Sensor Technology - FernUniversität Hagen · Radiation Sensors • Environmental Sensor Systems ... acoustic (mass) )SAW delay lines and bulk acoustic ... dialysis membranes. S

Prof. Dr. Reinhart Job: Sensor Technology1

Advanced Microsystems Technologies for Sensor Applicationsdocendo discimus

Sensor Technology

Summer School:Advanced Microsystems Technologies for Sensor Applications

Universidade Federal do Rio Grande do Sul (UFRGS)Porto Alegre, Brazil

July 12th – 31st, 2009



Prof. Dr. Reinhart Job: Sensor Technology

Outline of the Lecture:

•

Philosophy of Sensing •

Thermal Sensors•

Instrumentation and Systems •

Chemical Sensors

•

Semiconductor Basics •

Biological Sensors•

Radiation Sensors •

Environmental Sensor Systems

•

Mechanical Sensors •

Nanosensors•

Magnetic Sensors •

Recitatives



Biological SensorsIntroduction:

Biosensors → special class of chemical sensors→

take advantage of the high selectivity and sensitivity of biologically active materials

Biosensor → a device that produces an electrical signal proportionalto the concentration of a specific chemical or a set ofchemicals in the human body

→

packaging must be biocompatible (strong requirement)biosensor is more than a chemical sensor

Biosensor → sensor used in biomedical applicationsmore general definition



Biological SensorsPrinciple Structure of Biosensors:

Assembly of the general biosensor→

the general biosensor consists of a

transducerbiological-recognition membrane in intimate contact with the transducerbiologically active material→ recognizes the analyte molecule through a shape-specific

recognitionTwo types of biosensors→

affinity-based biosensors

→

metabolic biosensors




Assembly of the general biosensor

S. M. Sze (Editor): Semiconductor Sensors, John Wiley and Sons, Inc. (1994), Chapter 9, Fig. 1, p. 416

Bio-recognition: “shape-specific binding“ or “key-lock-principle“




Bio-affinity recognition→ very strong binding→ transducer detects the bound receptor-analyte pair→ most common bio-affinity recognition processes

receptor-ligand bindingantibody-antigen binding

Bio-metabolic recognition→ after binding the analyte or co-reactants are chemically altered

⇒ product molecules are formed→ transducer detects

concentration changes of product molecules or co-reactantsheat released by the reaction

→ common bio-metabolic processesenzyme-substrate reactionsmetabolism of specific molecules by organelles, tissues and cells




Two classes of bio-recognition processes ⇒ two sensor types→

affinity-based biosensors

binding of the analyte and the bioactive molecule⇒

chemical signal detected by the transducer

→

metabolic biosensorsthe biologically active material converts the analyte (and any co-reactants) into product moleculestransducer converts the reaction result into an output-signalpossible transactions •

measurement of concentration changes of the product or co-reactants

•

heat released by the reaction •

etc.




Biological recognition element→ immobilized on the surface of a transducer or in a membrane⇒ bioreactor on top of a traditional transducerResponse of biosensor is determined by the→ diffusion of the analyte→ reaction products→ co-reactants or interfering chemical species→ kinetics of the recognition processVarious kinds of biosensors based on

chemically sensitive semiconductor devicesthermistorschemically mediated electrodessurface acoustic waves devicespiezoelectric micro-balancesetc.



Biological SensorsMicrobalance:

Principle of the micro-balance sensor: →

an electrical voltage (AC) causes the resonator (i. e. the piezo layer) to oscillate

→

a target molecule binds with a receptor according to the lock-and-key principle⇒

resonance frequency changes of because of the weight change

→

frequency change is translated into an electrical signal and processed further

http://w1.siemens.com/innovation/en/ publikationen/publications_pof/ pof_fall_2004/sensors_articles/

biosensors.htm




A biosensor consists of a biological sensing element and a transducer→

biological sensing elements:

organisms, tissues, cells, organelles, membranes, enzymes,receptors, antibodies, nucleic acids

→

transducer types: transducer examples:•

electrochemical a) potentiometric ion-selective field-effect transistors

and micro-electrodesb) amperometric micro-electrodesc) impedometric micro-electrodes

•

optical fiber optodes and luminescence•

calorimetric (thermal) thermistors and thermocouples

•

acoustic (mass) SAW delay lines and bulk acousticwave micro-balances



Biological SensorsRecognizable Biomaterials:

