Permittivity Distribution of Biomaterials. In: International Microwave Symposium (IMS

2014); 2014.

71. Couniot N, Afzalian A, Van Overstraeten-Schlögel N, Francis LA, Flandre D. Capacitive biosensing of

bacterial cells: Analytical model and numerical simulations. Sensors and Actuators B: Chemical 2015,

211:428-438.

72. Jamal FI, Guha S, Meliani C. A SiGe BiCMOS Dielectric Sensor utilizing an Open-ended Microstrip Line in

a 28 GHz Colpitts Oscillator. In: European Microwave Week (EuMW): IEEE; 2014.

73. Nishizawa J-i, Sasaki T, Suto K, Tanabe T, Saito K, Yamada T, Kimura T. THz transmittance

measurements of nucleobases and related molecules in the 0.4- to 5.8-THz region using a GaP THz

wave generator. Optics Communications 2005, 246:229-239.

74. Saha SC, Grant JP, Ma Y, Khalid A, Hong F, Cumming DRS. Application of terahertz spectroscopy to the

characterization of biological samples using birefringence silicon grating. Journal of Biomedical Optics

2012, 17:0670061-0670065.

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Birkholz et al.: Technology modules … 16

75. Wolf A. Aufbau und Funktionsweise eines kontinuierlich-strahlenden Terahertz-Spektrometers. 2013.

76. Schmalz K, Mao Y, Borngräber J, Neumaier P, Hübers HW. Tunable 500 GHz transmitter array in SiGe

technology for gas spectroscopy. Electronics Letters 2015, 51:257-259.

77. Basmer T, Kulse P, Birkholz M. Systemarchitektur intelligenter Sensorimplantate. Biomed.

Eng./Biomed. Tech. 2010, 55:P43.

78. Johansson AJ. Performance of a radio link between a base station and a medical implant utilising the

MICS standard. In: Engineering in Medicine and Biology Society, 2004. IEMBS '04. 26th Annual

International Conference of the IEEE; 2004.

79. ETSI. Electromagnetic compatibility and Radio spectrum Matters (ERM); Short Range Devices (SRD);

Ultra Low Power Active Medical Implants (ULP-AMI) and Peripherals (ULP-AMI-P) operating in the

frequency range 402 MHz to 405 MHz; Part 1: Technical characteristics and test methods. ETSI EN 301

839-1 V1.3.1 (2009-10) 2010. Vol. ETSI EN 301 839-1 V1.3.1 (2009-10), Page 52.

80. Basmer T, Genschow D, Fröhlich M, Birkholz M. Energy budget of an implantable glucose

measurement system. Biomed. Tech./Biomed. Eng. 2012, 57:259-262.

81. Birkholz M, Glogener P, Basmer T, Glös F, Genschow D, Welsch C, Ruff R, Hoffmann KP. System

integration of a silicone-encapsulated glucose monitor implant. Biomed. Eng./Biomed. Tech. 2014,

59(s1):S1089 – S1092.

82. Dillschneider R, Posten C. Closed Bioreactors as Tools for Microalgae Production. In: Lee JW, ed.

Advanced Biofuels and Bioproducts: Springer New York; 2013, 629-649.

83. Todtenberg N, Basmer T, Klatt J, Schmalz K. Estimation of 433 MHz Path Loss in Algae Culture for

Biosensor Capsule Application. In: European Microwave Conference (EuMC 2013); 2013.

84. Todtenberg N, Schmitz-Hertzberg S-T, Schmalz K, Klatt J, Jorde F, Juttner B, Kraemer R. Autonomous

Sensor Capsule for Usage in Bioreactors. Sensors Journal, IEEE 2015, 15:4093-4102.

85. Baratchi S, Khoshmanesh K, Sacristan C, Depoil D, Wlodkowic D, McIntyre P, Mitchell A. Immunology

on chip: Promises and opportunities. Biotechnology Advances 2014, 32:333-346.

86. Kling J. Moving diagnostics from the bench to the bedside. Nat. Biotechnol. 2006, 24:891-893.

87. Terry SC, Jerman JH, Angell JB. A gas chromatographic air analyzer fabricated on a silicon wafer.

Electron Devices, IEEE Transactions on 1979, 26:1880-1886.

