Chemical sensors and

biosensors
 Chemical- and biosensors
Industrial, Environmental, and Clinical Applications

• Chemical sensors • Biosensors

measure and characterize measure and characterize
chemical compounds. organic materials.
• These sensors include • These sensors include
conduct metric sensors, enzyme sensors and DNA
catalytic sensors, and gas analysis systems
sensors.
 We want to measure?
– Presence/Absence
– Identity
– Concentration
– Qualitative or Quantitative
 How can we measure?
• Magnetic & Electric Fields
• Resistance
• Capacitance
• Inductance
• Frequency
• Optical
• etc etc..
Some examples
 What can we gain by
micro/nanotechnology?
• Microdomain => laminar flow conditions => difficult to mix

•Shorter diffusion distances => rapid diffusional mixing

Time to diffuse across a channel increases with (channel width)2

e.g 1 mm channel takes 100 seconds to diffuse accross =>
10 um channel takes 10 milliseconds

• Surface area to volume ratio increases with r -1 => surface influence increases

• Surface tension and viscosity befomes ruling fluidic parameters over inertia

• Evaporation becomes a very influential parameter

• Miniaturised sample volumes => multiple/alternative analysis

 What are the possible
challenges?
• Noise
• Drift
• Low sensitivity
• System stability
• Reuse possible?
• Sampling problems
• Measurements system
• Complexity and cost
• User prejudice against technology?
• …
 Problems with scaling down

• Smaller volumes = less analyte

1 nL injection av 1pM = 600 molecules
• Requires high sensitivity detection
• Integration issues (connections and
other equipment)
• Fouling/clogging
• False-positives with single mol.?
Chemical Sensors
 Biosensors
a biological element senses
 Biosensor = a biological element senses

The component used to bind the target molecule.

Must be highly specific, stable under storage conditions, and immobilized.

Microorganism
Tissue
Cell
Organelle
Nucleic Acid
Enzyme
Enzyme Component
Receptor
Antibody http://www.chemistry.wustl.edu/~edudev/LabTutorials/HIV/DrugStrategies.html
 Systematic Evolution of Ligands by
Exponential Enrichment (SELEX)

DNA ”Antibodies”

Schematic Reproduced From: http://surgery.duke.edu/wysiwyg/images/surgery_SELEX.jpg

Molecularly Imprinted Polymer (MIP)
Sensor Array

Greene, N.T.; Shimizu, K.D. J. Am. Chem. Soc. 2005, 127, 5695
Principle of Electrochemical Biosensors
substrate product

Enzyme
electrode

Apply voltage Measure current prop.

to concentration of substrate
 Chemical Sensor Modalities
Sensing Mode: Example Device
• Sensing modes Type:

Resistive Chemresistor

gas/analyte
Capacitive Chemocapacitor

Physico-chemical
Thermistor
interaction Calorimetric Pellistor

Sensitive layer

Surface Acoustic Wave

Transducer Mass
Cantilevers
 CO sensor on the wall
• Measures the
CO in order to
regulate the
ventilation
• Pris 3400 sek

www.senseair.se
 Metal-oxide sensors

• CO sensor

• Consists of a heater and a

thin layer of SnO2
 Metal-oxide sensors -
operation
• Conductivity of the oxide can be written as:
 = 0 + kP m
0 is the conductivity of the tin oxide at 300C, without
CO present
P is the concentration of the CO gas in ppm (parts per
million),
k is a sensitivity coefficient (determined experimentally
for various oxides)
m is an experimental value - about 0.5 for tin oxide.
Using Interdigitated Capacitors as
Chemical Sensors
• Interdigital geometry
maximizes
capacitance.
• Highly Sensitive to
environmental
changes.
• Arrays can be used to
increase selectivity.
• Compatibility with
MEMS fabrication
Processes.
Capacitive moisture sensor
 MOS chemical sensors

• Example, by simply replacing the metal

gate with palladium, the MOSFET
becomes a hydrogen sensor
 FETs for
Forensic applications
Drugs, bombs, Chemical Sensors
biowarfare agents..... •Hydrogen Cyanide (HCN)
•Ammonia (NH3)
•Chlorine (Cl2)
•Acetaldehyde (C2H40)
•Sulfur Dioxide (SO2)
•Hydrochloric Acid (HCl)
 MOS chemical sensors
ISFET
• The ISFET requires an external
reference electrode where the gate
voltage is applied.
 Nanowire FET
•Label free