Classes of recognizable biological chemicals and some examples

A large variety of biological reactions can be exploited for biosensors

Analyte Examples

metabolic chemicals oxygen, methane, ethanol, other nutrients

enzyme substrates glucose, penicillin, urea

Ligands neurotransmitters, hormones, pheromones, toxins

antigens and antibodies human Ig, anti-human Ig

nucleic acids DNA, RNA



Biological SensorsReaction Kinetics in Biologically Active Materials:

Example: affinity reaction→

binding of an antibody with its antigen

ka : binding reaction rate kb : dissociation (un-binding) reaction rate Ka : equilibrium constantof the binding reaction [Ab]: concentration of the antibody [Ag]: concentration of the antigen [Ab⋅Ag]: concentration of the bound antibody-antigen complex

→

in a biosensor either [Ab] or [Ag] is fixed in or on a suitable membrane, which is coupled to a transducer

→

if the antibody is fixed:subscripts tot, eq : total concentration, equilibrium concentration

AgAbAgAb ⋅↔+ka

kb

[ ][ ] [ ]AgAb

AgAbkkK

b

aa ⋅

⋅==

[ ] [ ] [ ] eqeqtot AgAbAbAb ⋅+=



Biological SensorsReaction Kinetics in Biologically Active Materials:

Example: affinity reaction→

bound antibody-antigen complex concentration as function of the antigen concentration

antigen ↔ analyte, [Ab] is fixed

ideal caseantibody-antigen binding can bevery complicated when multiple binding sites are involved

[ ] [ ][ ]

[ ] tot

eqa

eqeq Ab

AgK

AgAgAb ⋅

⎟⎟⎟⎟

⎠

⎞

⎜⎜⎜⎜

⎝

⎛

+=⋅ 1

S. M. Sze (Editor): Semiconductor Sensors, John Wiley and Sons, Inc. (1994),

Chapter 9, Fig. 2, p. 419





Biological SensorsStructure of a Cell Membrane:

Membrane consists of a fluid bilayerof phospholipid moleculesPhospholipid molecules

hydrophobic tails inside the membrane (bilayer)hydrophilic tails outside the membrane (bilayer)

⇒

trans-membrane conductance to aqueous ions is very low

Proteins float in the fluid bilayer of phospholipid moleculesProteins can be either

trans-membrane orjust exist on one side of the bilayer

Trans-membrane proteins can be ion channels or receptors



Biological SensorsBiomimetic Structures:

Biomimetic structures→

artificial structures that mimic processes in natural cell membranes

Cell membranes→

most sophisticated biosensor/actuator systems known

→

receptor in the cell membrane recognize different molecular speciescause a change in the membrane permeability to certain other chemical species → receptor controlled channels open / close the channel

(directly or indirectly by messenger protein)→

many of the natural transduction mechanisms even include chemical amplification

Couple natural sensing systems to artificial transducers→

very difficult challenge due to fragile nature of cell membranes



Biological SensorsImmobilization of Biological Elements:

Immobilization of biological elements→

immobilization of the biological element on the physical transducer

key role for a high-sensitivity, long-lived biosensor→

immobilization:

confine the biologically active material on the transducerkeep it from leaking out over the lifetime of the biosensorallow contact to analyte solution allow any products to diffuse out of the immobilization layerdo not denature the biological active material**) critical requirement:

enzymes, antigens, organelles, cells, tissues→ fragile biological materials easily rendered inactive

• mechanical damage • heat • freezing • chemical toxins • chemical modification of the wrong part of the material • changes in the conformation of the molecules • etc.




Biologically active materials for biosensors→

proteins or

→

chemical structures that contain proteinsFundamental unit in protein structure → α-amino acid (figure)

20 naturally occurring protein units→

differentiated by the functional group R

→

functional groups includehydrogen, methyl, isopropyl, isopropyl groups, acid groups, alcohol groups, amine groups, aromatic rings, thiols

→

many different functional groups exist on the protein chain ⇒

allow for different coupling reactions






Four different immobilization schemes→

membrane confinement (a) →

physical adsorption (c)

→

matrix entrapment (b) →

covalent bonding (d)


B → biologically active material




Membrane confinement→

solution containing a biologically active material is entrapped on the surface of the transducer

→

semi-permeable membranepores have to be large enough⇒ analyte, products and solution

can pass the semi-permeablemembrane

pores have to small enough⇒ biologically active material has to be retained

→

candidates for the semi-permeable membraneultrafiler membranes based on polymers of polyamide or polyether sulfurdialysis membranes