88. Marschmeyer S, Fraschke M, Milewski T, Schulze S. Characterization of Fluorocarbon Polymers

Deposited with Different Chamber Pressure and Source Power in the Deposition Cycle of the Bosch

Process. In: Plasma Etch and Strip in Microelectronics (PESM); 2011.

89. Hwang T, Popa D, Sin J, Stephanou HE, Leonard EM. BCB wafer bonding for microfluidics. In:

Micromachining and Microfabrication Process Technology IX. San Jose, CA: SPIE; 2004.

90. Bauer J, Kulse P, Haak U, Kaynak M, Ehwald K-E, Marschmeyer S, Birkholz M, Schulz S, Old G, Scheuring

G, et al. Alignment Technology for Backside Integration. Proceedings SPIE 2011, 7985:798508.

91. Baristiran-Kaynak C, Kaynak M, Wietstruck M, Marschmeyer S, Kulse P, Schulz K, Silz H, Krüger A, Barth

R, Schmalz K, et al. Modeling and Characterization of BiCMOS Embedded Microfluidic Platform for

Biosensing Applications. In: Silicon Monolithic Integrated Circuits in RF Systems; 2014.

92. Birkholz M, Ehwald K-E, Kaynak M, Semperowitsch T, Holz B, Nordhoff S. Separation of extremely

miniaturized medical sensors by IR laser dicing. J. Opt. Adv. Mat. 2010, 12:479-483.

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Tables

Table 1

SG25H1

igh

performance 0.25 µm technology with

npn

HBTs up to

max

180/220 GHz

(compare Figure 4A)

SG25H3 0.25 µm technology with a set of npn-HBTs ranging from a higher RF performance (f

max

= 110/180 GHz) to

higher breakdown voltages up to 7 V.

SGB25V Cost-effective technology with a set of npn-HBTs up to a breakdown voltage of 7 V.

SG13S High-performance 0.13 µm BiCMOS with npn-HBTs up to f

max

= 250/300 GHz, with 3.3 V I/O CMOS and 1.2

V logic CMOS.

SG13G2 0.13 µm BiCMOS technology with the same device portfolio as SG13S, but much higher bipolar performance

with f

max

= 300/500 GHz.

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Figure Legends

Figure 1. A. View into IHP clean room. B. Wafer lot consisting of 24 Si Wafers having a diameter of 200 mm. C.

An almost full-processed wafer showing the separation of the surface into single dies of the same test field.

Figure 2. SEM micrograph of an intermediate step during the preparation of a doping lattice. The picture was

taken after implantation of n-doped areas and prior to etching off the photoresist.

Figure 3. A. TEM micrographs of increasing magnification from the cross section of a MOSFET having a channel

length of 130 nm as routinely produced in 0.13 µm CMOS technologies. Source and drain regions are situated

directly below the vertical tungsten plugs (W VIAs). The thin SiO

film covering the channel exhibits a thickness

of 2 nm. C. TEM cross section micrograph of a most-recent hetero-junction bipolar transistor (HBT); the emitter

and the base, consisting of 20 nm thin SiGe:C, have been emphasized. The electrical connection to a tungsten

VIA and the lowest metal layer M1 can clearly be recognized.

Figure 4. A. Schematic drawing of SG25H1 chip architecture in 0.25 µm technology. Blue areas are formed by

ILD layers that have to establish the electrical isolation between electrical connections. Metal layers M1…M5

are horizontally oriented, while vertical currents are transported by VIAs. Active devices like n-type and p-type

MOSFETs as well as a HBTs are formed directly on the Si wafer and can be seen at the bottom. The layer stack is

terminated on top by a passivation layer of silicon nitride (grey) having openings only in the area of bond pads.

B. SEM cross section micrograph of a chip architecture processed until to ILD3. The framing of metal layers M1

to M3 into a top and bottom TiN layer may clearly be recognized as well as the VIAs connecting them.

