1 March 2011 GBM8320 - Dispositifs Médicaux Intelligents 2 Laboratory-on-Chip : Purpose • A multidisciplinary approach to miniaturize biological assays or procedures in analytical chemistry. • To embed the required equipments for performing the biological assays in a single chip for single purpose. GBM8320 - Dispositifs Médicaux Intelligents 3 • Low sample consumption; • Fast biochemical reactions & Miniaturization; • Point-of-care. Laboratory-on-Chip : Advantage
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March 2011
GBM8320 - Dispositifs Médicaux Intelligents 2
Laboratory-on-Chip : Purpose • A multidisciplinary approach
to miniaturize biological assays or procedures in analytical chemistry.
• To embed the required equipments for performing the biological assays in a single chip for single purpose.
GBM8320 - Dispositifs Médicaux Intelligents 3
• Low sample consumption;
• Fast biochemical reactions & Miniaturization;
• Point-of-care.
Laboratory-on-Chip : Advantage
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GBM8320 - Dispositifs Médicaux Intelligents 4
Laboratory-on-Chip : CMOS technology
• Low voltage, and low power;
• Addressable sensing or manipulating sites;
• Standard technology.
GBM8320 - Dispositifs Médicaux Intelligents 5
I. Introduction
II. Biochemistry
III. Microfluidic Packaging
IV. Capacitive Sensors
V. On-Chip Cells Detection and Manipulation.
Laboratory-on-Chip : Outline
GBM8320 - Dispositifs Médicaux Intelligents 6
Laboratory-on-Chip : Miniaturization
• Low voltage E=V/d (d: 1cm to 1um, V:10kV to 1V) • Low-sample low-cost experiment with expensive
biomaterials 1ml to 1nl • Fast biological assays 1 hr to 1ms • Miniaturized devices • Home healthcare, Point-of-care monitoring, Home
diagnostic,… -------- • Portable devices • Miniaturization is only solution for single cell
detection : Sensitivity = DVolume/Volume
d!
+! -!
V!
E!
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GBM8320 - Dispositifs Médicaux Intelligents 7
Application Method Microfluidic CMOS Year Authors Cells
monitoring Capacitive
Sensor Adhesive technique 0.5um 2007 Prakash et al
Organic solvent Sensor
Core CBCM capacitive Sensor
DWFP 0.18um 2007
Ghafar-Zadeh et al
Bioluminane detection
Optical Method
Rapid Prototyping 0.18um 2007 Eltoukhy et al
DNA detection Capacitive
Sensor Rapid
Prototyping 0.5um 2006 Stagni et al
Magnetic manipulation
Array of !coils
MEMS based Procedures 0.18um 2006 Lee et al
Virus detection
Capacitive Sensor
Rapid Prototyping 0.35um 2005
Balasubramanian et al
Cell localization
Capacitive Sensor
Adhesive technique 0.35um 2004 Romani et al
Dielectrophoresis Array of Rapid 0.35um 2003 Medoro et al manipulation !electrodes prototyping
Laboratory-on-Chip : CMOS-Based !systems
GBM8320 - Dispositifs Médicaux Intelligents 8
Affymetrix Inc.!
Requires scanner for reading out!
EZ Smart Monitoring
Laboratory-on-Chip : Technologies
Glucose Detection DNA !array Rapid Bacterial Diagnosis
DNA (Deoxyribonucleic) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known
living organisms.
Laboratory-on-Chip : Fundamental of Biochemistry!
GBM8320 - Dispositifs Médicaux Intelligents 18
Blood Chromosomes!
DNA Strands!
Fundamental of biological particles Blood ; Cells ; Chromosomes ; Molecules ; Genes ; DNA ; Fractioning…
• Genetic info is stored in the cell chromosomes • A chromosome consists of long supercoiled strands of molecules. • Each strand is a string of DNA fragments grouped as genes, each
expressing an identifiable function of the organism.
Laboratory-on-Chip : Fundamental of Biochemistry!
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GBM8320 - Dispositifs Médicaux Intelligents 19
Sampling Concentration Purification
Amplification Detection Signal Analysis
A typical biological test through desktop, or room size systems
PCB
Microfluidic
Sensor
Analog Digital and Software Microfluidic and Temperature control system
Microfluidic needle Dielectrophoresis (no charge) Electrophoresis (charge)
• Dielectrophoresis (DEP) for Separation, levitation, rotation, etc.
• Electrophoresis for molecule level preparation.
Laboratory-on-Chip : Fundamental of Biochemistry!
Polymerase Chain Reaction (PCR)
Centrifuge system Fragmentation
PCR
Cells
DNA
Molecules
GBM8320 - Dispositifs Médicaux Intelligents 20
Laboratory-on-Chip : Fundamental of Biochemistry!
• Gold electrode on CMOS • Solution is spread on electrodes for 18 h. • Single stranded DNA molecules immobi-
lized on the electrodes. • Unknown molecule detected through a
CMOS capacitive sensor.
Affymetrix Inc. -- On-chip DNA Detection --
LoC innovation : Gene chip. It requires: • Optical Scanner for readout / data mining ! On-Chip Reader is needed, capacitive
sensor is a good candidate.
GBM8320 - Dispositifs Médicaux Intelligents 21
Fundamental of Biochemistry : DNA!• There are four types of nucleotides corresponding to four different
bases: adenine, guanine, cytosine, and thymine (A, G, C and T). • DNA Individual bases are hydrophobic, but strands of DNA are
quite soluble in water due to the polar backbone. • Single-stranded DNA tends to attach (or hybridize) through weak
hydrogen bonds to another strand of complementary base pairs (G–C and A–T), forming a double strand.
• In humans, for example, each of the 46 chromosomes is 5x400 exp (6) units long, while the single chromosome in the E. coli bacteria is 4x10 exp (6) units long.
• Each nucleotide consists of a base (B), a sugar linkage (S) and a phosphate bridge (P).
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GBM8320 - Dispositifs Médicaux Intelligents 22
Fundamental of Biochemistry : Microarrays!
Ink jet
Pin Quill Pen
Pin Ring
• Robotic DNA Arrays : dispensing artificial DNA molecules (or probes) for diagnosis purposes.
• Photolithography method to create artificial DNA probes for diagnosis purposes (very large scale immobilized polymer array synthesis).
Light Mask
Gene-Chip
• Modify the surface by various chemical reactions to create the required T, C, G, A..
GBM8320 - Dispositifs Médicaux Intelligents 23
• An antigen is defined as a substance that can be bound by an antibody molecule through its antigen-binding sites, also called epitopes.