CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing Roland Thewes roland.thewes@ieee.com Munich, Germany 13 February 2009 Dallas, TX Page 1 Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Outline 1. Introduction 2. Bio Molecules 2.1 Operation Principle and Applications of Microarrays 2.2 Functionalization 2.3 CMOS Integration 2.4 Electrical Readout Techniques 2.5 Assembly and Packaging Issues 3. Cells and Tissue 3.1 Cell Manipulation 3.2 Nerve Signal Recording 3.3 Neural Tissue Imaging 4. Summary Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 2 Seite 1
Introduction • Beyond classical CMOS scaling driven performance increases, summarized as “More Moore”, the ITRS roadmap considers a second branch entitled “More than Moore”. There, CMOS generates value by functional diversification and application specific extensions. • Among the related areas, “Biochips ” are explicitly highlighted. • Biotechnology and life sciences as such have gained huge attention in recent years due to the achievements of these disciplines on the one hand and due to the belief in their potential for forthcoming decades on the other. • Purpose of this talk is to provide an overview about status, challenges, and opportunities where Silicon and CMOS meet these disciplines. Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 3 Outline 1. Introduction 2. Bio Molecules 2.1 Operation Principle and Applications of Microarrays 2.2 Functionalization 2.3 CMOS Integration 2.4 Electrical Readout Techniques 2.5 Assembly and Packaging Issues 3. Cells and Tissue 3.1 Cell Manipulation 3.2 Nerve Signal Recording 3.3 Neural Tissue Imaging 4. Summary Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 4 Seite 2
DNA* Microarray Chips Purpose: Highly parallel investigation concerning the presence / absence / quantitative amount of specific (pre-defined) DNA sequences in a given sample Basic setup: Slide (“chip”) of the order mm 2 ... cm 2 made of glass / polymer material / Si Most important applications: • Genome research • Drug development • Medical diagnosis Application dependent requirements: • Sensitivity / dynamic range ( � gene expression, drug development) • Specificity ( � medical diagnosis ) * Within the context of this lecture, the DNA molecule is taken as a representative also for other important bio molecules such as proteins etc, since the biochemical boundary conditions required here can be easily explained by using the example of DNA only and since technical statements concerning CMOS extension etc. apply for other bio molecules as well. Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 5 Basic Operation Principle of DNA Microarray Chips Immobilize Flood whole chip Wash whole different DNA with sample & DNA chip chip & detect sequences on the let hybridization hybridization different positions take place match species 1 (probe molecules) species 2 species 3 sensor area sensor area sensor area mismatch microarray species N chip (probe molecules) sensor area sensor area sensor area Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 6 Seite 3
Why Electronic Readout? Light State-of-the-art commercially detector available DNA microarrays: Filter Light ( λ 1 ) optical readout by labeling the target Light ( λ 2 ) ..... ... strands with fluorescence marker ... ... Fluorescence molecules marker (“Label”) Sensor area Opportunities provided by fully Basic principle: optical readout techniques electronic readout techniques: • increased robustness • increased user friendliness • decreased system cost • increased flexibility • ... Requirement of large arrays: • CMOS integration Typical result: overlay from a number of experiments (artificial color presentation) ("large": = 10...100 sensor sites) Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 7 Entire Manufacturing / Application Chain of Microarrys Sample Opportunities to operate a CMOS ASIC Sample preparation, PCR, ... Chip Interpretation Functionali- (processed Packaging Storage Readout (i.e. make use solid state zation of the result) material) or vice versa! Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 8 Seite 4
Outline 1. Introduction 2. Bio Molecules 2.1 Operation Principle and Applications of Microarrays 2.2 Functionalization 2.3 CMOS Integration 2.4 Electrical Readout Techniques 2.5 Assembly and Packaging Issues 3. Cells and Tissue 3.1 Cell Manipulation 3.2 Nerve Signal Recording 3.3 Neural Tissue Imaging 4. Summary Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 9 DNA Microarray Functionalization Techniques ... and related application areas Optical control on-chip of in-situ growth DNA synthesis Electronic control of in-situ growth 10 0 10 1 10 2 10 3 10 4 10 5 10 6 Test sites per chip Placement controlled off-chip by electrophoretic forces Spotting Appl. Diagnostics Drug research area low medium high Density Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 10 Seite 5
Functionalization by Spotting Spotter provides / contains: � Pinhead with one or more pins, maneuverable in x-, y-, z- direction, positioning repeatability of order 10 µm � Reservoirs (e.g. microplates) with probe molecules in solutions + washing solution � Chips to be functionalized � Optionally: Position recognition system Example: Affymetrix m Procedure: 1 ~ Arrayer 417 � Pins load solutions from reservoirs and deposit small volumes (of order: 1 nl, various deposition techniques in use) at microarray target positions wash side micro- spotting station glass plates head E. Zubritsky, Anal. Chem., 2000, December 1, 72(23), pp. 761A-767A. Pinhead with Stealth™ 48 pin V. G. Cheung et al., Nat Genet., 1999, January, 21(1 Suppl), pp. 15-19. printhead four pins movies: www.bio.davidson.edu/courses/genomics/arrays/astart.html Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 11 Functionalization by electrophoresis driven movement of off-chip synthesized DNA receptor molecules to their on-chip target position (I) Noble metal site with permeation layer ELECTROLYTE to permit ion flow and to protect the G A DNA against damaging T C G C A electrophoretic G T C electrochemical reactions C G force Al wiring at the electrode. application of G positive voltage C C permeation A A T G G ~150 µm A layer C C G T T noble metal T T electrode G G +++ already under under to be funct. in a Sensor sites from a 20 x 20 Nanogen functionalized functionalization functionalization forthcoming step array using conventional optical readout. T. Sosnowski et al, Proc. Natl. acad. Sci. USA, 1997 Nanogen package M. Heller, IEEE Eng. Medicine and Biology Magazine, 1996 Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 12 Seite 6
Optically Driven In-Situ On-Chip DNA Synthesis * * Principle used by Affymetrix, NimbleGen, FeBiT Step n+1 After After Illuminate Switch off Provide Let binding Wash step n to un-protect illumination next base take place (under illumination) step n+1 probe strand and wash ( incl. protection group) � T T C A T C G T C A T C G T C A T C G C A T C G C A T C G C A T C G C A T C G protection group T T A G C T G A G C T G A G C T G A G C T G A G C T G A G C T G A G C T G Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 13 Electrically Driven In-Situ On-Chip DNA Synthesis * * Combimatrix (Seattle, WA), CEA (France) Step n+1 After After Activate Wash Switch off Provide Let binding step n un-protect (under “ un-protect” un-protect next base take place step n+1 signal switched on) signal and wash ( incl. protection group) � T T C A T C G T C A T C G T C A T C G C A T C G C A T C G C A T C G C A T C G ! ! ! un-protect protect protection group T A G C T G A G C T G A G C T G A G C T G A G C T G A G C T G A G C T G un-protect protect Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” • 13 February 2009 • Dallas, TX Page 14 Seite 7
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