Figure 5. A. Optical microscope picture of the surface of a microchip after storing it in electrolyte solution for

some days. A top-most metal layer has been subjected to corrosion as can be recognized by the color change

from yellow to green. SEM cross section micrograph of the same area shows a penetration of the passivation

layer, which turned out to be caused by the topography variation at the edge of TM1-induced surface

protrusion. Such defects can be avoided by usage of an alternative passivation nitride and by a CMP step for

planarization. C. Cyclic voltammogramm of a gold layer and a thin TiN film exposing the same area into 5 mM

{Fe(CN)

}/ 5 mM K

{Fe(CN)

} in 100 mM pH 7.4 phosphate buffer. The TiN electrode exhibits an almost zero

redox turnover when compared with the currents crossing the gold electrode, the latter exceeding 100 µA.

Figure 6. A. Color-scale representation of electric potential distribution in and above a doping lattice as

calculated by an FEM simulation for N

= 10

-3

. B. Course of surface potentials for the different cases of

= 10

, 10

and 10

-3

. Calculations were performed for the vacuum case

, which has to be

modified in aqueous solutions due to shielding by electrolyte ions and water dipoles. C. SEM view on a doping

lattice upon which MG 63 osteoblasts were cultivated. The orientation of cells along the direction of the lattice

(white arrow) can clearly be recognized

Figure 7. Fabrication process of microelectrode array for dielectrophoretic immobilization: a) metal deposition;

b) SiO

deposition, CMP and VIA etch; c) tungsten filling of VIAs and subsequent CMP; d) 3D side view; e)

confocal reflection microscopy of a part of the array, scale 50 µm; f) detail view of e), scale 2 µm; g) SEM cross

section micrograph of a single tungsten electrode with embedding SiO

and metal layer beneath, scale bar 500

Figure 8. A. Scheme of MEMS concept and operation of an affinity sensor. A cavity is filled by the assay

encompassing the receptor (small red balls) and the polymer of the analyte (large blue spheres). The network

formed by macromolecular receptors and polymers partially decomposes under inserting the monomeric

analyte, which leads to a change in viscosity. B. SEM picture of an assay-free MEMS with mechanically aving the

shape of an X. Beam and ground plate are prepared from biostable TiN with the beam thickness amounting to

50 nm only. C. The elastically restoring element in the middle of the beam takes the shape of an open double

U. D. The beam is formed immoveable for a parallel reference measurement by closing the double U.

Figure 9. A. Measurement set-up for dielectrophoretic electrode array on a microscope slide (75 x 25 mm). B.

Dielectrophoretic immobilization of anti-RPE anti-bodies and subsequent incubation with RPE. An alternating

voltage of 100 kHz and 18 V

rms

has been applied for 20 min. The Figure depicts the superposition of a reflection

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picture of the array (grey values converted to violet) and a fluorescence picture (grey values converted to

yellow).

Figure 10. Affinity-viscosimetric sensor chip. A. Electrical circuit of affinity sensor chip: the DC voltage

introduced is converted to a high-frequency AC voltage of 3.2 GHz via two ring oscillator circuits. The

configuration of beam and ground plate acts as a capacitor C with serial and parallel resistors R (shaded areas).

C and R may vary due to beam bending in the measurement circuit, which is indicated by arrows; both

quantities remain constant, however, during the measurement in the reference circuit. B. Chip photograph,

from which the measurement and reference MEMS can be recognized on top and at the bottom; also the

position of the different components on the chip for the signal transduction cascade are indicated. C. Transient

of the measurement parameter switching time t

for test solutions with varying glucose concentration c

and

temperature T as well as D. gauge curves t

) derived from them with T as a parameter.

Figure 11. A. Schematic drawing of real and imaginary part ε‘ and ε“ of an aqueous protein solution

. The

maximum of ε“ around 10

Hz is due to absorbing proteins, while the absorption maximum above 10 GHz is

caused by water molecules. B. Layout of an impedance measurement chip that can be used for the

determination of cell densities. The upper part shows square-sized bond pads, while sensor elements that will

come in contact with the biomilieu are arranged in the middle of the chip. The distance between both was

chosen rather large in order to establish a sufficient blocking of the biomilieu and protecting the electrical

contacts from corrosion. C. Schematic overview of a test field in a 0.25 µm CMOS/BiCMOS technology

occupying an area of 10.7 x 25.9 mm on a 200 mm wafer. There are about 70-120 exemplars of the same test

field to be processed on each wafer of a production lot.

