[IEEE 2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS) - Taipei, Taiwan (2013.01.20-2013.01.24)] 2013 IEEE 26th International Conference on Micro
[IEEE 2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS) - Taipei, Taiwan (2013.01.20-2013.01.24)] 2013 IEEE 26th International Conference on Micro
[IEEE 2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS) - Taipei, Taiwan (2013.01.20-2013.01.24)] 2013 IEEE 26th International Conference on Micro
[IEEE 2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS) - Taipei, Taiwan (2013.01.20-2013.01.24)] 2013 IEEE 26th International Conference on Micro

[IEEE 2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS) - Taipei, Taiwan (2013.01.20-2013.01.24)] 2013 IEEE 26th International Conference on Micro

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  • PIEZORESISTIVE MEMBRANE-TYPE SURFACE STRESS SENSOR

    ARRANGED IN ARRAYS FOR CANCER DIAGNOSIS THROUGH

    BREATH ANALYSIS

    Frdric Loizeau1, Hans Peter Lang

    2, Terunobu Akiyama

    1, Sebastian Gautsch

    1, Peter

    Vettiger1, Andreas Tonin

    2, Genki Yoshikawa

    3, Christoph Gerber

    2 and Nico de Rooij

    1

    1Ecole Polytechnique Fdrale de Lausanne, Switzerland

    2University of Basel, Switzerland

    3National Institute for Materials Science, Japan

    ABSTRACT

    We present the fabrication, characterization and

    successful medical application of a membrane-type

    surface stress sensor (MSS), arranged in arrays for

    molecular detection in gaseous phase. Made out of

    SOI substrate, a round membrane with a diameter of

    500 m and a thickness of 2.5 m is suspended by

    four sensing beams with integrated p-type

    piezoresistors, composing a full Wheatstone bridge.

    The membrane is coated with a thin polymer layer,

    which reacts with volatile molecules and produces a

    deflection of the membrane. The membranes were

    functionalized with various polymers and

    characterized as humidity sensors with a sensitivity of

    87 mV/%RH and a time constant (Tau63%) of 1.3 s.

    Finally, through breath analysis and the use of

    principal component analysis (PCA), we were able, in

    a double blind trial, to distinguish cancer patients and

    healthy persons.

    INTRODUCTION

    While cancer is still one of the most lethal

    diseases in the world, it is mostly highly curable if

    detected early. Cancer diagnosis is usually performed

    by endoscopy and taking a biopsy of suspect lesions.

    In order to reduce the complexity and the risks of

    such operations, non-invasive diagnosis tools are

    proposed using cantilever sensors [1]. The major

    sensing principle is based on analyte-induced surface

    stress, which makes a cantilever bend. Volatile

    organic compounds (VOCs) related to certain

    diseases [2], e.g. head and neck or lung cancer, can be

    detected.

    In the perspective of point-of-care systems or

    sensor networks, the bulky experimental setups

    placed in laboratories need to be reduced in size to fit

    in portable and easy-to-handle devices. Therefore, we

    focus on surface stress sensors with integrated

    piezoresistors rather than larger optical readout. To

    overcome the sensitivity issue of cantilevers with

    piezoresistive readout, we recently developed a

    membrane-type surface stress sensor (MSS) with a

    sensitivity increased by a factor of 20 compared to

    conventional piezoresistive cantilevers [3].

    Figure 1 shows a schematic of a MSS. A typical

    shape of a MSS is a round membrane with a thickness

    of 2.5 m and a diameter of 500 m. The membrane

    is supported with four sensing beams, onto which

    transvers and longitudinal piezoresistors are

    integrated. Depending on the target analyte, a specific

    polymer is coated on the top side of the membrane. Its

    swelling, upon absorption of volatile molecules, will

    produce the membrane deflection, which is detected

    by the piezoresistors. In this paper, we present the

    fabrication and characterization of the latest

    generation. We finally used arrays of membranes in a

    clinical trial to compare breath samples of four cancer

    patients to those from four healthy persons.

    Figure 1: Graphical representation of MSS. A

    round membrane is suspended by four constricted

    beams with integrated piezoresistors connected in a

    Wheatstone bridge. The membrane is coated with a

    polymer that reacts to surrounding molecules.

    METHODS AND RESULTS

    The fabrication of MSS is based on SOI wafers

    that are structured by deep reactive ion etching

    (DRIE). Figure 2 shows the main steps in the

    fabrication process of the membrane. The cross

    section shows one of the four constricted beams with

    a partial view of the suspended membrane.

    MEMS 2013, Taipei, Taiwan, January 20 24, 2013978-1-4673-5655-8/13/$31.00 2013 IEEE 621

  • Figure 2: Process flow of the membrane-type sensor

    fabrication. The cross section represents one of the

    four constricted beams with an integrated

    piezoresistor. The membrane is separated from the

    beam for clarity (e to f).

