20 Jan 03 i-STAT

Microanalytical Systems for Point-of-Care Blood Diagnostics

Eric Brouwer, R&D Scientistebrouwer@istat.ca

i-STAT Canada Ltdwww.istat.com

20 Jan 03 i-STAT

Outline

• Point-of-care diagnostics

• i-STAT cartridge - fluidics

• i-STAT cartridge – sensors

• Sensor processing

• Economics of POC

Reference: Lauks, I.R. Acc. Chem. Res. 1998, 31, 317-324

20 Jan 03 i-STAT

Point of Care (POC) Blood Diagnostics

VS

20 Jan 03 i-STAT

A good POC should be foolproof

• no user intervention should be required to• maintain the sensors

• perform calibration

• pre-treat the sample

• deliver the sample

• only good results should be reported• user and system errors are detected

20 Jan 03 i-STAT

i-STAT CartridgeSensor Chips

CalibrantPouch

Sample Holding Chamber

Sample Entry Port

Flow Channel

Sensor Chips

CalibrantPouch

Sample Holding Chamber

Sample Entry Port

Flow Channel

20 Jan 03 i-STAT

Cartridge construction

20 Jan 03 i-STAT

Fluidic control

time

13 14 15 16 70 72 74 76

R dry chipupstream fluid sensor wet

downstream fluid sensor wet

“T2” = time for fluid to transit channel

“cal time” --time at which fluid reaches first flow sensor

begin monitoring downstream flow sensor

Resist

ance

R drycalibrantfluid

Bubbles in Cal:SE onRcal

Motor Motion to push sample

“Uptime”

“Bubble Width”

R air segment

Bubbles in Sample:SE onRsam

Cartridge fill check

Time

time

13 14 15 161313 1414 1515 1616 70 72 74 767070 7272 7474 7676

R dry chipupstream fluid sensor wet

downstream fluid sensor wet

“T2” = time for fluid to transit channel

“cal time” --time at which fluid reaches first flow sensor

begin monitoring downstream flow sensor

Resist

ance

R drycalibrantfluid

Bubbles in Cal:SE onRcal

Motor Motion to push sample

“Uptime”

“Bubble Width”

R air segment

Bubbles in Sample:SE onRsam

Cartridge fill check

Time

Sequence:1. Calibrant2. Air bubble3. Blood

20 Jan 03 i-STAT

Reagent mixing

Sensor chip

Sample holding chamber

air bladder

Sample entry port

Reagent coating

0.4 cm position of reagent coating

reverse position of blood in mixing oscillation

forward position of blood in mixing oscillation

(a)

(b)

(c)

Sensor Channel in Cover

Cartridge Cover with reagent “Edge” Mixing

Sensor chip

Sample holding chamber

air bladder

Sample entry port

Reagent coating

0.4 cm position of reagent coating

reverse position of blood in mixing oscillation

forward position of blood in mixing oscillation

(a)

(b)

(c)