Figure 12. A. General system architecture of a bio-sensor implant. B. PCB of with microcontroller µC, radio

module (ZL70321) and ZIF connector for connecting to sensor chip. The lateral extension of 27 mm fits to that

of the battery positioned below. C. 3D integration scheme for antenna (1), sensor probe (2), flexible cable for

connecting to ZIF (3), printed circuit board (4), antenna adapter (5), µC (6), battery (7) and distance holder (8).

D&E. Top and bottom view of a silicone-encapsulated biosensor implant. The sensor probe is positioned in the

middle of the system in the left figure; in the picture to the right one may recognize the D-shaped battery

through the silicone. The outer dimensions of the implant amount to 38.6 × 49.3 × 15.5 mm.

Figure 13. Autonomous sensor capsule for application in photo-bioreactor with algae cultivation. A. Outward

appearance; B. configuration of sensor surfaces on equatorially positioned PCB; C. photographs of both sides of

the PCB: with microcontroller and transceiver (left) and sensor field (right). The semi-sphere above the sensor

field is permeable to the cultivation broth, while the opposite side is impermeable as is the PCB layer

Figure 14. Approach for microfluidics integration into microelectronic chips: A. conceptual sketch; B. FEM

simulation of flow; C. cross section micrograph of the produced wafer stack; D. optical microscope view on HF

impedance sensor with microfluidics channel below: unfilled and E. with fluorescence-labeled liquid

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Sustainable use of a smartphone and regulatory needs

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The significance of information and communication technologies (ICT) for the Paris Climate Agreement is continuously increasing because of its growing energy consumption. Here we examine the question for the smartphone and extend the investigation to more aspects of sustainability. Critical issues are identified for ten UN Sustainable Development Goals. Measurements of smartphone energy consumption show that a significant savings potential can be unlocked by reducing the data outflow and the large amount of personal data stored in data centers. Main discrepancies are also traced to the oligopolistic market structure of operating systems (OSs), messenger services, and social media apps. Technical means for a sustainable smartphone use are suggested as alternative OSs, social media channels of the Fediverse, as well as free and open‐source software. Finally, societal conditions are emphasized to make the market for OSs and apps more diverse so that a sustainable smartphone use can generally prevail.

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New techniques are revolutionizing single-cell research, allowing us to study microbes at unprecedented scales and in unparalleled depth. This review highlights the state-of-the-art technologies in single-cell analysis in microbial ecology applications, with particular attention to both optical tools, i.e., specialized use of flow cytometry and Raman spectroscopy and emerging electrical techniques. The objectives of this review include showcasing the diversity of single-cell optical approaches for studying microbiological phenomena, highlighting successful applications in understanding microbial systems, discussing emerging techniques, and encouraging the combination of established and novel approaches to address research questions. The review aims to answer key questions such as how single-cell approaches have advanced our understanding of individual and interacting cells, how they have been used to study uncultured microbes, which new analysis tools will become widespread, and how they contribute to our knowledge of ecological interactions.

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Nucleoside analogues are important compounds for the treatment of viral infections or cancers. While (chemo-)enzymatic synthesis is a valuable alternative to traditional chemical methods, the feasibility of such processes is lowered by the high production cost of the biocatalyst. As continuous enzyme membrane reactors (EMR) allow the use of biocatalysts until their full inactivation, they offer a valuable alternative to batch enzymatic reactions with freely dissolved enzymes. In EMRs, the enzymes are retained in the reactor by a suitable membrane. Immobilization on carrier materials, and the associated losses in enzyme activity, can thus be avoided. Therefore, we validated the applicability of EMRs for the synthesis of natural and dihalogenated nucleosides, using one-pot transglycosylation reactions. Over a period of 55 days, 2′-deoxyadenosine was produced continuously, with a product yield >90%. The dihalogenated nucleoside analogues 2,6-dichloropurine-2′-deoxyribonucleoside and 6-chloro-2-fluoro-2′-deoxyribonucleoside were also produced, with high conversion, but for shorter operation times, of 14 and 5.5 days, respectively. The EMR performed with specific productivities comparable to batch reactions. However, in the EMR, 220, 40, and 9 times more product per enzymatic unit was produced, for 2′-deoxyadenosine, 2,6-dichloropurine-2′-deoxyribonucleoside, and 6-chloro-2-fluoro-2′-deoxyribonucleoside, respectively. The application of the EMR using freely dissolved enzymes, facilitates a continuous process with integrated biocatalyst separation, which reduces the overall cost of the biocatalyst and enhances the downstream processing of nucleoside production.

