Chapter 9 Biomedical Sensors

Hee Chan Kim

CHAPTER 9. Biomedical Sensors

9.1 Introduction

9.2 Biopotential Measurements

9.3 Physical Measurements

9.4 Blood Gases and pH Sensors

9.5 Bioanalytical Sensors

9.6 Optical Biosensors

In Vitro Diagnostics Technology

지식과 수기

의사의 도구

의료기기의 정의

약 의료기기

생물학적제재

Medical Devices : the things that Biomedical

Engineers provide

진료재료–의료소모품-의료비품-의료장비

8,264점 2,088억원

MRI,Monitor 등 16,603점 115억원

침대,냉장고 등

8,274점 39억원

각종수술기구, 램프,전극,센서 등

Varieties in Medical Device

Instrument Instrumentation

Bio(medical)instrumentation

Definitions

Instrument : a tool used to facilitate work.

Instrumentation : 1) the application or use of

instruments, 2) the study, development, and

manufacture of instruments, as for scientific or

industrial use.

Instrument & Instrumentation 도구와 도구화(계측: 計셀계測헤아릴측)

The heart is the only broken

instrument that works.

- T. E. Kalem

Sensor Analog signal processing A/D conversion

Main Control Unit

Digital Signal Processing

Data Input

User Interface

Calibration

Feedback Control

Actuator

BioSystem

measurand

Display Storage Xmission

target

Processor /Algorithm

Diagnostic Instrument

Therapeutic Instrument

Basic Bioinstrumentation System Electrical Energy Other types

of Energy vs

Electronic System

정의 2

Processor & Algorithm Hardware & Software

• PC : general-purpose computer

• Embedded System : a special-purpose computer system designed to perform one or a few dedicated functions

• Programs : signal processing algorithm

Sensors & Actuators As Transducers

변환기 (Transducer)

입력신호(에너지1) 출력신호(에너지2)

Transducer : A converter of one type of energy into another

Sensor : A transducer producing an electrical output

센서 (Sensor)

입력신호 (에너지1)

출력신호 (전기에너지)

Actuator : A transducer accepting an electrical input

작동기 (Actuator)

출력신호 (에너지2)

입력신호 (전기에너지)

Actuators

• Mechanical – electrical motor, solenoid valve, piezoelectric

• Electrical - electrode

• Optical – LASER, LED, bulb

Sensor characteristics

• Common characteristics – Accuracy : The ratio (expressed as a percentage) between the

true value minus measured value and the true value. (cf. precision) – Operating range : The maximum and minimum values that

can be accurately measured. – Response time : The time to reach 90% of the final value

measured. – Sensitivity : The ratio of the incremental sensor output to the

incremental input quantity. (cf. Selectivity) – Resolution : The smallest incremental quantity that the sensor

can measure with certainty. – Reproducibility : The ability of the sensor to produce the

same output when the same quantity is measured repeatedly. (cf. repeatability)

• In vivo characteristics – Safety and Efficacy/Effectiveness

High accuracy, but low precision High precision, but low accuracy

Coefficient of variation : In probability theory and statistics, the coefficient of variation (CV) is a normalized measure of dispersion of a probability distribution. It is defined as the ratio of the standard deviation to the mean :This is only defined for non-zero mean, and is most useful for variables that are always positive. It is often reported as a percentage (%) by multiplying the above calculation by 100.

• Accuracy, Precision, and CV

Sensor characteristics

Biostatics

Disease

+ -

Test

+ 9990

True Positive (TP)

990 False Positive

(FP)

All with Positive Test

TP+FP

Positive Predictive Value=

TP/(TP+FP) 9990/(9990+990)

=91%

- 10

False Negative (FN)

989,010 True Negative

(TN)

All with Negative Test

FN+TN

Negative Predictive Value=

TN/(FN+TN) 989,010/(10+989,010)

=99.999%

All with Disease 10,000

All without Disease 999,000

Everyone= TP+FP+FN+TN

Sensitivity= TP/(TP+FN)

9990/(9990+10)

Specificity= TN/(FP+TN)

989,010/ (989,010+990)