Membrane confinement→

semi-permeable membrane (principle)

http://en.wikipedia.org/wiki/Hemodialysis




Matrix entrapment→

porous encapsulation matrix formed around biologically active material

e. g. gel containing biologically active material

→

matrixpores have to be large enough⇒ analyte, products and solution

can pass the matrixpores have to small enough⇒ biologically active material has to be retained

→

candidates for a matrixnatural materials are favorable (not toxic to biological materials)synthetic matrix polymers → polyacrylamides, polymethacrylathes






Physical adsorption→

simplest method of immobilization

→

advantagebinding forces are “gentle” and do not distort the conformation ofthe molecules

→

disadvantagemolecules are weakly bound to the transducer(desorption by temperature, pH or ion concentration changes)

→

transducer exposed to a solution of biologically active material→

biologically active material is held on the surface by

van der Waals forceshydrophobic forceshydrogen bondsionic forces



a variety of forces is active:biological materials are complexdifferent parts of the molecules orstructures are attracted on the surface by different forces




Covalent bonding→

provides a more permanent binding

→

transducer is treated to fix reactive groups on its surface to which biologically active material is bound

→

advantagesbioactive material is directly located on the transducer surface ⇒ reduced respond time of the biosensor since the diffusion

time is reducedcovalent binding is much stronger than physical adsorption⇒ lifetime of the biosensor is much longer

→

disadvantagescovalent binding may chemically modify important binding site of the biological material






Covalent bondingExample:→

surface treatment of an hydroxide-terminated surface (e. g. SiO2 ) for covalent protein immobilization using alkyl ethoxysilanes

→

the terminal group X can be a variety of reactive groupsamino groups, cyano groups, etc.





Covalent bonding→

Some examples of surface treatments for covalent the binding

S. M. Sze (Editor): Semiconductor Sensors, John Wiley and Sons, Inc. (1994), Chapter 9, Tab. 3, p. 427




Covalent bonding→

Some examples of surface treatments for covalent the binding

S. M. Sze (Editor): Semiconductor Sensors, John Wiley and Sons, Inc. (1994), Chapter 9, Tab. 3, p. 427



Biological SensorsMass Transport in Biosensors:

Biosensor → bioreactor coupled to a transducer→

recognition reactions take place in a membrane or molecular layer on the surface of the transducer

→

transport phenomena play an important roleResponse characteristics of biosensors greatly affected by→

transport of the analyte into the membrane

→

transport of reaction products to the transducer→

transport of reaction products out of the membrane

→

…Basic transport process→

diffusion (will be briefly considered in this lecture)

→

convection→

migration in an electric potential (can be neglected for biosensor)




Diffusion→

in the biosensor membrane the flow of analyte and products is governed by diffusion

→

Fick’s 1st law of diffusionamount of material diffusing in a given time period across a surface is proportional to the concentration gradient

→

Fick’s 2nd law of diffusionflux of material results inconcentration changes as time progresses

j: flux across a surface (m-2 s-2), C(x,t): concentration (m-3), D: diffusion coefficient (m2 s-1)

( ) ( )x

txCDtxj∂

∂⋅−=

,,

( ) ( )2

2 ,,x

txCDt

txC∂

∂⋅=

∂∂




Diffusion→

effect of diffusion on the sensor response

→

simple case: instantaneous complete recognition reaction takes place at the sensor’s surface in a stagnant solution this reaction consumes all analyte reaching the sensor’s surface

⇒

the sensor output is proportional to the flux of analyte arriving at the surfaceboundary conditions• C(x=0, t) = 0• C(x=∞, t) = Cbulk

⇒

the solution of the 2nd law of Fick is the error function:

( ) ⎟⎠⎞

⎜⎝⎛

⋅⋅⋅=

tDxerfCtxC bulk 2

,




Diffusion→

analyte concentration profiles in a stagnant solution for a biosensor instantaneously consuming all analyte that arrives at its surface

→

calculated from

→

sensor output is proportional to the flux of analyte arriving at the sensor surface (x = 0)

slope of the concentration profiles at x = 0

⇒

sensor response decreases with time

not desirable

( ) ⎟⎠⎞

⎜⎝⎛

⋅⋅⋅=

tDxerfCtxC bulk 2

,








Diffusion→

in a practical biosensor system the solution is well stirred or the sensor is part of a flow injection analysis (FIA) system

⇒

quasi-equilibrium condition by replenishing the analyte

→

general characteristics of the analyte concentration in the solution due to stirring

