LAB-ON-A-CHIP for SPECTROPHOTOMETRIC ANALYSIS of BIOLOGICAL FLUIDS

1

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

LABLAB--ONON--AA--CHIP for CHIP for SPECTROPHOTOMETRIC ANALYSIS SPECTROPHOTOMETRIC ANALYSIS

of BIOLOGICAL FLUIDSof BIOLOGICAL FLUIDS

Graça MinasUniversity of Minho

Dept. Industrial ElectronicsCampus de Azurém

4800-058 Guimarães, Portugal

2

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

OUTLINEOUTLINE

MOTIVATION and OBJECTIVES

THIS BIOLOGICAL MICROSYSTEM ADVANTAGES

LAB-ON-A-CHIP CONCEPT

LAB-ON-A-CHIP DESIGN and FABRICATION• Microfluids• Optical Filters• Detection and Readout Electronics

EXPERIMENTAL RESULTS

CONCLUSIONS

3

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

MOTIVATIONMOTIVATION

Disadvantages of nowadays clinical analysis systems

Results become available after several hours (days)

Mistakes in logistics: lost samples and mislabeling

Prevention, diagnostic and disease treatment

Biochemical analysis of biological body fluids by spectrophotometry

Carried out in clinical analysis laboratories

4

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

Automated equipment

Reduce errors

High sample and reagent volumes

Analysis system expensive

Does not contribute to patient comfort

MOTIVATIONMOTIVATION

5

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

Reagent strips

Available for a limited set of biomolecules to be analyzed

Color readout is merely qualitative

MOTIVATIONMOTIVATION

6

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

OBJECTIVESOBJECTIVES

Colorimetric detection by optical absorption

Instantaneous, reliable and precise results

Portable

Patient comfort

Small size

Low cost analysis system

Better quality in the health care services

Lab-on-a-chip to quantify the concentration of the biomolecules in biological fluids

7

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

ITS ADVANTAGESITS ADVANTAGES

Small size, low consumption and portability

In-situ measurements

Analytical testing times and costs reduced

Instantaneous results

Low quantities of reagents and samples

Reduction of the cost associated with the destruction of the used samples and reagents

Low cost for high-volume production equipment

Improve laboratory safety

8

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

Chip

Opticalfilters

Reagent

Mixture

Calibrator

Reagent

Sample

Photodetectorsand optical filters

Electronics

LABLAB--ONON--AA--CHIP CONCEPTCHIP CONCEPT

9

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

p substrate

n+p+Detectionsystem

Microfluids

Optical filter Opticalchannel

LABLAB--ONON--AA--CHIP OPERATIONCHIP OPERATION

495

Uric acid+

Infinityuric acid

Bilirubin+

Diazotizedsulfanilic acid

Wavelength (nm)

Abs

orba

nce

Albumin+

Bromcresolpurple

560 600595

Total protein+

Microprotein

10

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

MICROFLUIDICMICROFLUIDIC

Microchannels fabricated using SU-8 photoresist techniques

• Low-cost and biocompatible process

• UV lithography semiconductor compatible (transparency foil mask)

• Microchannels with very low roughness suitable for optical absorption measurements

11

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

OPTICAL FILTER DESIGNOPTICAL FILTER DESIGN

Structurally optimized for:

high transmittance

high selectivity (low FWHM)

FP thin-films optical resonators with dielectric mirrors (TiO2 and SiO2)

High reflectivity with low absorption losses

PortabilityPortability

p substrate

n+p+ n+

White light source

Layers post-processed on top of the photodiodes by Ion Beam Deposition (IBD)

12

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

1.6 μm n-well CMOS standard process, with double-metal and single-polysilicon

B AAA

Comparator

Each optical channel area is 500 μm × 500 μm

DETECTION and READOUTDETECTION and READOUT

13

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

CMOS CHIPCMOS CHIP

14

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

READOUT ELECTRONICSREADOUT ELECTRONICS

Light intensity increase

Light-to-frequency converter

The converter output frequency is directly proportional to the light intensity

Light intensity decrease

15

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

FLUIDS MIXINGFLUIDS MIXING

Fluids inlet and mixingFluids inlet and mixing

16

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

FLUIDS DETECTIONFLUIDS DETECTION

Transmittance measurementsTransmittance measurements

Fluids inlet and mixingFluids inlet and mixing

17

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

EXPERIMENTAL RESULTS EXPERIMENTAL RESULTS

0%

20%

40%

60%

80%

100%

400 450 500 550 600 650 700Wavelength (nm)

Tran

smitt

ance

(%)

Rise of uric acid concentration

50%

60%

70%

80%

90%

489 495 501490 500

Spectrophotometric analysis of uric acid in urineconcentrations from 5 mg/dl to 120 mg/dl

LP = 500 μm

18

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

EXPERIMENTAL RESULTSEXPERIMENTAL RESULTS

0.00

0.05

0.10

0.15

0.20

0.25

0 20 40 60 80 100 120Uric acid concentrations (mg/dl)

Abso

rban

ce a

t 495

nm

(a.u

.) AverageFit± Standard deviation

White light source

Linear conc. range (mg/dl)

Slope (a. u.) dl/mg Intercept (a. u.) Correlation coefficient (R2)

0 – 30 (1.9 ± 0.4)×10-3 (3 ± 2)×10-3 0.98016

19

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

CONCLUSIONSCONCLUSIONS

Lab-on-a-chip for biological fluid analysis by spectrophotometry with instantaneous results (analysis can be performed at any location)

Its performance was successfully demonstrated in the quantitative measurement of uric acid in urine

This lab-on-a-chip avoids the need of expensive readout optics and opens the door to low-cost disposable devices

20

University of MinhoSchool of EngineeringR&D Centre Algoritmi

Dept. Industrial Electronics

Open Industry-Day: Micro and Nano Technologies

ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS

Support: Portuguese Foundation of Science and Technology (FCT grant SFRH/BD/1281/2000) and R&D Centre Algoritmi, from University of Minho, Portugal

Some people of:

• Depts Industrial Electronics, Physics, Mechanics, Biology of UM

• INESC-Lisbon

• Delft University of Technology, Laboratory for Electronics and Instrumentation