Overview and Introduction to

Biosensors
Anthony P.F. Turner
Biosensors and Bioelectronics Centre
anthony.turner@liu.se

www.ifm.liu.se/biosensors

TFAY62 - Tuesday 27 January 2015

Overview and Introduction to Biosensors

What is a biosensor?

Why are biosensors important?

Electrochemical biosensors

Affinity biosensors

Whole-cell biosensors

Emerging technologies

Conclusions & further reading

Applications
Biosensors harness the immensely powerful molecular recognition
properties of living systems and engineer these into electronic
devices to provide easy-to-use sensing devices with applications
in:

Medicine
Biomedical research
Drug discovery
Environmental monitoring
Food content, quality and safety
Process control
Security and defence

The two most successful biosensors to date:

Mediated amperometric glucose biosensor
Real-time bioaffinity interaction analysis

Newman, J.D. and Turner, A.P.F. (2005)

Home blood glucose biosensors: a commercial perspective. Biosensors and Bioelectronics 20, 2435-2453.

The Biosensor

GAS!!!
Bioreceptor
Transducer

The Biosensor a definition

A biosensor is an analytical device incorporating a biological or
biologically derived sensing element either intimately associated
with or integrated within a physicochemical transducer. The usual
aim is to produce a digital electronic signal which is proportional to
the concentration of a chemical or set of chemicals.
Biosensors usually yield a digital electronic signal which is
proportional to the concentration of a specific analyte or group of
analytes. While the signal may in principle be continuous, devices
can be configured to yield single measurements to meet specific
market requirements. (One-shot biosensors)
Turner, A.P.F., Karube, I. and Wilson, G.S. (1987). Biosensors: Fundamentals and
Applications. Oxford University Press, Oxford. 770p. ISBN: 0198547242
&
The international journal Biosensors & Bioelectronics (Elsevier)

The Biosensor

The Biosensor

Tissues
Microorganisms
Organelles
Cell receptors

Electrochemical
Electrochemical
Optical
Optical
Thermometric
Thermometric
Piezoelectric
Piezoelectric

Enzymes
Antibodies
Nucleic acids
Synthetic receptors

Analytes

Magnetic
Magnetic
Micromechanical
Micromechanical

(Bio)receptor
Transducer
(affinity or catalytic)

signal
Electronics

Receptors for Biosensors

Biological materials: e.g. tissue, microorganisms, organelles,

cell receptors, enzymes, antibodies, nucleic acids, natural
products etc

Biologically derived materials: (e.g. recombinant antibodies,

engineered proteins, aptamers etc)

Biomimics: e.g. synthetic receptors, biomimetic catalysts,

combinatorial ligands, imprinted polymers etc

Transducers for Biosensors

Electrochemical: e.g. amperometric, potentiometric, conductimetric,

impedimetric etc

Optical: e.g. surface plasmon resonance (SPR), fluorescence,

interferometric, holographic

Piezoelectric: e.g. quartz crystal microbalance (QCM), surface

acoustic wave devices (SAW)

Thermometric: e.g. enzyme thermistor, thermal enzyme-linked

immunosorbent assay etc

Magnetic: e.g. magneto-resistive devices, paramagnetic labels etc

Micromechanical: e.g. resonating beam structures

Types of Biosensor

Catalytic Biosensor
e.g. enzyme electrode

Labelled Affinity Sensor

e.g. Fluorescence
Label-free Affinity Sensor
or Enzyme labelled
e.g. SPR, piezoelectric
or electrochem
Immunosensor

Biosensor Publications
Scopus biosensor*
6000
5000

>59,000 papers on
Biosensors

4000
3000
2000
1000

2014

2012

2010

2006
2008

2004

2000
2002

1998

1994
1996

1992

1988
1990

1986

1984

1980
1982

2 papers on Biosensors identified in 1980, 75 papers in 1985 and ~5,000 last year

Biosensors: World
Market
World Market for Biosensors (US$m)
18000
16000
14000
12000
10000
8000
6000
4000
2000
0
1996 2000 2002 2004 2006 2009 2010 2018

80% of market is still for glucose, but we are on the cusp of a new era
Turner, A.P.F. (2013) Biosensors: sense and sensibility. Chemical Society Reviews 42 (8), 3184-3196.

