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Lab on a Chip for

Live-Cell ManipulationGianni MedoroSilicon Biosystems

Roberto Guerrieri

University of Bologna

Nicolo Manaresi

Silicon Biosystems

Claudio Nastruzzi

University of Perugia

Roberto Gambari

University of Ferrara

&RECENT ADVANCES IN the life sciences stem from

a convergence of IT and new tools and machines for

large-scale analysis of the structure of DNA, proteins,

and cells. Projects such as the Human Genome Project

are striking examples of the power of this conver-

gence. Although these projects have demonstrated the

possibility of obtaining information directly from DNA,

its clear that the complexity of this task is enormous

and far from achievable with our limited understand-

ing of the basic processes that translate DNA into

structures. Fortunately, IT can provide a bridge be-

tween DNA and cells, considered here as the basic

building blocks of any complex living being.

In this article, we examine the new microelectronic

technology that gives scientists the ability to monitor,

sort, and analyze vast populations of cells and interact

with each cell individually. A microelectronic platform

called a lab on a chip (LoC) allows precise

manipulation of cells with no effect on their pheno-

types. The motivation for developing this technology is

that investigations in recent years have shown that

a few cells changing their behavior unexpectedly can

induce deadly diseases such as cancer. Current LoC

design and manufacturing techniques are spawning

new biotechnology methods with potential for re-

search, diagnosis, and therapy. Whetherthe new techniques will meet the

challenge remains to be seen, but the

urgent need to find these answers is

clear.

Dielectrophoresis principlesSeveral approaches to cell manipu-

lation in LoCs use dielectrophoresis (DEP), which in

some cases can substitute for or integrate with fluidic

technologies and perform complex analytical-protocol

steps in miniaturized devices. Pioneered by Pohl,

dielectrophoresis is the physical phenomenon where-

by neutral particles, in response to a spatially non-

uniform electric field (E), experience a net force

directed toward locations with increasing or decreas-

ing field intensity according to the physical properties

of the particles and the medium.13 When the force is

directed toward locations with increasing field in-

tensity, it is called positive dielectrophoresis (pDEP);

in the second case, it is called negative dielectrophor-

esis (nDEP). Figure 1 shows the basic principle

supporting the motion of neutral particles by dielec-

trophoresis. The theory states that the DEP forces

direction is independent of the sign of the voltages that

energize the electrodes. This is a fundamental property

of dielectrophoresis because it allows the use of time-

varying (AC) signals to avoid the drawbacks con-

nected with DC or low-frequency signals (for example,

electrolysis).

Switching the frequency of the electrical stimuli

causes the transition from negative to positive dielec-

trophoresis. In fact, there is a relationship between

Editors note:

Precisely manipulating and sorting live cells on a lab on a chip is still a major

challenge. This article shows how to use dielectrophoresis for cell sorting. The

authors also describe a prototype CMOS chip with a sensor-actuator array,

row-column addressing logic, and readout circuitry.

Krishnendu Chakrabarty, Duke University

Biochips

0740-7475/07/$25.00 G 2 00 7 IE EE Co pu bli shed by t he IE EE CS an d the I EEE CA SS IEEE Design & Test of Computers26

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dielectrophoretic force and stimulus frequency for any

specific kind of particle or cell.4 Graphs called

dielectrophoretic spectra plot such relationships.

Scientists have exploited this property to separate

different cell species.5,6

For spherical geometries, the first-order expression

of time-averaged DEP forces is

~FFDEP x,y,z, v ~ 2pe0emR3< fCM v f g~++E2rms

where e0 is the vacuum dielectric constant, em is the

medium dielectric constant, R is the particle radius,

Erms is the root-mean-square value of the electric

field, v is the angular frequency, R is the real part, and

fCM(v) is the Clausius-Mossotti factor. The latter is

a function of the complex permittivity of the particle

and medium, and is defined as

fCM v ~e

p v e

m v

ep v z 2em v

where ep v and em v are the complex permittivity of

particle and medium, defined as

ep v ~ ep z sp=jv

and

em v ~ em z sm=jv

whereep/mis the dielectric permittivity, and sp/mis the

conductivity. For nDEP, R

{fCM

(v)} ,

0; for pDEP,

R{fCM(v)} . 0. The electric fields minima corre-

spond to the attraction regions of nDEP, and the

maxima correspond to the attraction regions of pDEP.

