MEMS for Bio Applications MEMS for Bio Applications October 14, 2003 Kim, Yong-Kweon School of Electrical Engineering and Computer Science Seoul National University Lab. for Micro Sensors and Actuators, SNU since 1992 Contents Contents MEMS Applications • • Bio Applications - Micro Array: Peptide Micro Array - Bead Affinity Chromatography Chips - Enzyme Reaction in a Micro Fluidic System - Bio Measurement : Lens and Scanner • Summary Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 2/ 25
Applications of MEMS Applications of MEMS Lab. for Micro Sensors and Actuators, SNU since 1992 Applications of MEMS Applications of MEMS Applications of MEMS - MEMS has been developed as a break-through technology. - Pressure sensors - Pressure sensors - Accelerometer - Accelerometer Gyroscope - Gyroscope - Digital Micromirror Device - Digital Micromirror Device - I nkjet Head - I nkjet Head - - Optical Switch - Optical Switch Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 4/ 25
Conventional vs. MEMS I nertial Conventional vs. MEMS I nertial Measurement Units Measurement Units Conventional MEMS I nertial Measurement Unit Mass : 10 grams Size : 2 cm x 2 cm x 0.5 cm Mass : 1587.5 grams Pow er : ~ 1 mW Size : 15 cm x 8 cm x 5 cm Survivability : 100 kG’s Pow er : 35 W Cost : $ 500 Survivability : 35 G’s Cost : $ 20,000 - The merits of MEMS are to be small, light, cheap, multi-functional and integrated with mechanical and electronic components. From DARPA Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 5/ 25 Mass Spectrograph on a Chip Mass Spectrograph on a Chip Conventional MEMS I on Detection Array Magnet Filter Memory Mass Spec Chip I on Optics $ 20 Vacuum Pumps 0.2 kg 0.5 W Slits Processor 3 cm 3 Sample Dual Support I onizer Gas Filter Electronics $ 17,000 I nput 7 0 kg 1,200 W 20,000 cm 3 From DARPA - Mass spectrograph on a chip will be integrated with vacuum pumps, ionizer, an ion detector array, and control electronic circuits. - The MS on a chip enables potable measurement units and point-of-care will be available. - BioMEMS provides new methodologies to the biotechnology. - For examples, lab-on-a-chips, Affymetrix DNA chips, and high throughput screening chips continue to evolve the biotechnology. Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 6/ 25
Bio Applications : Peptide Micro Array Bio Applications : Peptide Micro Array Synthesized using Synthesized using Micromirror Micromirror Array Array Lab. for Micro Sensors and Actuators, SNU since 1992 DNA Micro Array DNA Micro Array Segment from DNA micro arrays • Probes that cell being test for: tested DNA -double helix strands - DNA sequencing assay - Microfabrication (a) Contact printing DNA broken (b) Inkjet printing into fragments (c) In situ fabrication using and tagged inkjet Base pair (d) In situ fabrication using being Strong Weak bonds bond investigated photolithography Merits • - One chip assay Field - Performance is improved - Assay time and cost are Enlarged reduced Gene view of four fields chip - Easy manipulation Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 8/ 25
Making Micro Arrays Making Micro Arrays Making micro arrays • - Just printing Contact I n situ fabrication using Wetted pin printing Photolithography (a) Contact printing Light at 365 nm (b) Inkjet printing Mask - In situ fabrication I nkjet Nozzle (c) In situ fabrication using inkjet printing (d) In situ fabrication using photolithography Photosensitive chemical • I n situ fabrication using photolithography Substrate - Light at 365nm is shone through a mask. I n situ fabrication using inkjet - The light releases the capping chemical, Nozzle Nucleotide exposing parts of the substrate. - A solution is then washed over the substrate. Nucleotide with photosensitive - The nucleotides attach to the unprotected Repeat chemical sites, adding their own capping layer. - The process is repeated, building up sequences of DNA. Suitable to mass production with • the same sequence. Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 9/ 25 Synthesis of Peptide Micro Array using Synthesis of Peptide Micro Array using Micromirror Array Micromirror Array Observation camera Reaction Wasting chamber port Reagent delivery Micro fluidic port systems 3 x 3 units operation (1 unit : 2 x 2 mirrors) UV illuminator SoEE Port connected to a biochip Micromirror reagent On-state Photoresist(AZ1512) patterns Micromirror produced by micromirror array Off-state Line 1 a b c de f g h Proje (Biotin) Schematic drawing of biochip fabrication system ction 2 Dut 4 time[ Line 2 Y distance y min] 6 (HPQI G) cycl 8 e of 1 Line 3 mir 0 1 (I HPQG) ror 2 1 = 4 1 0.6 Line 4 6 8 X (I GHPQ) distance Peptide micro array Mircromirror : 50 ㎛ x50 ㎛ Mirror array-16x16 Y.-K. Kim and Y.-S. Lee, SNU Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 10/ 25