Biosensors: $13b Market

Share

Leaders in the US$13 billion market

Blood Glucose
Roche Diagnostics
J&J Lifescan
Bayer Diagnostics
Abbott
Beijing Yicheng JPS-5
Subcutaneous Glucose
Medtronic
Dexcom
Others
Molecular Devices Corp (LAPs Affinity)
Bayer Contour
Affymetrix etc (DNA
chip)
Nova Biomedical etc (Critical care)
BIAcore etc (SPR affinity)

Some key drivers

Healthcare spending is growing unsustainably: 18% of GDP
for USA, 9.6% of GDP for Sweden

Individual choice and ownership of data

Consumer-driven delivery with evidence-based

reimbursement

Decentralisation and radical restructuring of services

Personalised Medicine

Mobility

As much data as all of humanity as a whole created from the dawn of

civilisation until 2013, is now being created every other day.

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In-Body Sensors: a Trillion US$

Healthcare Opportunity
Gate & speed

Head impact (sports)

Heart, skin, breathing

Exposure to sun

Body temperature

Biomechanical data

Calories & distance

Altitude & rate ascent

Sleep patterns

Location (3D)

Brainwaves & control

Speed & acceleration

Posture

Repetitive activity

There is an obvious omission from the above list: there is

presently no way to measure aspects of blood chemistry, or
other parameters that can only measured by sensor
technology that reside inside the body.
14

Wearable Technology: 2014. Company Profiles, Market Analysis & Forecasts. www.generatorresearch.com

Yellow Springs Instrument Company Inc (YSI)

The original YSI serumglucose biosensor for
diabetes clinics 1975

Glucose Biosensor 1975

Clark, LC & Lyons, C (1962). Annals New

YSI,ofOhio
1987102, 29.
York Academy
Sciences
2015

1987

Mediated Amperometric Glucose Sensors

MediSense ExacTech 1987

Cass, A.E.G., Davis, G., Francis,

G.D., Hill, H.A.O., Aston, W.J.,
Higgins, I.J., Plotkin, E.V., Scott,
L.D.L. and Turner, A.P.F. (1984)
Ferrocene-mediated enzyme
electrode for amperometric
determination of glucose.
Analytical Chemistry 56, 667-671.
16

Driving down cost Screen printing

17

The first pocket-sized device

The creation of the 1st pocket-sized electrochemical

analyser for home blood glucose monitoring in 1987 laid
the foundations for the current generation of instruments
(e.g. Abbott, Roche, J&J and Bayer)

US$10,000+ analogue lab instruments had to be reduced

to programmable devices, eventually costing $7-15

Production of hand-made enzyme electrodes had to be

automated (current costs 2-5.5 cents)

Biochemistries had to be formulated

as bioprintable materials

18

Newman, J.D. and Turner, A.P.F. (2005)

Home blood glucose biosensors: a commercial perspective. Biosensors and Bioelectronics 20, 2435-2453.

The Importance of the User Interface

Bayers DIDGET blood glucose

meter plugs into a Nintendo DS or
Nintendo DS Lite system
This helps encourage consistent
testing with reward points that children
can use to buy items and unlock new
game levels

Blood Glucose: Weve got

an App For That
Lifescan popularised the
iPhone route 2009

AgaMatrix Nugget iPhone

plug-in glucose meter gained
FDA 510(k) on 7 December
2011, marketted by Sanofi
Aventis with iBGStar app,
2012.

Short Break

20

The Arrival of Continuous Glucose Monitoring

(CGM)

Medtronic
Guardian

Dexcom
STS

Abbott Freestyle
Navigator

Meter Kit
Sensors/m
FDA
approval

$1,339
$350 (10x3day)
Aug 2005

$800
$240 (4x7day)
March 2006

$960-1,040
$360-390 (6x5 day)
March 2008 (CE June 07)

Reading
Frequency

1 per 5min (2h run in)

1 per 5min (2h)

1 per min (10h run in)