The tiny dimensions of electrodes available

through microlithography make it possible to realize

very high field gradients with low voltages (compatible

with microelectronic circuits). As a result, dielectro-

phoresis can manipulate microscopic neutral particles

such as cells or bacteria, whose dynamics aregoverned by the balance between the DEP force and

the effects of viscous friction. To estimate the effects of

this force on cells, we define the approximate

instantaneous velocity of a particle in a fluidic

medium as

~vvDEP~ ~FFDEP= 6pgR

where g is the medium viscosity. We can also define

a dielectrophoretic mobility:

mDEP~ (2e0em

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mobility, and a squared relationship with the ap-plied potentials.

From these equations, it follows that we can

improve the dynamics simply by increasing the field

gradient (by reducing the electrodes feature size);

decreasing the particle size strongly reduces the

dynamics, thereby limiting the dimension of thesmallest particles that can be manipulated.

Researchers have exploited this property to de-

velop an effective approach to separation and size

characterization of bioparticles.8 The novelty of the

approach is that it doesnt require fluid flow, using

moving dielectrophoretic cages instead. A dielectro-

phoretic cage is generated when an electric-field

configuration induces dielectrophoretic forces that

capture particles. By sequencing a set of cage patterns

in a microfabricated chip, we can selectively impart

a movement to bioparticles, depending on the ratiobetween dielectrophoretic mobility and cage speed.

Dielectrophoresis-based LoCsStudies of DEP action on biological or inorganic

matter suggest the use of dielectrophoresis not only to

sort cells but also to characterize them by differences

in physical properties, or, in general, to manipulate

them.9 For example, Suehiro and Pethig use both

pDEP and nDEP to precisely displace cells in

a microchamber formed between two facing glass

chips with elongated electrodes.10 The main drawbackis that cells contact device surfaces and usually stick to

them. Levitating the cells during manipulation can

overcome this problem. Because the electric fields

maxima cannot be established away from the elec-

trodes, stable levitation is possible only with nDEP

force. Hence, researchers have proposed using closed

nDEP cages. Muller et al. use 3D structures of elec-

trodes located at the vertexes of a cube for this

purpose.11 This techniques main limitation is that it

requires fluid flow to lead cells into and out of the DEP

cage. As an alternative to fluid flow, Huang et al. use

traveling waves combined with nDEP to move cells in

a microchamber.12 However, its difficult to position

cells as precisely as required by multistep experimen-

tal protocols, because cell speed depends on cell type.

Another approach to cell manipulation is the

moving cages mentioned earlier.13 This approach

combines the advantages of stable cell levitation and

the use of planar technologies. It relies on the

possibility of creating large arrays of electrodes

separated from the biological liquid by a thin (a few

nanometers) dielectric layer that avoids electrolytic

effects and contamination caused by metals. These

electrodes are polarized to create dielectrophoretic

cages that effectively trap particles. Because the

applied potentials are generated under software

control, cages can be flexibly generated within themedium. Several studies have proved the effectiveness

of this approach for implementing complex applica-

tion protocols.14,15 The devices studied used standard

technologies ranging from a PCB to a CMOS de-

vice.6,16,17 In the last case, small electrodes, comparable

in size to cells, trap single particles, keep them

levitated, and drag them across the entire chip surface.

In general terms, a dielectrophoresis-based LoC

consists of two juxtaposed main modules. The first

module contains a plurality of electrodes regularly

arranged on a substrate (if this module is realized in

the CMOS process, it can include memory elements

and sensors). The second module consists of a single

large electrode fabricated in a conductive, preferably

optically transparent material. Figure 2 shows a CMOS

chip for single-cell manipulation.