Sensor Channel in Cover

Cartridge Cover with reagent “Edge” Mixing

20 Jan 03 i-STAT

Temperature control

O2equilibrator

z-action instrument connector to sensors

thin TiW layer provides resistive heating

top side sensors

Covercalibrant O2level established ascalibrantequilibrates with air in channels

ther

mis

tor

ther

mis

tor

V V

Fluid Flow

O2equilibrator

z-action instrument connector to sensors

thin TiW layer provides resistive heating

top side sensors

Covercalibrant O2level established ascalibrantequilibrates with air in channels

ther

mis

tor

ther

mis

tor

V V

Fluid Flow

20 Jan 03 i-STAT

Self-testingbased on a potentiometric sensor wave form

100

110

120

130

140

150

15 20 25 30 35 40 45 50

min < caldV/dT < max

Mil

livo

lts

Seconds

Linear regressioncalV = caldV/dT x T + calO

QC CHECKS

CALIBRANT DATA

min < calO < max

Linear regression

smplV = sampldV/dT x T + samplO

SAMPLE DATA

QC CHECKSmin < sampldV/dT < max

min < smpldD/dT - caldV/dT < max

SE < ME

SE < ME

0

2

4

6

8

10

12

0 5 10 15 20 25 30

freq

uen

cy MAXMIN

n = 100,000

i - STAT

~ 4s

20 Jan 03 i-STAT

Point of Care Test PanelAcute Care IVD POC Market

Electrolytes Na, K, Cl, Ca Mg NH4+, Phos

Metabolites Glu, BUN Creatinine Lactate, Bilirubin uric

Hematology Hct T-Hb Platelets, WBC RBC

Blood Gases pH, p CO2, p O2 in line pH, p CO2, p O2

Coagulation PT, aPTT Heparin Factors

Cardiac CKMB-mass Troponin, Myoglobin

Gen. Chem. TP

Co-oximetry O2Hb, COHB, MetHb

Enzymes ALT Amylase, Alk. Phs

Hormones HCG Thyroids

TD Digoxin, Theophyline

DOA/TOX Alcohol, Salicylate

Infect. Dis.GeneticCancerLipids

HOT COLD

20 Jan 03 i-STAT

• Electrolytes: Na, K, Cl, Ca, NH4+

• Metabolites: Glu, BUN, Creatinine, Lactate

• Hematology: Hct

• Blood gases: pH, p(CO2), p(O2)

• Coagulation: PT, ACT, aPTT

• Cardiac Marker: Troponin-I

i-STAT sensors

20 Jan 03 i-STAT

Definitions

• Transducer (L. transducere: to translate, to transfer)

– a device that ‘translates’ a form of energy into another form of energy

• Sensor– a transducer that transforms any form of energy into an

electrical signal

• Biosensor– a sensor that makes use of a biological material for its

sensing function

20 Jan 03 i-STAT

Sensor Classification• based on the energy to be measured

– physical (mass, pressure, temperature, flow, distance, position, speed….)– chemical (ions selective sensors, gases, glucose, urea….)

• based on the construction principle– piezo sensors (piezo-electric, piezo-resistive, surface acoustic wave)– capacitive sensors– electrochemical sensors (pH, ions, glucose, oxygen….)– thermal sensors (thermistors, diodes....)– optical (colorimetric, fluorescent….)

• based on the application– immunosensors– gas sensors– ion sensors

20 Jan 03 i-STAT

i-STAT sensors use planar microtechnology

• specific electronic technology

• surface processing of a semiconducting substrate (Si/SiO2)

• largely relying on the photolithographic patterning

• allows – a high miniaturization

– a high reproducibility

• is well established for mass-production

• the higher the production the lower the cost per sensor

• it opens the way toward the ‘intelligent’ or ‘smart’ sensors

20 Jan 03 i-STAT

Blood gases sensors

0.8m gelatin

1.1m polyimide

0.1m gold

m silicone polycarbonate

silicon

1m SiO2

0.03m titanium tungsten

32m PVC membrane1.1m polyimide

0.03m titanium tungsten

silicon1m SiO2

1.m dimethyl polysiloxane2m sucrose, NaHCO3

0.1m gold

Blood Gas Panel

0.8m AgCl

0.66m silver

20 Jan 03 i-STAT

Thin film processing

SiO2 Platinum electrode

Enzyme Layer& H2O2 selective membrane

Cap layer

Glucose AnodeDiffusion Barrier

20 Jan 03 i-STAT

Thin Film Processing: Photolithography1. substrate

2. metal deposition

7. photoresist removal

3. photoresist spinning

4. photoresist (+) exposure (through a mask in UV light)

5. photoresist development

6. metal etching

substrate

photoresist

metal

mask

20 Jan 03 i-STAT

Thin Film Processing: Lift Off1. substrate

3. photoresist (+) exposure (through a mask in UV light)

4. photoresist development

substrate

photoresist

metal

mask

2. photoresist spinning

5. metal deposition - sputtering, evaporation

6. photoresist removal

20 Jan 03 i-STAT

Thick film processing

Partial Drop Dispensing

20 Jan 03 i-STAT

On-line visual inspection …

20 Jan 03 i-STAT

… and final visual inspection

20 Jan 03 i-STAT

Correlation with standard tests

pO2

pCO2

pH

20 Jan 03 i-STAT

20 Jan 03 i-STAT

Is all this cost effective?

25%

65% 10%

OverheadMaterialLabor

25%

38%

37%

3%

86%

11%

Hospital Lab: Total Cost $10.00

POC: Total Cost $6.70

Consolidated Lab: Total Cost $4.00

1999 analysis

20 Jan 03 i-STAT

Conclusions

Since 1992, i-STAT has provided a POC system which:• features an autonomous, hand-held blood analyzer

• uses dry-stored, disposable cartridges with sensors built on Si

• detects errors and calibrates itself

• requires 0.1 mL whole blood

• provides results in 2 minutes

• accuracy and the precision comparable with any other tool on the market

• Over 25,000 hand-held analyzers in hospitals around the world

• 16 million cartridges annually, with >20% annual growth rate

• Impact on health care: faster surgery, diagnostics, real-time monitoring