Reading must be checked by finger-stick method before adjusting insulin

Nova Biomedical CRT 16

Na+, K+, Cl-, TCO2,
Glu, BUN (urea), Creatinine
& Hct

22

i-Stat Clinical Analyser

Glucose
Creatinine
Lactate
Urea
Sodium
Calcium
Potassium
Chloride
pH
pCO2
Haematocrit

1992
23

Surface Plasmon Resonance (SPR) - BIAcore

Bo Liedberg, Claes Nylander and Ingemar Lunstrm (1983)
Surface plasmon resonance for gas detection and biosensing
Sensors and Actuators 4, 299-304

Ingemar, Claes & Bo, LiU

SPR interfaced to a Mobile Phone

Chemosensing based on angle-resolved

surface plasmon resonance is demonstrated on
intact cell phones using a disposable optical
coupler and software to configure illumination
and acquisition. This coupler operates on
different cell phones and is applied for classical
affinity assays with commercial chips and
custom-made tests with embedded calibration.
Measured performance (2.14x106 refractive
index units) is comparable with compact SPR
systems.
Preechaburana, P., Gonzalez, MC., Suska, A., Daniel Filippini, A. (2012). Surface Plasmon Resonance Chemical Sensing
on Cell Phones. Angewandte Chemie 51, 1158511588.

Biosensors Applications AB: technology for

drug and explosives detection

Biosens 600

Border control
Security
Correctional & Police authorities
Rehabilitation & Workplace control
www.biosensor.se

MicrobialGrowthDetection
withResonatingBeams
Resonating Beam Structures for Antibiotic Testing

Fluoresence-based affinity sensors

Multianalyte detection based on
total internal reflection on planar
waveguides

Zeptosens (Bayer)

DNA Chip

Up to 6.5 m
assays on a
1.3 cm2 chip

Confocal scanners and other

microscopy techniques now
routinely used for imaging
genomic and proteomic arrays

Raptor
Fluorescence immunoassaybased biosensor for real time
or near real time detection of
microbial pathogens, typical
assay times of 10-15 minutes;
4 disposable optical waveguide
sensors; may be reused if test
results continue to be negative.

www.resrchintl.com

Lateral Flow Affinity Assays

Membrane coating

Dispenser

Membrane drying and

cutting

Membrane cutter

Lateral flow device

assembly

Assembly roller

Original visually read pregnancy test

format patented by Unipath and launched
in 1988, based on blue latex label resulting
in one or two blue lines indicating hCG

Pregnancy Tests with Conception Indicator

Launched July 2008, measures urinary hCG
using both a low sensitivity and a high
sensitivity strip. Control lines and results
read using red light to measure density of
lines by reflectometry yielding 4 possible
semi-quantitative results:
1)
Not pregnant
2)
Pregnant with conception 1-2 weeks ago
3)
Pregnant with conception 2-3 weeks ago
4)
Pregnant with conception >3 weeks ago
>99% accurate in detecting pregnancy
& 92% accurate in time predictions.
Same price as visual strips.
Swiss Precision Diagnostics GmbH is a joint venture between Procter and Gamble and Inverness Medical

Whole-cell biosensors: Biochemical Oxygen

Demand (BOD)

B
A

Whole-cell Biosensors

Microorganisms engineered to react to the

presence of chemical signals with the
production of an easily quantifiable marker
protein

The regulatory system in the bacterial cell is

exploited to drive expression of a specific
reporter gene, such as bacterial luciferase,
green fluorescent protein, beta-galactosidase

This is achieved by fusing the DNA for a

promoterless reporter gene to an extra copy of
the selected regulatable promoter and
introducing this construction into the bacterial
or yeast cell

Examples include heavy metal resistance

(heavy metal sensors), organic compound
degradation (organic compound sensors),
cellular stress responses (to obtain general
toxicity sensors) and DNA damage repair
(mutagenicity).

Nanomaterials
Nanomaterials have impacted enormously on biosensor R&D over the last
10 years and are expect to filter through to commercial products in the near
future
Carbon Nanotube (Graphene) with dendrimer

Nanowires

Quantum Dots

Molecularly-imprinted Polymers

Aptasensors
SELEX searches ~1014 of possible 1018
20-60mers

B
A

Thrombin aptamer (TBA)

5-GGTTGGTGTGGTTGG3 interacts specifically with
the Fibrinogen recognition
exosite through the two TT
loops
Bini, A., Mascini, M., Mascini, M. and Turner, A.P.F. (2011). Selection of Thrombin-binding aptamers
by using computational approach for aptasensor application. Biosensors and Bioelectronics 26, 4411-4416.