⇒

first order approximation: (holds at any time)

linear concentrationgradient for x = 0 – XD

x > XD ⇒ constant concen-tration at bulk value

⇒

constant sensor response




Trans-membrane transport→

time response of a biosensor

mostly determined by the time response of the membrane containing the biological sensing elementsin a membrane only diffusion can occurmass flow described by Fick’s 2nd law of diffusion→

2nd-order partial differential equation

→

numerical solution for specific sensor structures and boundary conditions






Trans-membrane transport→

time response of a biosensor

mostly determined by the timeresponse of the membrane containing the biological sensing elementsin a membrane only diffusioncan occurmass flow is described by Fick’s2nd law of diffusion→

2nd-order partial differential equation

⇒

in general numerical solutions are requiredGraph: typical result for a simplified problem (metabolic sensor)

time lag occurs as the analyte diffuses into the membrane then the response rises to its steady-state value




Membrane loading effects→

amount of biologically active material in the membrane affects the sensitivity, saturation level and time response of biosensors

Effects of membrane loading (parameter: l⋅α1/2)→

high membrane loading ⇒

all of the substrate is consumed

⇒

normalized product concentration → 1

→

membrane parameter (l⋅α1/2) contains terms of •

thickness

•

enzyme concentration •

reaction kinetics

•

diffusion constantsS. M. Sze (Editor): Semiconductor Sensors,

John Wiley and Sons, Inc. (1994), Chapter 9, Fig. 10, p. 435





Biological SensorsTransduction Principles:

Electrochemical transductionExample:→

gas-sensitive potentiometric enzyme electrode made from an ion-selective electrode

→

enzyme layer is contained by a dialysis membrane

→

enzyme layer can be adsorbedcovalently bondedentrapped in a matrix

→

membrane is held in place with a rubber O-ring






Optical transductionExample:→

optical biosensor

→

competitive-binding scheme for optical biosensors

→

analyte molecules are indicated by A

→

fluorescently labeled analog molecules are labeled by L




Competitive-binding method (optical transduction)→

two competing reactions occur

analyte-receptor reactionanalog-receptor reaction

→

analog molecules fluorescently labeled moleculessimilar in structure than analyte moleculesbind to receptors (not as strongly as analyte molecules)

→

fixed concentrations of receptor and analog immobilized in the chamber on the tip of a fiber

→

measured optical change → analog-receptor reactionconcentration of the analyte changes⇒

amount of analog bound to receptors decreases

⇒

optical signal changes



Biological SensorsSilicon Based Biosensors:

Urea-sensitive ISFET ENFET (ENzyme FET)→

schematic cross-section and output voltage as function of the urea concentration

S. Middelhoek, S. A. Audet: Silicon Sensors, Academic Press Limited (1989), Chapter 6, Fig. 21, p. 282



Biological SensorsPackaging of Biosensors:

No sensor can be used without proper packaging!!!⇒

packaging should be an integral part of sensor design (not an afterthought)

Biosensor packaging (part 1)→

protection of the sensor against the environment

proper functionality within the designated lifetime•

electrical isolation or passivation of leads and electronics from ions and moisture (prevent leakage)

•

mechanical protection to ensure structural integrity and dimensional stability

•

optical and thermal protection to prevent undesirable effects of ambient light and heat that may alter the signal and sensor operation

•

chemical isolation (protection from harsh environments)




No sensor can be used without proper packaging!!!⇒

packaging should be an integral part of sensor design (not an afterthought)

Biosensor packaging (part 2)→

protect the environment from the sensor material

biocompatibilityfor biosensors materials interface should be inert to the chemical and biological environment of the measurement no toxic or other undesirable products should be released•

well selected sensor materials to eliminate or reduce body reaction

•

sensor operation and packaging selection to avoid toxic products

•

sensor sterilization




Effectiveness of sealant materials





Packaging techniques for biosensors (examples)Structure of a ph ISFET sensor





Packaging techniques for biosensors (examples)Backside contacts to an ISFET





Packaging techniques for biosensors (examples)Buried feed-throughs





Packaging techniques for biosensors (examples)Multi-wafer ENFET package →

protects the leads under the bonded Si-wafer

→

provides a well in which different biomembranes can be formed






Packaging techniques for biosensors (examples)Micro-machined chamber at the sensor surface for electrochemical electrodes




Packaging techniques for biosensors (examples)Multi-layer protection package of biosensors


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Sensor Technology - FernUniversität Hagen · Radiation Sensors • Environmental Sensor Systems ... acoustic (mass) )SAW delay lines and bulk acoustic ... dialysis membranes. S