Pre-Test Probability= (TP+FN)/(TP+FP+FN+TN) (in this case = prevalence)

10,000/1,000,000 = 1%

Mechanical

Thermal

Electrical

Magnetic

Radiant

Chemical

Stimulus/

Measurand

1. voltage,

current,

resistance, or

electric field

strength,

2. easy to

handle,

3. many good

tools are

ready,

4. PC

EtCO2

IR absorption

(2.7/4.3/14.7μm)

LED +

photo-

detector

Blood

Pressure

displacement

of diaphragm

strain

gauge

Transducible

Property

Principle of

Transduction

Detection

Means

Conversion

Phenomenon

SENSOR

Electrical

Output

Sensors - Definition and Principles -

Principle of

Transduction

Detection Means Conversion Phenomenon

Physical

Chemical

Biological

Physical

Chemical

Biological

Physical

Measurand/

Stimulus

“biosensor” chemical sensor

physical sensor

Thermoelectric Photoelectric Photomagnetic Magnetoelectric Electromagnetic Thermoelastic Electroelastic Thermomagnetic Thermooptic Photoelastic

ECG, EEG, EMG Pressure Flow Temperature pO2 spO2 Glucose DNA/RNA protein

Biological Chemical Electric, magnetic EM wave Heat, temperature Displacement, wave Radiation Radioactivity

SENSOR

Transducible

Property Electrical Output

Sensor Classification

biological detection element biolayer

Detection

transducer

Transduction

electronic signal

electronics

Output

Signal Conditioning

olfactory membrane

sample nerve cell brain

analyte (substrate)

impurity

Substances

바이오센서 정의(functional & structural)

High Selectivity & Sensitivity

Introduction to Biosensor

• 측정대상 : Any substance that is consumed or produced in a biochemical process and exists inside human body

Ions Gases Drugs Substrates Enzymes Microbiology

Sodium Potassium

Calcium pH

Oxygen Ammonia

CO2

Paracetamol Slaicylate

Amphetamine Barbiturates

Cocaine Morphine

Glucose Cholesterol Creatinine

Creatine kinase Amylase

Aspartate Aminotransferase

Chlamydia Strep A Strep B H. Pylori

I.M. Malaria

Tuberculosis

Hormones Cardiac Markers

Proteins Allergy Renal Dysfunction

Tumor Markers Viruses

hCG

FSH

LH

Prolactin

TSH

CK-MB

Myoglobin

TroponinI

CRP

IgE

Micro-Albumin

PSA

Hemoglobin

AFP

Ferritin

Adenovirus

HBsAg

HBsAb

Rotavirus

R.S.V.

Introduction to Biosensor

생물학적 감지요소

• Can attach/combine to one particular substrate but not to others

• High selectivity & sensitivity

• Examples Enzyme Antibodies Nucleic acids Receptors Microorganisms Cell/Tissue/Organ materials

Introduction to Biosensor

고정방법

• Adsorption

• Microencapsulation

• Entrapment

• Cross-linking

• Covalent bonding

B B B

B B B

B B B

B B B

B B B

Introduction to Biosensor

변환기(transducer)

• Electrochemical potentiometric, amperometric, voltammetric,

conductometric electrode, FET-based

• Optical absorption, fluorescence, luminescence,

IRS(ATR, TIRF, SPR), light scattering • Piezoelectric : QCM, EQCM • Surface Acoustic Waves • Thermal

Introduction to Biosensor

“최초의 바이오센서는 혈당센서!”

OHeOHO 442 22

1956, L.C. Clark (oxygen electrode) Chemical Sensor

Glucose + O2 Gluconic acid + H2O2

GOD

1962, L.C. Clark (enzyme electrode)

Biosensor

GOD

Introduction to Biosensor

Sensor Packaging

• Sensors for in vivo applications;

– Safe, functionally reliable

– Long operational lifetime, biocompatibility (esp. for implantable sensors) • Membrane fouling : protein adsorption, cellular response -

Change of membrane permeability – loss of sensitivity and stability

• Nonthrombogenic, nontoxic

• Polymeric covering materials

– Withstand sterilization procedure (steam, ethylene oxide, gamma radiation)

