Outline CMOS Sensor Arrays for Bio Molecule 1. Introduction and Neural Tissue Interfacing 2. Bio Molecules 2.1 Operation Principle and Applications of Microarrays 2.2 Functionalization Roland Thewes 2.3 CMOS Integration 2.4 Electrical Readout Techniques 2.5 Assembly and Packaging Issues roland.thewes@ieee.com 3. Cells and Tissue Munich, Germany 3.1 Cell Manipulation 3.2 Nerve Signal Recording 3.3 Neural Tissue Imaging 13 February 2009 4. Summary Dallas, TX Page 1 Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Page 2 Outline Introduction • Beyond classical CMOS scaling driven performance increases, 1. Introduction summarized as “More Moore”, 2. Bio Molecules the ITRS roadmap considers a second branch entitled “More than 2.1 Operation Principle and Applications of Microarrays Moore”. 2.2 Functionalization There, CMOS generates value by 2.3 CMOS Integration functional diversification and application specific extensions. 2.4 Electrical Readout Techniques 2.5 Assembly and Packaging Issues • Among the related areas, “Biochips” 3. Cells and Tissue are explicitly highlighted. 3.1 Cell Manipulation • Biotechnology and life sciences as such have gained huge attention in recent 3.2 Nerve Signal Recording years due to the achievements of these disciplines on the one hand and due to 3.3 Neural Tissue Imaging the belief in their potential for forthcoming decades on the other. 4. Summary • 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 Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Page 3 Page 4 Seite 1
DNA* Microarray Chips Basic Operation Principle of DNA Microarray Chips Purpose: Highly parallel investigation concerning the presence / absence / quantitative Immobilize Flood whole chip Wash whole amount of specific (pre-defined) DNA sequences in a given sample different DNA with sample & DNA chip chip & detect sequences on the let hybridization hybridization Basic setup: different positions take place Slide (“chip”) of the order mm 2 ... cm 2 made of glass / polymer material / Si match species 1 (probe molecules) species 2 Most important applications: species 3 • Genome research • Drug development sensor area sensor area sensor area • Medical diagnosis mismatch Application dependent requirements: microarray species N • Sensitivity / dynamic range ( � gene expression, drug development) chip (probe molecules) • Specificity ( � medical diagnosis) sensor area sensor area sensor area * 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 Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Page 5 Page 6 Entire Manufacturing / Application Chain Why Electronic Readout? of Microarrys Light State-of-the-art commercially detector available DNA microarrays: Filter Sample Light ( λ 1 ) Light ( λ 2 ) optical readout by labeling the target Opportunities to ..... ... strands with fluorescence marker ... ... Fluorescence operate a CMOS ASIC molecules marker (“Label”) Sample Sensor area Opportunities provided by fully preparation, Basic principle: optical readout techniques electronic readout techniques: PCR, ... • increased robustness • increased user friendliness • decreased system cost Chip Interpretation • increased flexibility (processed Functionali- Packaging Storage Readout (i.e. make use solid state zation • ... of the result) material) Requirement of large arrays: • CMOS integration Typical result: overlay from a number of experiments (artificial color presentation) ("large": = 10...100 sensor sites) or vice versa! Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Page 7 Page 8 Seite 2
DNA Microarray Functionalization Techniques Outline ... and related application areas 1. Introduction Optical control on-chip 2. Bio Molecules of in-situ growth DNA synthesis 2.1 Operation Principle and Applications of Microarrays Electronic control 2.2 Functionalization of in-situ growth 2.3 CMOS Integration Test sites 2.4 Electrical Readout Techniques 10 0 10 1 10 2 10 3 10 4 10 5 10 6 per chip 2.5 Assembly and Packaging Issues Placement controlled off-chip 3. Cells and Tissue by electrophoretic forces 3.1 Cell Manipulation Spotting 3.2 Nerve Signal Recording 3.3 Neural Tissue Imaging 4. Summary Appl. Diagnostics Drug research area Density low medium high Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Page 9 Page 10 Functionalization by Spotting Functionalization by electrophoresis driven movement of off-chip synthesized DNA receptor molecules to their on-chip target position (I) Spotter provides / contains: � Pinhead with one or more pins, Noble metal site with permeation layer ELECTROLYTE maneuverable in x-, y-, z- direction, to permit ion flow and to protect the positioning repeatability of order 10 µm G A DNA against damaging T C G C A electrophoretic G T C � Reservoirs (e.g. microplates ) with probe C electrochemical reactions G force Al wiring at the electrode. molecules in solutions + washing solution application of G � Chips to be functionalized positive voltage C C � Optionally: Position recognition system A A permeation T Example: G G A layer ~150 µm Affymetrix ~ 1m C C G Procedure: T T Arrayer 417 noble metal T T � Pins load solutions from reservoirs and electrode G G deposit small volumes (of order: 1 nl, various deposition techniques in use) +++ at microarray target positions 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. 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. T. Sosnowski et al, Proc. Natl. acad. Sci. USA, 1997 printhead four pins Nanogen package movies: www.bio.davidson.edu/courses/genomics/arrays/astart.html 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 Roland Thewes • “CMOS Sensor Arrays for Bio Molecule and Neural Tissue Interfacing” •13 February 2009 • Dallas, TX Page 11 Page 12 Seite 3
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