A spacer inserted between the upper and lower

modules creates a chamber that contains the sample to

be analyzed or manipulated. The same spacer can also

establish separation walls in thedevice to create multiple

chambers optionally connected by dedicated ports.

8.1 mm

7.8mm

Figure 2. CMOS chip for single-cell manipulation

by dielectrophoresis (Source: Manaresi et al.16).

An electronic circuit is associated with each

element of an array of 100,000 electrodes to

program the location of up to 10,000 closed

DEP traps.

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CMOS design constraints and specifications

The CMOS device mentioned earlier is optimized

for handling eukaryotic cells (such as the lymphocytes

in blood) in the range of 10 to 20 microns in

diameter.16,17 A design guideline derived from an

analysis of simulated horizontal DEP forces as

a function of particle size with respect to theelectrodes suggests that the electrode pitch should

be similar to the cell size. Increasing the cages width

to encompass more than one electrode enables the

device to handle larger particles. Increasing the

number of electrodes in the array increases the

devices capacity (number of cells in the input

sample) and selectivity (ability to select a smaller

percentage of cells).

However, silicon cost increases with chip size.

Accordingly, the designers of the device chose the

total number of cages to be on the order of 10,000. This

is sufficient to recover a significant number of cells (10

to 100) that may be present in a low percentage (0.1%

to 1%) in the starting sample. At the same time, the

chip size (8 3 8 mm2) is reasonable.

The time constants for cell motion caused by DEP

forces arerelatively slow (about one second or more for

a 20-micron step). This relaxes timing constraints for

array programming, as well as forthesensing frame rate.

Fabrication and technology constraints

To choose the most appropriate CMOS technology,

the device designers took the following considerations

into account. Because the DEP force is proportional to

the square of the voltages applied, the supply voltage

should be as large as possible, to limit actuation

voltages. In contrast to conventional IC designs, the

lower the technology resolution, the lower the chip

cost, because die size is set from other specifications

related to cell size. Scaling beyond the point at which

the required number of transistors fits in the microsite

area doesnt improve cost or performance. Scaling is

required only for manipulating smaller cells, such as

individual bacteria (which are typically 1,000 to

3,000 nm in diameter) or viruses (100 to 300 nm in

diameter).

In addition, LoC designers must consider some

constraints that are unusual for electronic designers.

For example, they must pay attention to the effects

of contact of the liquid sample with the top metal

electrodes. Excessive chip passivation thickness can

limit the electric fields capability to penetrate the

liquid at the desired operation frequency, especially

when biological science specifies the liquids con-

ductivity at rather high levels (for example, the

physiological solution has a conductivity of greater

than 1 siemens/meter. Fortunately, process options

that reduce this thickness to a few nanometers are

available.

Other typically biological aspects such as auto-fluorescence of materials used are also involved. In

fact, background fluorescence from the chip surface

can impair the chips ability to detect a weak signal

for example, from fluorescently labeled antibodies

typically used to identify key cells in many biological

protocols.

Another limitation of CMOS technology is the

silicon dies opaqueness. To overcome this limitation,

researchers have proposed an approach to the

massively parallel individual manipulation of biopar-

ticles that is compatible with transistorless and trans-

parent chips.18 They have built a prototype micro-

system using gold and indium tin oxide (ITO) on glass

to implement a 2D array of microsites, establishing

hundreds of dielectrophoretic microtraps. Each trap

can gain control over an individual cell (or mi-

crobead) and can be reconfigured by software to

transfer the cell to any adjacent trap. This approach

allows digital control of the movement of many

individual cells along different paths. Figure 3 shows

a diagram of the transparent chip.

Unlike solutions using optical or optoelectronic

tweezers,19 this approach doesnt require external

bulky instruments, and it manipulates cells without

contactwhich is impossible with transistorless tech-

niques, such as those based on positive dielectrophor-

esis.10 Its main limitation is the high number of signal

controls, which is comparable to the square root of the

maximum number of traps.

Other cell manipulation techniques, including

optical tweezers,20 magnetic tweezers,21 acoustic traps,

and hydrodynamic flows, have severe limitations if

both high throughput and high resolution are required.