•CMOS-compatible

•Low fM sensitivity

Patolsky, F. et al. 2004. Electrical detection of single viruses. Proceedings of the National Academy of Sciences 101:14017-14022.
Eric Stern, et. al., Nature 445, 519-522 (1 February 2007)
 Thermistor based chemical sensors
• Principle: sense the small change in temperature due to the
chemical reaction.
• A reference temperature sensor is usually employed to sense
the temperature of the solution
• The difference in temperature is then related to the
concentration´of the measured substance.
• The most common approach is to use an enzyme based
reaction (enzymes are highly selective - so the reaction is
known).
 Mass sensors
• Uses piezoelectric crystals such as quartz
• Setting them into oscillation at their resonant frequency
• This resonant frequency is dependent on the way the crystal is
cut and on dimensions but once these have been fixed, any
change in mass of the crystal will change its resonant
frequency.
• The sensitivity is generally very high - of the order of 10 g/Hz
and a limit sensitivity of about 10g.
• Since the resonant frequency of crystals can be very high, the
change in frequency due to change in mass is significant and
can be accurately measured digitally.
 Biosensor for drug
detection
Narcotics discovery without a dog

www.nyteknik.se
Mass sensor - cantilevers
 Optical sensors
• Opto-chemical sensing are the properties of some
substances to fluoresce or phosphoresce under
optical radiation.
• These chemiluminescence properties can be sensed
and used for indication of specific materials or
properties.
• Luminescence can be a highly sensitive method
because the luminescence is at a different frequency
(wavelength) than the frequency (wavelength) of the
exciting radiation.
• This occurs more often with UV radiation but can
occur in the IR or visible range as well and is often
used for detection.
 Blood sugar
• 0.3 ul blood
• 5 sec
• Pris 400 sek

Blodprovstagare Teststicka Mätare

www.abbott.se
Array-based fluorescence
detection of biomolecules

Surface area, chemistry and deposition

technique important
 Amplifying the signal for optical
biosensors
Elisa RCA
Rolling circle amplification
Enzyme-Linked Immunosorbent Assay
 Quantum dot's
• Use as a labels on e.g. an antibody
• 2 to 10 nanometers, corresponding
to 10 to 50 atoms
• Size defines color of emitted light
 Bioluminescent quantum dots

So, M. K.;Xu, C.;Loening, A. M.; Gambhir, S. S.; Rao, J.Self-Illuminating Quantum

Dot Conjugates for in vivo Imaging. Nat. Biotechnol.2006, 24, 339-343.
 Surface Enhanced Raman
Spectroscopy - SERS

•Nanostructured surface gives 106-109 increase in signal

•High sensitivity, on par with heterogeneous, amplified systems
•SERS signal is photostable and, unlike fluorescence, cannot be “quenched”
•Signal is unaffected by ionic strength or temperature variations
•Does not work for all analytes

http://www.oxonica.com/
 SPR (Surface plasmon resonance)

www.biacore.com

Surface plasmons, are surface electromagnetic waves that propagate

parallel along a metal/dielectric interface
 Chromatography

• Multicomponent samples are separated in specially treated separation

columns before measurement with a detector
• Samples are separated by different migration speed inside column due to
differing adsorption characteristics
– Liquid/Ion Chromatography (HPLC, IC)
• Solid column, liquid samples
– Gas Chromatography (GC)
• Solid column, gas samples
Migration speed : v  u (1  KVS / VM )
(u : flowrate of eluent, K : equilbrium coef. between adsorbed amples and mobile samples,
VM : volume of mobile samples, Vs : Volume of stationary sample)
 Chromatography

Stanford Gas
chromatograph
• 2” silicon wafer
• Isotropic etch
• Pyrex lid
• 1.5 meter column

Terry SC (1975)
 Micromachined Capillary Electrophoresis

Microfluidic Chips Electrophoresis Chip

for Integrated with Integrated
DNA Assays Fluorescence Detector
(University of Michigan) (University of Michigan)
 Parallel Plate Capacitance Detection

– Application: Sensing particle

concentration in a fluid sample
» How it works: The dielectric
constant of the fluid between the
plates fluctuates with varying
concentrations of the particles to
be detected. This change in the
dielectric constant results in a
change in the capacitance of the
plates, which is then measured in
an electric circuit. Minute changes
in capacitance are used to
determine concentration

Lung-Ming Fu, National Pingtung University, Tawain

Thermal lens

Lablel free, but requires

a clean sample
 Nanopore DNA reader
The device would work by running an electric current across a DNA strand
as it is drawn through a nanopore, using electrodes built into the pore's
sides. Detecting the changes in current that correspond to the four
different bases, or "letters", that make up DNA would read off the
sequence as it passed.