• Measurand

– physical quantity, property, or condition that the system measures

– accessibility :

• internal (Blood Pressure)

• surface ( ElectroCardioGram, ECG or EKG)

• emanate from body (IR radiation)

• separated form body (sample) – in vitro

diagnostics

Sensing Parameters

9.2 Biopotential Measurements

• Origin of Bioelectricity = action potential of

excitable cells

Medical Devices based on Bioelectricity

“Sensor” “Actuator”

Bioelectricity Electrical Machine Electrical Machine

Electrode(전극) Electrode(전극)

Therapeutic Instruments Diagnostic Instruments

Active cell bathing medium body surface (Constant Current Source) (Volume Conductor) (Potential Difference)

Na+ Cl-

BAT

e e V

sea

Biopotential Measurement- principle

Source identification problem from projections

ECG lead EEG lead

Biopotential Measurement

v source lead

ECG EEG EMG/EP

ENG,EOG,ERG ECoG,EGG,E氣G,ExG?

Bioelectric Signal Instruments

ECG의 종류

28

심전도(Electrocardiogram)

심전도술(Electrocardiography)

심전계(Electrocardiograph)

Cardiac Pacemaker

Cochlear Implant

Deep-brain Stimulator

Advanced Pain Therapy-Neurostimulation

Functional Electrical Stimulation - restoring function through electrical stimulation -

Electrical Stimulation

World War I Navy ship spark-gap transmitter at Harvard Univ.

1925 : W.T. Bovie Harvey Cushing for neurosurgery

1950 : widely used with nonflammable anesthetics

Electrosurgical Unit(ESU) - Bovie

radio frequency oscillator : 300kHz - 3 MHz, noise generator

voltages : 1,000 - 10,000 volts peak-to-peak

breakdown field intensity in air : 30kV/cm 0.33cm @ 10,000 V

mode select : cutting, coagulation

return electrode : low resistance

Electrosurgical Unit(ESU) - principle

Equivalent circuit of a cell and tissue model

Let-go current from arm to arm as a

function of frequency

How doesn’t ESU produce electrical shock in patients? - 6.3A is required @ 500kHz to generate action potential - causing the cells to vaporize rather than depolarize

Electrical Safety - ESU

Energy levels

- External defibrillation: 2 - 360 J

- Capacitor charging time: 8sec to 360J/4sec to

200J.

Defibrillation pulse

- Waveform: Damped sinusoidal halfwave (Edmark)

- Synchronized delay: @ 40 ms from R-wave trigger

Defibrillation electrodes

- Hard paddles: Hard paddles (80 cm2)

Pediatric adapter (17 cm2).

Defibrillator

Cl- Cl- Cl-

Na+ Na+ Na+ Na+

e-

Electrode as a sensor : ion to free electron conversion

Biopotential Measurement-electrode

Electrode - definition

• Electrolyte : a substance with ionic dc conductivity.

– Pure electrolytes: charge carriers are ions, no separate

flow of electron.

– Living tissue : electrolytic conductor (intracellular and

extracellular liquids contain ions free to migrate.)

• Electrode :

– Two current carrying electrodes in an electrolyte are

the source and sink of electrons

– The electrode is the site of a charge carrier shift, a

charge exchange between electrons and ions.

EMG Surface Electrodes

Monopolar Needle Electrodes Concentric Needle Electrodes

EEG Single Disc Electrodes Disposable ECG Electrodes

Electrode Types

9.3 Physical Measurements

• Pressure / Force

• Temperature

• Blood Flow

– Volume Flow

– Velocity

– Blood Volume Change

• Gas Flow

• Oxygen Saturation

Unbonded Strain-Gauge

Pressure Sensor

(a) with increase pressure, the strain on

gage pair B & C is increased, while that

on gage pair A & D is decreased,

(b) Statham Pressure Transducer

P23XL

(a)

(b)

Pressure Measurement

Disposable Semiconductor

Pressure Sensor

Strain Gage Sensor

• Strain Gage : a fine wire strained within its elastic limit converts extremely small displacement into resistance change due to changes in D, L, and

2

(1 2 )

(1 2 )