Researchers have proposed another cell manipulation

technique, which combines optical images and

dielectrophoresis for parallel manipulation of many

individual cells.22 This technique requires a bulky

external instrument and is therefore not suitable for

point-of-care applications.

Packaging LoC devicesIntegrating microelectronics and biology requires

the construction of a hybrid technology with adequate

JanuaryFebruary 2007 29

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fluid transport capabilities. Thus, researchers have

introduced the concept of microfluidics, the building

block of integrated LoCs. Vulto et al. describe an

example of this process integration.23 They propose

using Ordyl SY300/550 dry film resist (DFR) from Elga

Europe to build microfluidic structures. DFR, originally

developed for PCB fabrication, offers many advan-

tages over liquid resist: conformability, adhesion to

any substrate, flatness, no liquid handling, no edge

bead formation, uniform distribution, low exposure

energy, low cost, short processing time, and near-

vertical sidewalls.24 DFR is an excellent material for fast

prototyping of fluidic structures. Its low number of

simple processing steps make DFR ideal for industrial

applications as well, particularly because the process-

ing steps are fully compatible with CMOS silicon

technology. Moreover, manufacturers can perform

DFR processing on a full wafer scale with great

advantages for mass production over conventional

microfabrication techniques. Figure 4 shows photos of

resist structures on a silicon substrate. (These struc-

tures are examples of building blocks used in several

common situations.) The smallest reproducible

features for freestanding

structures are 20 microns

wide for a resist thickness

of 54 microns. The smal-

lest gap dimension for the

same parameters is 40

microns wide.An alternative tech-

nique for creating micro-

fluidic prototypes is poly-

dimethylsiloxane (PDMS)

molding. PDMS allows

easy sealing and fast fa-

brication of complicated

structures.25 Other com-

monly used fabrication

techniques are glass wet

etching,26 silicon etching,27

and polymer molding us-

ing the LIGA technique

(LIGA is an acronym for

the German words for x-

ray lithography, electro-

forming, and molding).28

Fluidic structures can also

be sandwiched between

two processed substrates.

The most common method of making such hybrid

chips is to pattern the fluidic structures in SU-8

photoresist.29,30 UV-laser-photoablated polymers,31 CO2-

laser-engraved polymers, and even double sticky

tape32 have also been reported suitable for creating

fluidic gaskets. SU-8 has advantages over the other

techniques in resolution and in requiring no additional

adhesives for double-bonding the substrate.

Whatever the technology used to realize an LoC,

the device must move a biological sample through the

channels of a microfluidic circuit to load the sample or

recover selected cells. One mechanism proposed for

this liquid transport is the micropump, a device that

can move volumes of liquid in the micro-to-nanoliter

range. So far, the use of this mechanism is limited,

mainly because micropumps with the right combina-

tion of cost and performance are unavailable.33

In most cases, scientists achieve liquid transport in

microfluidic chips through manual pipetting with

external pneumatic sources or through electro-osmot-

ic flow. To selectively recover separated particles, they

use a double pipette that establishes a laminar flow in

the separation chamber and recovers two halves of the

Figure 3. Fully transparent chip using a glass substrate for single-cell manipulation by

dielectrophoresis (Source: Medoro et al.18 Reproduced with permission). The cell

manipulation approach is based on the changing phases of the stimuli applied to rows

and columns. With N + M control signals, the array can control up to N 3M cells.

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sample liquid.34 In this

case, interface hole dia-

meters are adapted to the

pipette tips size, enabling

liquid actuation by pipette

pressure. Because the sep-

aration mechanism is verysensitive to unwanted liq-

uid flow, scientists prevent

hydrostatic flow by direct-

ly inserting the sample

into the chamber. They

control the resulting liq-

uid-air interface by intro-

ducing phase guides (reg-

ular spatial structures

characterized by different

wettability that can create

a precise movement di-

rection of the fluid). This

technique is excellent for

recovering spatially separated particles and requires

minimal surface area for microfluidics. This is

especially important with expensive silicon chip

technology. Figure 5 shows an example of a working

LoC designed as just described.