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A compact integrated circuit is an intellectual property core at the heart of the decades of embedded devices on embedded systems. Using a microcontroller-based electronic module manufactured as desired or direct service of the board of Arduino as a control system for many purposes has become a certainty. Defining the problem formulations is related to the manufacture, assembly of the mechanical apparatus, and integrated wiring of several electronic modules. The acquisition of research contributions is expected to get the miniature embodiment of the physical machine equipped with a user program and perform the machine driver. The research methods consist of several steps to carry out each research objective. The miniature embodiment is carried out through (i) manufacturing and assembling to obtain the physical machine, (ii) integrating the electronic modules and all components and support systems by wiring to form an embedded system as a mini-PCB printing machine, and (iii) making a program structure based on Arduino IDE. Performing the machine driving mechanism is operating tests of calibration and moving on the axes of X, Y, and Z. Concluding based on the implementation process, testing, and analysis are carried out that the stages for performing the Mini PCB Printing Machine assisted by Arduino board with driven by GRBL Gru can be realized according to the initial design of hardware and software design.

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Microalgae constitute an abundant source of poly-unsaturated fatty acids which are applied in various biotechnological fields such as pharmaceuticals and food supplement. Separating microalgae cells with respect to their lipid content would establish a relevant at-line analytical technique. The present study demonstrates an electrical approach for the separation of the lipid-producing microalgae Crypthecodinium cohnii using the effect of dielectrophoresis (DEP) in a microfluidic flow cell. Microalgae were cultivated for 8 days, while cell growth was characterized by optical density, dry cell weight, glucose concentration and lipid content via fluorescence microscopy. The size distribution of cells during cultivation was thoroughly investigated, since the DEP force scales with cell volume, but also depends on lipid content via cell electrophysiological constants. Thus, the challenge was to deconvolute one separation effect from the other, while the electrical cell constants of C. cohnii are not known yet. The DEP-dependent separation was realized by slanted top-bottom electrodes with the flowing cell suspension between them. Turning on the voltage deflected the cells from their initial path as determined by the streaming and thus changed their direction of flow. The separation efficiency of DEP was tested for various electrical field strengths and its performance was determined by quantitative analysis of optical and fluorescence videos. It could be shown for all size groups that the most lipid-containing cells were always subject to DEP separation and that the method is thus not only suitable for process analysis, but also for strain selection of the most productive cell lines.

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Full-text available

Nov 2020

In this work we study the influence of dielectric surface and process parameters on the geometry and electrical properties of silver electrodes obtained by electrohydrodynamic inkjet printing. The cross-section and thickness of printed silver tracks are optimized to achieve a high conductivity. Silver overprints with cross-section larger than 4 µm 2 and thickness larger than 90 nm exhibit the lowest resistivity. To fabricate electrodes in the desired geometry, a sufficient volume of ink is distributed on the surface by applying appropriate voltage amplitude. Single and multilayer overprints are incorporated as bottom contacts in bottom gate organic field-effect transistors (OFETs) with a semiconducting polymer as active layer. The multilayer electrodes result in significantly higher electrical parameters than single layer contacts, confirming the importance of a careful design of the printed tracks for reliable device performance. The results provide important design guidelines for precise fabrication of electrodes in electronic devices by electrohydrodynamic inkjet printing.

