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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