Biotechnological LoC applicationsLoC devices offer a unique opportunity for in-

tegrating complex protocols on single miniaturized

platforms. The platforms combine sophisticated

sensing and computational technologies in miniatur-

ized analytical instruments for manipulating single

living cells or cell populations. Reproducing a com-

plete biological experiment on a single cell, the

smallest living element, can provide scientists with

exclusive deterministic information rather than the

statistical results so far available with conventional

laboratory procedures. The ability to manipulate cell

populations enables scientists to perform programmed

interactions between cells, or between cells and

microspheres, without requiring complex laboratory

toolsenabling new experimental plans as well as

diagnostic procedures. This explains scientists grow-

ing interest in exploiting microelectronics in combi-

nation with live biological matter.

Cell isolation

Researchers have reported on using DEP-based LoC

platforms to isolate cell populations or single cells.15,35

Isolating rare cells from biological fluids, such as

whole blood and bone marrow, would provide new

scope for cell-based diagnosis, cell-based therapy, and

phenotypic characterization of cell population sub-

sets. For instance, characterizing a few metastatic

cancer cells for the purpose of further molecular

analysis can play an important role in the diagnosis

and prognosis of cancer patients. Isolating so-called

Figure 5. A working LoC (a CMOS biosensor-

actuator for cell analysis). The LoC developers

implemented the fluidic microchamber

packaging by double-bonding the ITO-coated

glass, patterned with dry-resist film, to a CMOS

chip. (ITO is indium tin oxide.)

Figure 4. Resist structures on a silicon substrate, with exposure energy 150 mJ/cm2

,

85uC/(5 min): castellated channels with 50-micron dimensions (a); square and round

pillars with dimensions of 50 and 20 microns (b). Insets show detailed top views (Source:

Vulto et al.23 Reproduced by permission of The Royal Society of Chemistry).


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cancer stem cells might lead to diagnostic and

therapeutic innovations.

Yu et al. describe an application of DEP-based

protocols to cell isolation.35 They have developed an

efficient method for trapping neurons and construct-

ing ordered neuronal networks on bioelectronic chips

using arrayed nDEP forces. According to their pro-tocol, neurons adhere and are then cultured directly

onto the bioelectronic chip, exhibiting good neuron

viability and neurite development.

Cell population separation

Huang et al. describe a dielectrophoretic field-flow-

fractionation method for purging human breast cancer

cells from hematopoietic stem cells.36 The same group

also demonstrated high performance in separating

human blood cells: T or B lymphocytes from mono-

cytes, T or B lymphocytes from granulocytes, and

monocytes from granulocytes.

Another interesting application is using dielectro-

phoresis to separate viable from nonviable yeast

cells. Researchers used known mixtures of viable

and heat-treated cells of Saccharomyces cerevisiae

(bakers yeast) with 60% nonviable cells present; the

results demonstrated that the DEP-separated non-

viable portion contained only 3% viable cells, and

the viable portion contained 8% dead cells. Impor-

tantly, the separation procedure didnt affect cell

viability.

Another example is using DEP-based LoCs to

isolate infected cells from noninfected counterparts.

LoC platforms carrying spiral electrodes can isolate

malaria-infected cells from blood. Parasitized cells

cluster at the center of a spiral electrode array

because during development of Plasmodium falci-

parum (the malaria pathogen), the ionic permeabil-

ity of the plasma membrane of infected erythrocytes

increases.

Borgatti et al. have demonstrated the application

of a PCB-based chip to generating DEP-based

cylinder-shaped cages for separation and recovery

of white blood cells from erythrocytes.37 This work is

an important contribution to developing low-cost

LoC devices for diagnostic purposes. The researchers

showed that white blood cells recovered from their

LoC are suitable for polymerase-chain-reaction-based

molecular-diagnosis procedures using DNA sequenc-

ing, or biospecific-interaction analysis based on

surface plasmon resonance and biosensor technol-

ogy.

