Prof. Je Je- -Kyun Kyun Park Park Dept. of BioSystems, KAIST Dept. of BioSystems, KAIST

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2003 Je-Kyun Park, Ph.D.

Bio Bio - - fusion and fusion and Biosystems Biosystems Technology

Technology

Prof.

Prof. Je Je- -Kyun Kyun Park Park Dept. of BioSystems, KAIST Dept. of BioSystems, KAIST

http://nanobio.kaist.ac.kr

2003. 09. 19

Contents Contents

• Introduction: Bio-fusion

• Fundamentals of BioElectroMechanical Systems

• Bio-fluidics: Theory and Applications

• Miniaturized Total Analytical Systems

• NanoBio Systems

• Summary

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2003 Je-Kyun Park, Ph.D.

Bio- Bio -fusion fusion

2003 Je-Kyun Park, Ph.D.

“Two technologies will Two technologies will dominate the 21st century dominate the 21st century scientifically and industrially : scientifically and industrially :

biotechnology and biotechnology and information technology information technology”

Bill Gates

http://www.microsoft.com/billgates/default.asp

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The Human Genome Project is unlocking The Human Genome Project is unlocking

the secrets of our genes the secrets of our genes

• The Human Genome Project involves:

– genetic and physical mapping of chromosomes – DNA sequencing

– comparison of human genes with those of other species

Systems Biology Systems Biology

WIREDSystems biology looks at the connections between components in

cells.

Integrative approach in which scientists study pathways and networks will

touch all areas of biology, including drug discovery

C & EN / May 19, 2003 (Volume 81, Number 20)

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2003 Je-Kyun Park, Ph.D.

“There is Plenty of Room at There is Plenty of Room at the Bottom

the Bottom”

Prof. Richard P. Feynman December, 1959

California Institute of Technology

http://www.zyvex.com/nanotech/feynman.html

Definition and Scope of Nanotechnology Definition and Scope of Nanotechnology

• Science for exploring the materials and phenomena in the nanometer (atomic, molecular) scale

• Technology for manipulating and controlling the structure and components in the nanometer scale, thus inventing new materials, devices and systems

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Nanotechnology for Biomolecular Assays Nanotechnology for Biomolecular Assays

Biochip

MEMS/ NEMS

Micro/nano Fluidics

Self-assembled Monolayers

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2003 Je-Kyun Park, Ph.D.

Nanoparticles

Nanoparticles , Proteins, and , Proteins, and Nucleic Acids:

Nucleic Acids:

Biotechnology Meets Biotechnology Meets

Materials Science Materials Science

Molecular Scale Molecular Scale

< Source >Nanozine.com

0.1 ~ 100 nm

Bacteria 1µm HIV 100nm

Cell membrane 7~10nm

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Nanobarcodes

Nanobarcodes TM TM Particles, Particles, Nanoplex Nanoplex

• Cylindrically-shaped, striped metal particles, readout based on differential reflectivity using an optical microscope

www.nanoplextech.com

Au Ag Au Ag Au Ag

6 µm

250 nm

Multiplexed DNA assays Multiplexed Oligo Titrations Multiplexed Sandwich immunoassays Proximity-based Bioassays

2003 Je-Kyun Park, Ph.D.

Biology is not only for Biology is not only for biologists

biologists

Harold E. Varmus

The 1989 Nobel Prize Winner in Physiology or medicine

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New Paradigm for Bio

New Paradigm for Bio- -Related Industry Related Industry

Miniaturization of chemical instrumentation has become an increasingly important component for genomic and proteomic applications, as well as drug discovery and development research

Microfluidic Technology High Throughput Screening

BioArray

BioArray Technologies Technologies

Diagnostics

Normal Cancer

Screening

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The Challenges for Biotech Business The Challenges for Biotech Business

• Scientific Creativity

– Discovery: You have discovered something wonderful.

– Platform Technology: You can do something wonderful.

– Research has ‘fashions’: The biotech industry follows the fashion.

• Market Need

– Product company – Tools company – Solution providers

• Competitive Advantage

– You hold the patenton doing it.

– You have the toolsnecessary to do it.

– You have the skillsnecessary to do it.

– You have a lot of resources or moneyto do it.

– You are the firstto do it.

What is What is BioSystems?

BioSystems?