An Approach to Ring Resonator Biosensing Assisted by Dielectrophoresis: Design, Simulation and Fabrication

Article

Full-text available

Oct 2020

The combination of extreme miniaturization with a high sensitivity and the potential to be integrated in an array form on a chip has made silicon-based photonic microring resonators a very attractive research topic. As biosensors are approaching the nanoscale, analyte mass transfer and bonding kinetics have been ascribed as crucial factors that limit their performance. One solution may be a system that applies dielectrophoretic forces, in addition to microfluidics, to overcome the diffusion limits of conventional biosensors. Dielectrophoresis, which involves the migration of polarized dielectric particles in a non-uniform alternating electric field, has previously been successfully applied to achieve a 1000-fold improved detection efficiency in nanopore sensing and may significantly increase the sensitivity in microring resonator biosensing. In the current work, we designed microring resonators with integrated electrodes next to the sensor surface that may be used to explore the effect of dielectrophoresis. The chip design, including two different electrode configurations, electric field gradient simulations, and the fabrication process flow of a dielectrohoresis-enhanced microring resonator-based sensor, is presented in this paper. Finite element method (FEM) simulations calculated for both electrode configurations revealed ∇E2 values above 1017 V2m−3 around the sensing areas. This is comparable to electric field gradients previously reported for successful interactions with larger molecules, such as proteins and antibodies.

Dielectrophoretic separation of blood cells

Article

Full-text available

Aug 2022
BIOMED MICRODEVICES

Microfluidic dielectrophoretic (DEP) devices enable the label-free separation and isolation of cells based on differences in their electrophysiological properties. The technique can serve as a tool in clinical diagnostics and medical research as it facilitates the analysis of patient-specific blood composition and the detection and isolation of pathogenic cells like circulating tumor cells or malaria-infected erythrocytes. This review compares different microfluidic DEP devices to separate platelets, erythrocytes and leukocytes including their cellular subclasses. An overview and experimental setups of different microfluidic DEP devices for the separation, trapping and isolation or purification of blood cells are detailed with respect to their technical design, electrode configuration, sample preparation, applied voltage and frequency and created DEP field based and related to the separation efficiency. The technique holds the promise that results can quickly be attained in clinical and ambulant settings. In particular, point-of-care-testing scenarios are favored by the extensive miniaturization, which would be enabled by microelectronical integration of DEP devices.

Functionalization of Oxide-Free Silicon Surfaces for Biosensing Applications

Article

Full-text available

Nov 2021

As an alternative to standard silicon biofunctionalization protocol based on alkoxysilanes that bind to SiO2 on oxidized silicon substrates, several protocols to form bifunctional interlayers that directly bind to the silicon surface via a strong Si-C bond have been developed during the last decades. These interlayers are more stable, and the lack of an insulating layer between the substrate and the interlayer reduces electric noise in biosensor devices. Si-C monolayers are not yet regularly applied as the protocols are more complex and generally require an inert gas atmosphere. However, a variety of applications and new methods to form bifunctional Si-C interlayers are recently developed. Here, the role these innovative protocols and interlayers play in biofunctionalization of silicon surfaces is reviewed and their applications in electrochemical, microelectromechanical, and optical biosensing are reported. From the analysis of the current situation, it can be concluded that the advantageous properties offered with this approach in many cases more than outweigh the additional processes to form Si-C bonded interlayers and the approach is predicted to expand the applications of future silicon-based biosensors.

Silicon Nitride Stop Layer in Back-End-of-Line Planarization for Wafer Bonding Application

Conference Paper

Full-text available

Nov 2014

We introduce an approach that combines a 3” InP-DHBT transferred-substrate process with a SiGe-BiCMOS process. First, silicon and InP wafers are processed separately in different fabs. The silicon wafer runs through the complete 0.25 μm BiCMOS production process with five metal layers aluminum/tungsten back-end-of-line using silicon dioxide as dielectric. The processing was adapted for the following wafer bond process by planarization of the topmost metal level. This process flow was improved by using a SiN CMP stop layer on top of the metal layer stack, comparable to trench fill planarization. In that way a low surface topography was reached, this guarantees proper bonding results.