LR

A

dL ddR A LdA L

A A

R L A

R L A

R L

R L

R RG

L L L L

where Poisson’s ratio: D/D = - L/L

where gage factor G is useful in comparing various strain-gage materials

dimensional effect Piezoresistive effect

Strain Gage Sensor

Temperature Measurement

Tympanic thermometer

Respiration Detector

구강용 수은체온계

액와 수은체온계

항문용 수은체온계

이마용

액체 수은체온계

전 자 체 온 계 수은체온계

Infrared Pyrometer

thermistor

Overview

The Thermocouple is a thermoelectric temperature sensor which consists of two dissimilar metallic wires, e.g., one chromel and one constantan. These two wires are connected at two different junctions, one for temperature measurement and the other for reference. The temperature difference between the two junctions is detected by measuring the change in voltage (electromotive force, EMF) across the dissimilar metals at the temperature measurement junction.

Typical Thermocouples

Thermocouple

Overview

The Resistance Temperature Detector (RTD) or resistance thermometer uses the fact that the resistance of metals increases with temperature. Examples are RTD's are shown schematically below.

Resistance Temperature Detectors

RTD

Thermistor Overview

Similar to Resistance Temperature Detectors (RTD), the Thermistor (Bulk Semiconductor Sensor) uses resistance to detect temperature. However, unlike an RTD's metal probe where the resistance increases with temperature, the thermistor uses ceramic semiconducting materials which respond inversely with temperature. Examples of thermistors are shown in the following schematic.

Typical thermistor sensors can measure temperatures across the range of -40 ~ 150 ±0.35 °C (-40 ~ 302 ±0.63 °F). The shape of the thermistor probe can take the form of a bead, washer, disk, or rod as illustrated in the above figure. Typical operation resistances are in the kW range, although the actual resistance may range from several MW to several W.

Thermopile Overview

A thermopile is an electronic device that converts thermal energy into electrical energy. It is composed of several thermocouples connected usually in series. Thermopiles do not respond to absolute temperature, but generate an output voltage proportional to a local temperature difference or temperature gradient. Thermopiles are used to provide an output in response to temperature as part of a temperature measuring device, such as the infrared thermometers widely used by medical professionals to measure body temperature.

infrared thermometer module

Measurement of Flow and Volume

of Blood

[O2] & other nutrients in the cells

Blood Flow

Blood Pressure

ECG

measurement

Primary

2nd

-class

3rd

-class

4th

-class

Difficulty

invasiveness

Quantity to be known

Ci

Indicator’s input

concentration

Co

Indicator’s output

concentration

F : volume flow

dm/dt :rate of indicator injection

i o

o i

dmC F C F

dt

dm

dtFC C

Verify dimension (unit) of

flow F

• Concentration – principles of mass transport

INDICATOR-DILUTION METHOD

CONTINUOUS INFUSION

Volume flow

• Fick Technique

a v

dm

dtFC C

Where

F : blood flow [L/min]

dm/dt : consumption of O2 [L/min]

= [O2] - [CO

2]

Ca : arterial concentration of O

2 [L/L]

Cv : venous concentration of O

2 [L/L]

Fig. 8.1 Several methods of measuring

cardiac output

INDICATOR-DILUTION METHOD

CONTINUOUS INFUSION

Volume flow

INDICATOR-DILUTION METHOD

RAPID(Bolus) INJECTION

• equation

Bolus injection [m] Sampling site

dm/dV F

1

1

0

1

0

at sampling site

( )

( ) ( )

( ) or ( )

where t is the point C(t) reaches zero (pre-injection level)

( )

t

t

dm C t dV

dm dVC t C t F

dt dt

dm C t Fdt m F C t dt

mF

C t dt

Fig. 8.2 Rapid injection indicator-

dilution curve

Volume flow

• Dye dilution

– Indocyanine green(cardiogreen)

– Optical absorption peak at 805nm

(independent of blood oxygenation)

– Injected into pulmonary artery

– Concentration curve obtained at femoral

or brachial artery

Volume flow

where Q : heat content of injectate [J = ViΔT

iρ

ic

i]