Molecular Imprinting (Plastic antibodies)

Reversible interactions between the template and the polymerisable functional monomer may involve: (a) reversible
covalent bonds, (b) covalently attached polymerisable binding groups that are activated for non-covalent interaction by
template cleavage, (c) electrostatic interactions, (d) hydrophobic or van der Waals interactions. Following polymerisation,
the template is then removed through the disruption of the interactions with the polymer, and subsequently extracted from
the matrix. The target analyte or his analogues can then be selectively rebound by the polymer.

Poma A, Turner A.P.F. and Piletsky S. (2010) Advances in the manufacture of MIP nanoparticles.Trends in Biotechnology 28, 629-637.

Printed Electronics Arena at Norrkping

NILPETER
Roll-to-roll label printer
for screen & flexo
- 5 printing stations (flexo/screen)
- Dryers (hot air/UV curing)
- Web width: 180-330 mm
- Web velocity: speed 3-180 m/min
- Die cutting
- Lamination
- Min feature size: 100 m
- Flexible substrates

Dry Phase Patterning

- Metallic (Al) foil laminates
- Patterning through dry process
- Up to 150 m/min
- Web width: 300 mm
- Environmentally friendly

Hybrid line to be added shortly

36

2 Flat bed screen printer s &

Conveyor feed dryer
- Rigid/flexible substrates
- Vacuum substrate table
- Substrate size <DIN A6-DIN A3
- Pneumatic driven filler and
squeegee
- Registration accuracy ~50 m
- Minimum feature size: 100 m
- Min ink 150 ml/printing unit
(screen)
- Hot air/UV/IR drying units

Dimatix
Inkjet
- Bioprinting: DNA, lipids, proteins
- Ag ink, PEDOT:PSS ink
- 1-10 pL drops
- Min ink amount to be printed: 0.5 ml
- Substrate thickness 40 m-25 mm
- Substrate heating up to 60 C

Towards the fully-printable instrument

37

Turner, A.P.F. (2013). Biosensors: sense and sensibility. Chemical Society Reviews 42 (8), 3184-3196.

Conclusions
Biosensors have achieved considerable success in both the
commercial and academic arenas and the need for new, easy-to-use,
home and decentralised diagnostics is greater than ever

Amperometric biosensors continue to dominate the market

Electrochemical biosensors are available for a range of decentralised

analyses, including medical, food and environmental applications

Array-based fluorescence sensors are now well established for genomic

and proteomic assays

Label-free assays based on SPR dominate the laboratory affinity sensor

market especially in drug development

The search continues for a new disruptive technology!

www.ifm.liu.se/biosensors

6.451
2013

Turner, A.P.F. (2013) Biosensors: sense and sensibility. Chemical Society Reviews 42 (8), 3184-3196.
Newman, J.D. and Turner, A.P.F. (2008). Historical perspective of biosensor and biochip development. In:
Handbook of Biosensors and Biochips (Eds R. Marks, D. Cullen, I. Karube, C. Lowe and H. Weetall) John Wiley
& Sons. ISBN 978-0-470-01905-4 www.wiley.com/go/biosensors
Newman, J.D. and Turner, A.P.F. (2005). Home blood glucose biosensors: a commercial perspective.
Biosensors and Bioelectronics 20, 2435-2453
39

Some Web Sites

www.ysilifesciences.com YSI Analysers
www.minimed.com/products/guardian Implantable glucose sensors
www.youtube.com/watch?v=GxThyTTztmQ video: Printing sensors
www.accu-chek.com.au/au/products/metersystems/advantage.html
www.bayerdiabetes.com/sections/ourproducts/meters/breeze2
www.lifescan.com/
www.abbottdiabetescare.com/index.htm
www.biacore.com/lifesciences/index.html
www.ifm.liu.se/biosensors
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