Springer Handbook of Condensed Matter and Materials Data

Chapter

Jan 2005

Werner Martienssen Prof

The organization of this section follows a two-step approach. The first step corresponds to searching for the substance of interest, that is, the relevant group of substances. The second step corresponds to the physical property of interest. This section has three subsections, characterized by the groups of the Periodic Table that the constituent elements belong to. The first subsection, Sect. 4.1.1, deals with the elements of Group IV of the Periodic Table and semiconducting binary compounds between elements of this group (IV–IV compounds). The second subsection, Sect. 4.1.2, treats the semiconducting binary compounds between the elements of Groups III and V (III–V compounds); Sect. 4.1.3 treats compounds between the elements of Groups II and VI (II–VI compounds). These two subsections are subdivided further according to the first element in the formula of the compound. The elements and compounds treated in Sect. 4.1.1 (Group IV and IV–IV compounds) are treated as one group; the data in the tables are given for the whole group in all cases. In Sects. 4.1.2 (III–V compounds) and 4.1.3 (II–VI compounds), data are given separately for each subdivision of those subsections. For each group of substances, the physical properties are organized into four classes. These are A.: Crystal structure, mechanical and thermal properties. B.: Electronic properties. C.: Transport properties. D.: Electromagnetic and optical properties.

Autonomous Sensor Capsule for Usage in Bioreactors

Article

Jul 2015

An autonomous biochemical sensor capsule for the remote monitoring of an algae culture cultivated in a photobioreactor is presented. The encapsulated system has a spherical shape with a diameter of 44 mm. Radio communication with a carrier frequency of 433 MHz is used to transfer the acquired sensor data in the bioreactor to a base station outside. Experiments with the first prototype inside the bioreactor filled with nutrient solution were performed to determine the reliability of the communication link. The packet error rate converged to 26% and the path loss on average was 96 dB. The functionality of the signal processing chain of acquired biochemical sensor values was evaluated using an experimental setup. Our second capsule prototype with potentiometric sensors demonstrates the pH-measurements of different buffer solutions dropped on the sensor electrodes with a pipette.

A SiGe BiCMOS Dielectric Sensor utilizing an Open-ended Microstrip Line in a 28 GHz Colpitts Oscillator

Conference Paper

Oct 2014

In this paper, a microwave dielectric sensor is presented using an open-ended microstrip line. It is fabricated in a standard 0.25 μm SiGe BiCMOS process (fT/fmax = 180/220 GHz). A theoretical basis of open-ended microstrip line as dielectric sensor has been proposed and it is used as a permittivity dependent capacitor in the Colpitts oscillator. The sensor distinguishes permittivities ranging from 1 to 20 in the frequency range 26 to 29 GHz. With no material on top of the sensor, oscillation frequency settles at 28.72 GHz. Air, honey, epoxy resin (gray and orange) were used to verify and calibrate the sensor experimentally. In a further step, the sensor has been used to characterize water fraction in supersaturated sugar solution (honey). A sensitivity of 250 MHz/Unit permittivity has been shown. It spans an area of 0.6 mm2 and consumes 4.5 mA from a 3.3 V supply.

Capacitive biosensing of bacterial cells: Analytical model and numerical simulations

Article

Feb 2015
SENSOR ACTUAT B-CHEM

Impedimetric biosensors with a passivation layer, also called capacitive biosensors, have recently shown great promise towards sensitive, selective and rapid detection of pathogen bacterial cells. However, few studies focus on their modeling, yet critical for the optimization of their sensitivity. To address this issue, we propose a comprehensive framework by developing analytical models and 2D numerical simulations of passivated interdigitated microelectrodes (IDEs) with adherent bacterial cells in electrolyte. While models provide a qualitative and semi-quantitative analysis of the AC impedance spectroscopy based on the system cutoff frequencies, Finite Element Method (FEM) simulations based on Poisson-Nernst-Planck equations enable accurate quantification of the sensitivity to bacteria versus the applied frequency thanks to modeling of complex phenomena such as ion transport, surface and space charges, multi-shell bacterial dielectric properties and sensor topology. These numerical simulations are assessed by experimental results and compared to analytical models.