Department of BioSystems Department of BioSystems

Scientific Knowledge (Biology, Neuroscience)

Engineering Tools (Electronics, Information,

MEMS)

Biologically-Motivated Intelligent Systems Biologically-Oriented Information Systems

-

-New Department at KAIST (Spring 2002) -New Department at KAIST (Spring 2002) -

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Interdisciplinary Education & Research Interdisciplinary Education & Research

Fusion of Biotechnology (including Medical Science, Neuroscience) and Engineering (including Computer

Science, Electronics, Mechanical Engineering, Nanotechnology, …)

Biology Bio-

Informatics

Bio- Electronics

Bio- MEMS BioSystems

2003 Je-Kyun Park, Ph.D.

Fundamentals of Fundamentals of BioElectroMechanical

BioElectroMechanical Systems Systems

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Microelectromechanical

Microelectromechanical Systems (MEMS) Systems (MEMS)

• Integrated micro devices or systems combining electrical and mechanical components fabricated using integrated circuit (IC) compatible batch-processing techniques and range in size from micrometers to millimeters

In US: MEMS, Micromachining

In Europe: Micro Systems Technology (MST) In Japan: Micromachines,MicroRobots

Biotechnological & Biomedical Biotechnological & Biomedical

Microsystems Microsystems

• Tools for Chemistry, Molecular Biology and Biochemistry – Sample preparation, Molecular separation

– Small-scale organic synthesis

– Amplification of nucleic acids/ Sequences

• Tools for Cell Biology

– Cell mechanics & dynamics, Cell culture devices – Dielectrophoresis, Flow cytometry, Cell sorting

• Tools for Medicine, Biomedical Devices – Minimally invasive surgery

– Neural prosthesis – Implantable devices, DDS

• Miniaturized analytical systems – Genomics and proteomics

– Clinical analysis, Environmental testing, and Warefare defense – High throughput screening

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• Implementation of MEMS to Bio-related areas (Bio Micro Electro Mechanical Systems)

• Fluid delivery system at sub-microliter scale

Needs

- Lower chip cost (Glass or plastic chips)

- Reduction of expensive reagents & test compound used - Integration of multiple functions onto a single chip

(Micro total analysis system (µ-TAS), Lab-on-a-chip) - Point-of-care (POC) diagnostics (Easy sample preparation) - High throughput (Microfluidic HTS disposables)

BioMEMS and Microfluidics BioMEMS and Microfluidics

BioMEMS Applications BioMEMS Applications

Ref) NEXUS market study

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2003 Je-Kyun Park, Ph.D.

Bio- Bio -fluidics: Theory and fluidics: Theory and Applications

Applications

What is Microfluidics?

What is Microfluidics?

Technologies/devices capable of controlling and transferring tiny quantities of liquids to allow biological assays to be integrated and accomplished on a small scale

• Microfluidics is the science of designing and manufacturing devices and processes for manipulation of extremely small volumes of liquid

• Microfluidics promises to minimize the time and cost associated with routine biological analysis while improving reproducibility

• The first wave of micro-laboratories (referred to as µ-TAS, micro total analysis systems)

• The next generation of drug discovery tools

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Generation of Concentration Gradients Generation of Concentration Gradients

Using

Using Microfluidic Microfluidic Networks Networks

• Network of capillaries generates gradient by repeatedly splitting, mixing, and combining streams of varying concentration.

• At the end, all streams carrying different concentrations are combined in a broad channel.

• Custom gradients achieved by varying initial inlet concentrations.

Anal. Chem 73(6): 1240-1246 (2001)

What is Computational Fluid Dynamics?

What is Computational Fluid Dynamics?

• CFD provides engineers a virtual laboratory to test their ideas

• Use CFD to solve the equations governing the physics of fluid behavior

• Benefits:

- Model physical fluid phenomena that cannot be easily measured with an experiment

- Investigate designs in a more cost-effective and timely manner than experiments

Make better products, and make them faster & cheaper

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Liquid Filling Simulations Liquid Filling Simulations

Sample preparation through

Sample preparation through Microfluidic Microfluidic Cartridge

Cartridge

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Sorting by Diffusion Sorting by Diffusion

PNAS 96: 13762-13765 (1999)

Microfluidic

Microfluidic Strategies Strategies

Piezoelectric IMM, IEMN,

Tronic’s Microsystem, Piezoelectric

IMM, IEMN, Tronic’s Microsystem, Centrifugal

Tecan, Gyros Centrifugal Tecan, Gyros

External actuation bioMerieux, Micronics External actuation bioMerieux, Micronics

Capillary forces Steag MicroParts Biosite Diagnostics Capillary forces

Steag MicroParts Biosite Diagnostics

Electrophoresis/

Capillarity/ Osmosis Caliper Technologies,

Nanogen, Philips Research Center

Agilent Technologies Electrophoresis/

Capillarity/ Osmosis Caliper Technologies,

Nanogen, Philips Research Center

Agilent Technologies

Magnetism/ Acoustic Aviva BioSciences Magnetism/ Acoustic

Aviva BioSciences

Pumping Techniques

Electrowetting on Dielectric

UCLA Electrowetting

on Dielectric UCLA

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2003 Je-Kyun Park, Ph.D.