    We start with an SOI wafer with a device layer of

    3.5 m that is thinned down to 2.5 m by thermal

    oxidation and subsequent removal of the oxide (Fig.

    2a). The p-type piezoresistors are then created with

    two distinct doping processes: deep and highly

    conductive zones are initially created with the

    deposition of boron silicate glass (BSG) and diffusion

    of the boron atoms into the silicon at 1000C for 30

    minutes. Shallow layers, which are very sensitive to

    surface stress, are then created by ion implantation

    (Fig. 2b and 2c). The boron ions are implanted with a

    dose of 2.5E+14/cm2 followed by a rapid thermal

    annealing (RTA) at 1000C for 10 s. After a

    deposition of an 80 nm thick layer of Si3N4 as a

    passivation layer (Fig. 2d), aluminium wires are

    structured and encapsulated with a thick oxide layer

    of 1 m. The membrane and its sensing beams are

    then structured into the device layer with deep

    reactive ion etching (DRIE) (Fig. 2e). A 5 m thick

    layer of Parylene is deposited on the front side to

    protect the membrane prior to its final backside

    release by DRIE (Fig. 2f and 2g). The Parylene serves

    both as a mechanical stiffening of the membrane

    during the DRIE and as a protection layer during the

    BHF wet etching of the buried oxide. It is removed

    afterwards by oxygen plasma. Figure 3 shows SEM

    pictures of the released membranes before their

    functionalization.

    Figure 3: SEM pictures of (a) a silicon chip

    containing two arrays of membrane-type sensors and

    (b) a close view on one membrane suspended by four

    constricted beams.

    As preliminary characterization, MSS was tested

    as a humidity sensor since polymers react strongly

    with water molecules. Two sensors within an array

    were functionalized by inkjet spotting with cellulose

    acetate butyrate (CAB). 500 droplets (10 nl each) of a

    1 mg/ml solution were spotted onto each membrane,

    resulting in a thickness of 700 nm after evaporation of

    the solvent. The dynamic response of two

    functionalized MSS to four relative humidity pulses

    of 62% is displayed in Fig. 4. We measured a

    response time of 1.3 s during the purging. The output

    signal of a non-coated membrane is also shown on the

    plot as a reference. We also characterized the static

    response of an MSS within the humidity range of our

    setup, i.e. 0% and 80% of humidity (Fig. 5). The

    response is linear with a sensitivity of 87 mV/%RH.

    622

  • Figure 4: Dynamic responses of three membranes to

    four humidity pulses of 62% relative humidity. One of

    the membranes was used as a reference without

    coating, while the others were coated with a CAB

    layer. The others showed a response time of 1.3 s. The

    gain of the amplification stage is 500.

    Figure 5: Static response of the membrane #1 to

    humidity values from 0% to 80%. The measured

    sensitivity is 87 mV/%RH.

    Finally, an array of 2x8 MSS was functionalized

    with 16 different polymers. The various absorption

    properties of these polymers make them react

    differently to the same analyte, creating a unique

    signature (Fig. 6). Principal component analysis

    (PCA) is used to differentiate complex mixtures of

    gases and molecules.

    Breath samples of both healthy people and

    patients suffering from a head and neck cancer were

    analyzed in a double blind trial. The breath samples

    were transported and stored in Tedlar bags at a

    temperature of 4 C for 5 hours before analysis. Each

    sample was pumped into a gas chamber containing

    the functionalized MSS array. The sensors responses

    were recorded six times and transformed by PCA to

    reveal the differences between samples (Fig. 7). The

    results show a good discrimination between the breath

    samples of healthy persons and the ones of patients

    suffering from a head and neck cancer.

    Figure 6: Dynamic responses of six functionalized

    MSS to ethanol pulses and nitrogen purges. The

    functionalization polymers are PSS, Dextran, CMC

    and PVP.

    Figure 7: Principal Component Analysis case

    scores for breath samples of 4 healthy persons and

    4 cancer patients. Each sample has been measured

    6 times (colored dots). A breath sample bag

    containing saturated water vapor has been

    measured as a control (blue dots). Healthy persons

    can be clearly distinguished from cancer patients

    (the ellipses are a guide to the eye.)

    CONCLUSION

    A new type of surface stress sensor consisting of

    a suspended membrane and its fabrication process

    have been presented in this paper. By clamping the

    membrane in the four directions, the whole stress is

    efficiently transduced on the constricted beams,

    where the piezoresistors are located. Its sensitivity is

    therefore increased compared to a standard

    piezoresistive cantilever with a free-end. With the use

    of different functionalization poly