Tunable 500 GHz transmitter-array in SiGe technology for gas spectroscopy

Article

Feb 2015

A 500 GHz system for gas spectroscopy is presented, which includes an integrated SiGe 4x1 transmitter (TX)-array, a Golay cell, and a 1.9 m long gas absorption cell. The local oscillator (LO) of the TX-array is controlled by an external phase-locked loop (PLL), whose reference frequency is swept. The four TX-branches involve frequency quadruplers (x4). The TX-branches are fed by a 120 GHz power division network, which is connected to the LO. The estimated radiated output power of the TX array is 7 dBm at 500 GHz. The absorption spectrum of methanol is shown for 494 – 500 GHz.

Modeling and characterization of BiCMOS embedded microfluidic platform for biosensing applications

Conference Paper

Jan 2014

In this paper, modeling and characterization of BiCMOS embedded microfluidic platform for biosensing applications is presented. The novel process integration scheme with two bonded wafers provides microchannels, accessing to the inlets and the outlets as well as the mm-wave sensor easily. The developed microfluidic platform provides very flexible size of microchannels in BiCMOS chip and it is able to bring the fluid very close to the sensor. A fully integrated 120 GHz dielectric sensor has been used for the demonstration of the platform. The high reproducibility, micron size, high throughput and low-cost process make the presented BiCMOS integrated microfluidic channels as a key platform for bio and THz sensing applications.

An 8 GHz CMOS near field bio-sensor array for imaging spatial permittivity distribution of biomaterials

Conference Paper

Jun 2014

In this paper a CMOS biosensor array operating around 8 GHz is presented, for characterizing biomaterials by imaging the spatial distribution of permittivity. The sensor is fabricated in standard 250 nm SiGe BiCMOS process. The sensor operation is based on the frequency shift of cross-coupled oscillator circuit due to capacitance change of the core LC tank. Non-uniform four finger interdigitated capacitor is used as the sensor unit. A four element sensor array system is used in this work for the proof of concept of spatial dielectric imaging. Measured sensitivity is observed to be 22 MHz per unit permittivity change. After first sensitivity tests, the spatial discrimination capability of the array is shown by further testing the array with biomaterials of different permittivity on different sensor units, showing unique frequency shift for individual sensors.

BiCMOS integrated microfluidic platform for Bio-MEMS applications

Conference Paper

Jun 2014

In this paper, a fully BiCMOS integrated microfluidic platform for bio-MEMS applications is demonstrated. The novel integration process flow provides very flexible size of micro-channels in BiCMOS chip and brings the fluid very close to the sensors. The platform is demonstrated with BiCMOS integrated 120 GHz dielectric sensor and the changes of the dielectric constant of different fluids in the channel are successfully detected. The high reproducibility, small size, high throughput and low-cost process make the presented BiCMOS integrated microfluidic channel technology as a key platform for bio-MEMS and THz-sensing applications.

A 1024-Channel CMOS Microelectrode Array With 26,400 Electrodes for Recording and Stimulation of Electrogenic Cells In Vitro

Article

Nov 2014

To advance our understanding of the functioning of neuronal ensembles, systems are needed to enable simultaneous recording from a large number of individual neurons at high spatiotemporal resolution and good signal-to-noise ratio. Moreover, stimulation capability is highly desirable for investigating, for example, plasticity and learning processes. Here, we present a microelectrode array (MEA) system on a single CMOS die for in vitro recording and stimulation. The system incorporates 26,400 platinum electrodes, fabricated by in-house post-processing, over a large sensing area (3.85 2.10 mm ) with sub-cellular spatial resolution (pitch of 17.5 μm). Owing to an area and power efficient implementation, we were able to integrate 1024 readout channels on chip to record extracellular signals from a user-specified selection of electrodes. These channels feature noise values of 2.4 μV in the action-potential band (300 Hz-10 kHz) and 5.4 μV in the local-field-potential band (1 Hz-300 Hz), and provide programmable gain (up to 78 dB) to accommodate various biological preparations. Amplified and filtered signals are digitized by 10 bit parallel single-slope ADCs at 20 kSamples/s. The system also includes 32 stimulation units, which can elicit neural spikes through either current or voltage pulses. The chip consumes only 75 mW in total, which obviates the need of active cooling even for sensitive cell cultures.

Technology modules from micro- and nano-electronics for the life sciences

Abstract

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