Marker-specific rare-cell sorting

Most of the available high-speed cell-sorting tech-

niques, especially for isolating rare cells, are limited by

parameters such as throughput, purity, and rare-cell

recovery. One approach for efficiently isolating

marker-specific rare cells from complex mixtures is

an electrokinetic sorting methodology exploiting DEPin microfluidic channels.38 This approach modulates

the dielectrophoretic amplitude response of rare target

cells by labeling cells with particles that differ in

polarization response.

A second approach is DEP-based routing of

identified rare cells to selected recovery fields of the

LoC platform. In this case, the cells might be identified

through fluorescence labeling using monoclonal

antibodies. Fuchs et al. provide a proof of principle

of this strategy.39 They demonstrated the sorting and

recovering of specific live cells from samples contain-

ing less than a few thousand cells. An important

feature of this approach is that the cells maintain

viability and proliferation ability. The LoC manipulated

cells using dynamic dielectrophoretic traps controlled

by an electronic interface.

Pharmaceutical LoC applicationsMicrofluidic technologies that improve the cost-

effective productionof established drugs haveprovided

significantbenefitssuchasimprovedsafetyandefficacy,

increased patient compliance, greater ease of use, and

expanded indications. Pharmaceutical scientists use

LoC platforms to control single biological objects,

including liposomes or microspheres immersed in

a liquid overhanging and in contact with the chip.

Two important classes of microparticles are micro-

spheresandliposomes.Thefirstclasscomprisesparticles

characterized by a rigid structure made of biocompat-

ible materials. A common use of microspheres is the

activation of their surface with compounds that have

a well-defined biological activity when in contact with

cell membranes. Liposomes are lipidic shells that

contain chemical compounds, such as drugs. A useful

property of liposomes is that when properly prepared

they release their content into the cell cytoplasm.

Microparticles for LoC applications

We classify microparticles by size: Large micro-

particles are more than 100 microns in diameter,

medium microparticles are from 10 to 100 microns in

diameter, and small microparticles are less than 10

microns in diameter.

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Several types of microparticles are suitable for LoC

preparation, including experimental laboratory-made

microparticles specifically tailored to selected applica-

tions. Many types of special microparticles are

commercially available. They consist of materials such

as polystyrene, silica, melamine, glass, magnetite,

carboxymethylcellulose, biodegradable polymers, tri-

glycerides, partial glycerides, fatty acids, steroids, and

waxes. To produce microparticles, pharmaceutical

companies use experimental approaches such as

solvent extraction,40 melt dispersion and solvent

evaporation,41 ultrasound, high-shear and high-

pressure homogenization,42 air jet milling,43 coacerva-

tion,44 salting out,45 fluid bed coating (hot air

coating),46 and spray drying.47 In addition, many

companies supply fluorescent or dye-loaded micro-

particles. Most microparticles are supplied in deio-

nized water and have a shelf life of several years at 4uC.

Biodegradable microparticles, such as starch-based

microparticles, have a shorter shelf life.

Researchers have tailored some classes of micro-

particles, including lipospheres and cellulose acetate

microspheres, for specific LoC applications.48,49 They

found that the dimensions of microparticles play a very

important role. Accordingly, the researchers tested

stabilizers and plasticizers to obtain useful micropar-

ticle characteristics.

Microparticle-cell interactions

The current literature contains a few examples of

LoC applications of microparticles. For example,

Borgatti et al. showed that an LoC can achieve

software-guided interactions between microspheres

and target cells.37 The DEP-based device used parallel

electrodes to force interactions between microspheres

and K562 (human leukemia) cells, after moving them

to the central electrode in the corresponding DEP

cage.

Figure 6 shows an experiment demonstrating that

an LoC is suitable for directing single microspheres to

a single identified target cell.50 The figure shows three

cationic microspheres (M1, M2, and M3) and two

K562 cells, entrapped in five independent spherical

DEP cages. Only one of the two cells was the three

Figure 6. Programmed sequential interactions (a-c) between three cationic microspheres (M1, M2, and M3) and one

target K562 cell. Moving M1 produced the K562-M1 complex (d). Moving M2 and M3 produced the K562-M1M2 (e)

and K562-M1M2M3 (f) complexes (Source: Borgatti et al.50 Reprinted with permission).