Miniaturized Total Analytical Miniaturized Total Analytical

Systems Systems

Flow Injection Analysis Flow Injection Analysis

• Flow Injection Analysis (FIA) is based on the injection of a liquid sample into a moving carrier stream of a suitable liquid.

• The injected sample forms a zone, which is then

transported toward a detector that continuously records the absorbance, electrode potential, or other physical parameters as it continuously changes due to the passage of the sample material through the flow cell.

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The Response of Continuous Flow The Response of Continuous Flow

µ- µ -TAS (Total Analysis System) TAS (Total Analysis System)

• Classifying the µ-TAS field

– The analyte phase (liquid/gas)

– Mode of operation: flow-type & separation type – Application-oriented classification

• Elements of a µ-TAS

Micro Total Analysis System (µ-TAS)

Sampling units

Microfluidic

units Detectors Electronic control/signal processing Sample

Input

Output Signal

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LabCard Microfluidic

LabCard Microfluidic Devices Devices

Genomic and proteomic applications, such as RNA and DNA analysis, as well as high- throughput pharmaceutical drug screening

Aclara Biosciences

Microfluidic arrays for high-throughput submicroliter assays using CE

Caliper’s high-throughput AMS 90 SE

Electrophoresis system. This assay will analyze nanoliter sample volumes of protein mixtures from 96- and 384-well plates. The assay automatically determines constituent protein sizes and relative concentrations.

Caliper's

Caliper's LabChip LabChip® ® High Throughput High Throughput Screening System

Screening System

Caliper 250 HTS System

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Putting The Lab on a Chip Putting The Lab on a Chip

Test tubes, beakers and other glassware are replaced by microscopic channels in the chip

www.calipertech.com

The Growth of Microfluidics and Lab

The Growth of Microfluidics and Lab- -on on- -a a- - Chip Market

Chip Market

• To increase throughput and reproducibility

• To decrease cost and time to do experiments in order to streamline and accelerate laboratory assays

• To supply analytical tools and solutions dedicated primarily to the drug development research.

• To speed up and simplify the sample preparation steps in genomic and proteomic experiments

• To offer high-throughput, low-cost versions of traditional research methods

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University of Michigan

Micromechanical

Micromechanical Integrated DNA Analysis Integrated DNA Analysis

• Metering samples

• PCR reaction

• Gel electrophoresis

• Sensors and actuators Science 282: 484-487 (1998)

The

The µChemLab µ ChemLab™ : Micro Total Analysis System : Micro Total Analysis System

Sandia National Laboratories

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Requirements for Microfluidics Product Requirements for Microfluidics Product

Development Development

• Patent Analysis

– Based on selection of the appropriate patented portfolio to achieve the type of microfluidic processing needed for the individual application requirements

• Surface Chemistry/Materials Analysis

– It is one thing to know the specific microfluidic approach (“How it’s done”). It is also critical to assess the environment (“Where it’s done”) with respect to surface chemistries and possible interactions with materials used in the assay.

• Fluidic Modeling

• Detection

– How the results of microfluidic interactions on a lab card will be detected, interpreted, and reported.

2003 Je-Kyun Park, Ph.D.

NanoBio

NanoBio Systems Systems

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• Operator

• Micromanipulator

• Microscope

• Pipette puller

• Microforge

• Faraday cage

• Air table

• Perfusion system

Conventional Patch Clamp vs. Microchip

Photon Fueled Biomolecular Motor Photon Fueled Biomolecular Motor

Powered NEMS

Powered NEMS

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Nanoscale

Nanoscale Silicon Wires for Biomolecule Silicon Wires for Biomolecule Detector Detector

To detect a disease- related protein in a blood sample, a silicon wire just 10

nanometers wide is coated with

biomolecules that bind only to that protein (below). When the disease protein binds to a molecule on the wire (inset), the wire’s conductance changes, providing an instant electric signal.

Charles Lieber, Harvard University

DNA Pipeline DNA Pipeline

• To identify a particular sequence on a strand of DNA, researchers first mix the DNA with fluorescent probes that attach to that sequence. Then, on a microchip (above), an electrical field draws DNA through a channel 50 nanometers wide. An embedded optical reader detects any attached probes, identifying the sequence.

Harold Craighead, Cornell University

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NanoGate

NanoGate Implant, Implant, iMEDD iMEDD , Inc. , Inc.

Drug diffuses out through membrane at constant rate

Nanopore Wafer intelligentMicroEngineeredDrugDelivery

CHUNG MoonSoul Building (E16) ( E16)

Please visit the web site at http://biosys.kaist.ac.kr

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