Meller, A., L. Nivon, E. Brandin, J. Golovchenko, and D. Branton. 2000. Rapid nanopore discrimination
between single polynucleotide molecules. Proc. Natl. Acad. Sci. USA 97: 1079-1084.
 Important dates

Project meeting Thursday 21/5

Poster finished Monday 27/5, 12.00

Poster presentation Wednesday 29/5, 9.15 - 12

Tenta, E:1328 Thursday 3/6, 8-12

 Project meeting 3
Sensor Time

Accelerometer 21/5, 9.15

Pressure sensor 21/5, 10.15

Flow sensor 21/5, 11.15

Poster presentation 29 / 5
 Poster presentation

Wednesday 29/5 9.15 - 12

10 minutes presentation from the group

5 minutes questions from the opponents

Questions from the audience….-----------------------------

----------------------------------
 Tenta

Monday 3/6
8 - 13
Calculator, ruler,
20 short questions 1p
1 longer 5p
1. So what’s the big deal about microsensors?
How can you answer to that? Write at least four advantages of microsensors compared to
traditional sensors.

2. There are two main production techniques for silicon for electronics and micromechanics:
Czochralski and Float-zone. Describe the two techniques.

3. Write two etch methods that give you the etch profile showed below.

4. The figure show a projection map of a silicon <100> wafer crystal structure. I you intend
to etch a so called v-groove in such a wafer, how would you orient your mask. Mark a line
in the projection map where your channels should be aligned.
 Atomic force microscope
• Detecting cancer by probing the elastic properties of cells. The
elasticity of benign cells and malignant cancer cells were
mechanically probed with an atomic force microscope.
 AMF binding measurement

T. Sulchek et al., “Dynamic Force Spectroscopy of Parallel Individual

Mucin1-Antibody Bonds,” Proc. Natl. Acad. Sci. 102, 16638 (2005).
 End users for the technology

• Research- discover new biology by

faster and more sensitive analysis
• Diagnostics – biomarkers, POCT,
personal medicine
• Biopharmaceuticals - screening, QA
mm
• + Food Industry, Environmental,
forensic and military applications
 Detection of Magnetic Beads
Giant MagnetoResistive (GMR) Sensor Hall Sensor

(Source: NRL Technical Proposal (Source: B. Boser, European IAB, 2004)

ATL-415-NAVALRL-FPTECH-4)
 Future scenario
Hospital
Emergency
Health Center

Pharmacy

Clients
LAN Firewall

Region 2

ISDN
analog
XDSL
mobile PC
Server

Home
A80218-Siemens© GT
http://www-GT.med.siemens.de
 Multi-analyte Differential Sensing
• Nature often does not use highly selective
receptors

• “Differential” receptors used in arrays

• Response from each of these receptors for a

particular mixture of stimuli creates a
pattern
Microdispensing

2.6 uL

1 mL
100 nL
100 nL

Lund University
 Small spots = higher MALDI MS
sensitivity

0,4 mm

2,5 mm

Analytical Chemistry, 73, 2001, 214-219

Chip integrated solid phase microextraction
Bead trapping silicon microgrid
System set-up for solid phase microextraction
in a chip capillary

Problem
 Solid-phase extraction
Pressure driven flow Capillary driven flow

Proteomics, 2002, 2, 413–421 Electrophoresis

2004, 25, 3778-3787
 Integrated Sample Enrichment
Target
• Very low complexity
• Interfaces standard
pipetting robotics
• Highly parallel
• Short path length
• Minimal no. of
Same dimensions as the standard MALDI
transfers as the ISET
target. e.g. 5.5 x 5 cm and 96 perforated is both a sample
nanovials (30 nL volume) preparation and
presentation device
ISET- sample preparation and
presentation
Detection of Analytes

500 mm
ISET Applications
Spothomogeneity
 Protein chips based on porous
silicon as substrate surface

• Increased surface area

• Reduced spot size
• Homogenous spot profile
 Non-homogenous spots
“coffee stain” effect

Silanized glass Macroporous silicon

 Different Manufacture Process

MEMS technologies such as;

• SOI, CMOS, etc, etc, process
• Vapor deposition (metaloxide)
• Serial Electrodeposition
• Printing process (conductive polymers)
• .......