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microspheres cellular target. The device first moved

microsphere M1, generating the cell-microsphere

complex shown in Figure 6d; then it moved micro-

sphere M2, generating the K562-M1M2 complex shown

in Figure 6e. Finally, it moved microsphere M3 for

a further targeting of the K562 cell, obtaining the K562-

M1M2M3 complex shown in Figure 6f. The bufferemployed was 280 milliMolar (mM) mannitol and

6.5 mM potassium chloride. The experimental condi-

tions were 50 kHz for the AC electric field used to

create dielectrophoretic patterns, and 37uC for the

supernatant. The passivation layer provides protection

against metal contamination and inhibits electrolysis.

THE BENEFITS OF CARRYINGout experiments based on

single cells open new horizons in several key fields,

although the implications of this novel source of

information are still poorly understood. In general,

variability has always been a hallmark of living beings,

and scientists have tended to manage it with statistical

techniques. We hope that understanding the deviant

behavior of unique renegade cells will provide the

key to diagnosis and therapy for pathologies that still

lack adequate treatments. &

AcknowledgmentsOur work is supported by FIRB-2001 (Italian

Fund for Basic Research, of the Italian Ministry of

Education), Development of a Lab on a Chip Based

on Microelectronic Technologies and Its Biotech-

nological Validation, to Roberto Guerrieri, Roberto

Gambari, and Claudio Nastruzzi. Our research is

also supported by the Italian Foundation for Cystic

Fibrosis, the Italian Association for Cancer Re-

search, and the Veneta Association for the Fight

against Thalassaemia. Funding from the European

Commission for the eInfrastructure for Thalassae-

mia Research Network is gratefully acknowledged.

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Gianni Medoro is cofounder and

chief scientific officer of Silicon Bio-

systems, in Bologna, Italy. His re-

search interests include lab-on-a-chip

modeling and design. Medoro has

a PhD in electrical engineering and computer science

from the University of Bologna.

Roberto Guerrieri is a full pro-

fessor and teaches design of in-

tegrated systems at the University of

Bologna. His research interests in-

clude IC modeling and design, in-

cluding digital systems and biometric sensors, and

applications of microelectronics to biotechnology.

Guerrieri has a PhD in electrical engineering from

the University of Bologna.

Nicolo Manaresi is cofounder and

chief technology officer of SiliconBiosystems. His research interests

include analog design, fuzzy systems,

integrated sensors, and microelec-

tronic devices for analysis and manipulation of

biological particles. Manaresi has a PhD in electrical

engineering from the University of Bologna.

Claudio Nastruzzi is an associate

professor in the Department of Chem-

istry and Pharmaceutical Technology

at the University of Perugia, Italy. He

also heads the universitys Laboratory

of Biomaterials and Bioencapsulation. His research

interests include drug delivery microsystems, nerve

repair conduits, microparticle application to lab-on-a-

chip systems, lipospheres, and multifunctional micro-

capsules for cell entrapment. Nastruzzi has a PhD in

pharmaceutical sciences from the University of

Ferrara, Italy.

Roberto Gambari is a full professor

of biochemistry, chair of the PhD

program in biotechnology, and direc-

tor of the Biotechnology Center at the

University of Ferrara. His research

interests include pharmacogenomic and gene thera-

py of thalassaemia, molecular diagnosis, regulation

of gene expression, and transcription alteration using

decoy molecules and peptide nucleic acids. Gambari

has a PhD in biological sciences from the University

of Rome.

&Direct questions or comments about this article to

Roberto Guerrieri, ARCES University of Bologna, Viale

Pepoli 3-2, 40136 Bologna, Italy; roberto.guerrieri@

unibo.it.

For further information on this or any other computing

topic, visit our Digital Library at http://www.computer.org/

publications/dlib.

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