MMA Systems for Peptide Synthesis on a Chip MMA Systems for Peptide Synthesis on a Chip UV light • Virtual mask pattern illumination • Virtual mask pattern generator generator Inlet - Micromirror array(MMA) - Micromirror array(MMA) • UV imaging optics for MMA • UV imaging optics for MMA photolithography photolithography MMA Slide chip UV Imaging optics • Flow cell for surface (lens, filter, stop) • Flow cell for surface synthesis chemistry synthesis chemistry Reaction - Reagent delivery to the chamber - Reagent delivery to the Flow system for flow cell flow cell peptide/ligand Outlet Y.-K. Kim, SNU synthesis Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 11/ 25 Peptide Array Synthesis on a Chip using MMA and Peptide Array Synthesis on a Chip using MMA and Protein Binding Assay Protein Binding Assay UV illuminator A Amino acids Amino acids A 11 A 12 A 13 G: Glycine G: Glycine A 21 A 2 2 A 2 3 A’ I : I soleucine Micromirror A 31 A 3 2 A 3 I : I soleucine UV On-state 3 Q : Glutamine Micromirror Q : Glutamine Selective Off-state Fabricated photolithography P : Proline biochip P : Proline H : Histidine NVOC NVOC H : Histidine Micromirror array UV NVOC NVOC NVOC G G G G G G NVOC NVOC NVOC N N N H H H N N N H H H N N N H H H N N N H H H NVOC NVOC NVOC NVOC NVOC NVOC NVOC NVOC spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer 2 ) i) UV(365nm, 30mW/ cm N N H H N N H H N N H H N N H H spacer spacer spacer spacer spacer spacer spacer spacer i) UV(365nm, 30mW/ cm 2 ) ii) 5mM NVOC- I Glass Glass BOP,HOBt in DMF ii) 5mM NVOC- G Glass H H I I I I BOP,HOBt in DMF H H G G P P NVOC H H Q Q P P I NVOC I I Q Q P P NVOC NVOC NVOC G G G G G G NVOC NVOC NVOC i) 0.5% (w/ v) BSA in 50mM phosphate N N N H H H N N N H H H N N N H H H N N N H H H Biotin Biotin Biotin Biotin G G G G G G G G Q Q Q Q buffer ( pH= 7.4 ) spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer N N N N H H H H N N N N H H H H N N N N H H H H N N N N H H H H ii) FI TC -streptavidin spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer spacer in 50mM phosphate buffer ( pH= 7.4 ) Glass Glass Glass Glass Glass Y.-S. Lee, SNU Total ; 9 photolithography processes Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 12/ 25
Ligand Ligand I nteraction using MMA I nteraction using MMA � Assay on a chip � Assay on beads � Assay on a chip � Assay on beads Line 1 Line 1 Background Background Line 2 Line 2 0.7 Intensity of fluorescence[au] 90 Y distance Line 3 Line 3 Error range 0.6 Opitical Density[a.u.] 80 Line 4 Line 4 0.5 70 X distance 0.4 60 0.3 50 Error range 0.2 40 0.1 30 0.0 20 Biotin HPQIG IHPQG IGHPQ Bg Line 1 Line 2 Line 3 Line 4 Biotin HPQIG I HPQG IGHPQ � Fluorescence assay v s Enzyme assay � Sensitivity & S/N � One chip analysis v s 4 times ELISA with sophisticated controlled condition Assay time( labor) reduced ( < 1/ 7days) , Convenience( automated synthesis Assay time( labor) reduced ( < 1/ 7days) , Convenience( automated synthesis by MMA systems), I mprovement of assay reliability by comparison on a chip Y.-S. Lee, SNU by MMA systems), I mprovement of assay reliability by comparison on a chip Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 13/ 25 Merits of the Synthesis using MMA Merits of the Synthesis using MMA On resin(bead) On surface(chip) Comments NH 2 NH 2 Surface density 0.1 mmol/ g 1 nmol/ cm 2 5 mM solution in 200 Quantity resin 500 mg ㎕ flow cell 150 μ mol / reaction 1 μ mol / reaction Required amino acid 100 mg resins for each penta peptide for 3 kinds GI QPH GI QPH of sequence Application example QPHGI QPHGI G:Glycine, I : I soleucine, GQPHI GQPHI Q: Glutamine, P: Proline, H: Histadine 15 times x 150 μ mol Reagent quantity 3 sequences x penta 15 μ mol = 2250 μ mol peptide = 15 times (Amino acids) affinity assay of Assay time (labor) ~ 7 days < 1 day streptavidin - The MMA system provides the flexibility on biopattern design and fast turn- around analysis. Y.-K. Kim and Y.-S. Lee, SNU Lab. for Micro Sensors and Actuators, SNU Kim, Yong-Kweon 14/ 25
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