ρb : density of blood [kg/m

3]

cb : specific heat of blood [J/kg°K]

• Thermodilution

– Cold saline

– 4-lumen catheter (Swan-Ganz catheter)

1

0

( )

t

b b b

QF

c T t dt

Volume flow

ELECTROMAGNETIC FLOWMETERS

• PRINCIPLE – Faraday’s law of induction

1

0

L

e u B dL

where B : magnetic flux density (T or Wb/m2)

L : length between electrodes (m)

u : instantaneous velocity of blood (m/s)

Fig. 8.3 Electromagnetic flowmeter

Velocity

ULTRASONIC FLOWMETERS

• Transit-time Flowmeter

2 22 2

distance

conduction velocity cos

2 cos 2 cos

cos

(nsec order)

Dt

c u

Du Dut

cc u

u t

Velocity

• Continuous–wave Doppler Flowmeter

Velocity

THERMAL-CONVECTION

VELOCITY SENSORS

• Principle :

logW

a b uT

where W : power dissipated by current passing through Ru,

ΔT : temperature difference above blood temperature,

u : blood velocity

• Probes :

Fig. 8.13 Thermal velocity probes

Velocity

•Plethysmography is a test used

to measure changes in blood

volume or air volume in different

parts of the body.

•Photoplethysmography (PPG)

is the electro-optic technique of

measuring the cardiovascular

pulse wave found throughout the

human body

Volume Change Measurement

MEASUREMENT OF

GAS-FLOW RATE

Fig. 9-3 Pneumotachometer for measurements at the mouth

P=f(Q)

- differential pressure flowmeters (pneumotachometers)

- Turbine flow meter

http://spirxpert.com/technical.htm

MEASUREMENT OF

GAS-FLOW RATE

- Hot wire anemometer

- A chip is required to linearize the output

of hot wire anemometers.

- As anemometers are insensitive to the

direction of flow, two heated wires need

to be placed in series; the flow direction

can then be determined from the wire

that cools first.

- A disadvantage of this type of meter is

its sensitivity to gas composition and

gas temperature; in addition these

measuring systems are very vulnerable

to damage and need to be handled with

special care.

http://spirxpert.com/technical.htm

MEASUREMENT OF

GAS-FLOW RATE

Pulse oxymeter analyzes the light absorption at two

wavelengths of only the pulse-added volume of oxygenated

arterial blood.

① transmission type : fingertips, toes, ear lobes, or nose

② reflectance type : at various locations on the body surface

including more central locations (such as chest, forehead, and

limbs)

NONINVASIVE BLOOD-GAS MONITORING

-Beer's law : "equal thickness of an absorbing material will absorb

a constant fraction of the energy incident upon it"

where P0 = radiant power arriving at the cuvette

P = radiant power leaving the cuvette

a = absorptivity of the sample

L = length of the path through the sample

C = concentration of the absorbing substance

Absorbance A is defined as log(P0/P), so

: obey Beer's law.

where u : for unknown concentration material

s : for standard material

010 aLCP P

0log( )

( )uu s

s

PA aLC

P

AC C

A

Ext = the extinction coefficient, function of & absorber, c = the concentration of a single light absorber, d = thickness of absorber

)exp(

][][

][

0

2

22

dcExtII

HbOHb

HbOSO

4 unknowns

Oxygen Saturation - Pulse Oxymetry (SpO2)

Lambert-Beer’s Law

),(),()),(),((

),(),(

),()1)(,(

),()1)(,(

)(I

)(Iln

)(I

)(Iln

]))[,(])[,(()(I

)(Iln

])))[,(])[,((exp()(I)(I

)),(exp()()(I

112222

122

22222

21221

2m

2m

1m

1m

22

m

m

22mm

1

m

HbExtHbOExtHbOExtHbExtR

HbExtHbRExtSpO

SpOHbOExtSpOHbExt

SpOHbOExtSpOHbExtR

HbOHbOExtHbHbExtd

HbOHbOExtHbHbExtd

dciExtI

in

ax

in

ax

in

ax

axin

N

i

iiLEDax

Oxygen Saturation - Pulse Oxymetry (SpO2)