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  • B i och ip S imu l a to r F l o w - B a s e d M i c r o f l u i d i c B i o c h i p S i m u l a t i o n Morten Foged Schmidt

    Subm i t ted to the depa r tmen t o f I n fo rma t i cs and Ma themat i ca l Mode l i ng on Ju l y 31 , 2012 a t the Techn ica l Un i ve rs i t y o f Denmark . !

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    Techn ica l Un i ve rs i t y o f Denmark

    ! I n fo rma t i cs and Ma thema t ica l Mode l l i ng !

    Bu i l d i ng 321, DK-2800 Kongens Lyngby , Denmark

    Phone +45 45253351, Fax +45 45882673 recep t ion@ imm.d tu .dk !

    www. imm.d tu .dk

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    !I S U M M A R Y

    Microf lu id ic biochips are min iatur ized devices that are able to integrate, on-chip, the funct ional i t ies needed to execute biochemical analys is appl icat ions. The development of microf lu id ic biochips is in a hasty development phase and the need for s imulat ion and design tools is increasing. The design and archi tecture of b iochips changes al l the t ime and designers need to know how thei r b iochip designs wi l l work before physical ly bui ld ing them. F low-based microf lu id ic biochips are one k ind of b iochip, where s imulat ion could help f ind new ways of construct ing the biochip archi tecture and schedul ing the exper iments on biochips. To the best of our knowledge no s imulat ion method has been developed so fare.

    This thesis presents a method to s imulate the logic of f low-based microf lu id ic biochips. The presented s imulat ion method could be character ized as a workf low, f rom creat ion of b iochip archi tectures and biochemical appl icat ion to the resul ts in the form of usefu l formats and v iews. Since, no f low-based biochip s imulat ion tools are avai lable at the moment, th is project includes a work ing implementat ion support ing the f indings in th is thesis. The tool is cal led Biochip Simulator.

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  • B ioch ip S imu la to r F low-Based M ic ro f l u id i c B ioch ip S imu la t i on

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    I I P R E F A C E

    This thesis documents my M.Sc. in Computer Science and Engineer ing degree at the Technical Univers i ty of Denmark (DTU). The thesis was performed in col laborat ion with the Embedded System Engineer ing (ESE) sect ion at the department of Informat ics and Mathemat ical Model l ing ( IMM). The thesis and implementat ion was done dur ing a s ix-month per iod f rom February-July 2012.

    The outcome includes an implementat ion of a f low-based microf lu id ic biochip s imulator, cal led Biochip Simulator. A user guide and the documentat ion needed to use the s imulator have been publ ished to a web page, https://s i tes.google.com/si te/biochipsimulator/. V ideo recordings showing evaluat ion cases are avai lable on the websi te, together with a v ideo showing the main features in the s imulator as wel l .

  • B ioch ip S imu la to r F low-Based M ic ro f l u id i c B ioch ip S imu la t ion

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    I I I A C K N O W L E D G E M E N T S

    I thank professor Jan Madsen for superv is ing th is thesis and research. I would a lso l ike to thank Ph.D. student Waj id Hassan Minhass and professor Paul Pop for thei r superv is ion on th is thesis and research. Waj id Hassan Minhass has given me essent ia l feedback as a f low-based microf lu id ic biochip archi tecture synthesis- and schedule designer. He met with me on a weekly basis to discuss problems and solut ions. The three superv isors have part ic ipated in and scheduled meet ings with me through the whole thesis per iod; here the progress of the thesis have been discussed and guidance have been prov ided.

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  • B ioch ip S imu la to r F low-Based M ic ro f l u id i c B ioch ip S imu la t i on

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    Table of Contents

    I ! SUMMARY ................................ ................................ ........... 4 !

    I I ! PREFACE ................................ ................................ ............ 5 !

    I I I ! ACKNOWLEDGEMENTS ................................ ......................... 6 !

    CHAPTER 1 ! INTRODUCTION ................................ ................... 11 !SECT ION 1.1 ! RELATED WORK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 !SECT ION 1.2 ! OBJECT IVES & MOT IVAT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 !SECT ION 1.3 ! CONTR IBUT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 !

    CHAPTER 2 ! SYSTEM MODEL ................................ .................. 16 !SECT ION 2.1 ! B IOCHIP ARCHITECTURE MODEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 !SECT ION 2.2 ! B IOCHEMICAL APPL ICAT ION MODEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 !SECT ION 2.3 ! SCHEDULERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 !SECT ION 2.4 ! SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 !

    CHAPTER 3 ! MOTIVATIONAL EXAMPLE ................................ ...... 26 !

    CHAPTER 4 ! FLOW-BASED BIOCHIP SIMULATION ........................ 29 !SECT ION 4.1 ! ARCHITECTURE DES IGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 !SECT ION 4.2 ! APPL ICAT ION DES IGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 !SECT ION 4.3 ! V ISUAL IZE S IMULAT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 !SECT ION 4.4 ! CONTROL DATA GENERAT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 !SECT ION 4.5 ! SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 !

    CHAPTER 5 ! IMPLEMENTATION ................................ ................ 43 !SECT ION 5.1 ! B IOCHIP ARCHITECTURE DES IGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 !SECT ION 5.2 ! ARCHITECTURE MODEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 !SECT ION 5.3 ! B IOCHEMICAL APPL ICAT ION DES IGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 !SECT ION 5.4 ! V ISUAL IZE S IMULAT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 !SECT ION 5.5 ! DATA CONTROL GENERAT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 !SECT ION 5.6 ! SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 !

    CHAPTER 6 ! EXPERIMENTAL EVALUATION ................................ .. 57 !

    CHAPTER 7 ! FUTURE WORK ................................ .................... 64 !

    CHAPTER 8 ! CONCLUSION ................................ ...................... 67 !

    REFERENCES ................................ ................................ ......... 68 !

    APPENDIX A ! BIOCHIP SIMULATOR COMPONENTS ................... 70 !

    APPENDIX B ! BIOCHIP SIMULATOR FILE FORMATS ................... 79 !

    APPENDIX C ! BIOCHIP SIMULATOR USER GUIDE ...................... 90 !

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    List of Figures

    F IGURE 1 - M ICADO SCREENSHOT. RED DOTS ARE PRESSURE SOURCES. BLUE DOTS ARE FLU ID IC INPUT SOURCES. FLU ID IC CHANNELS ARE IN-BETWEEN THE BLUE DOTS. (AM IN , M ICADO, 2008) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 !

    F IGURE 2 - S IMULAT ING IDEA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 !F IGURE 3 - FUNCT ION OF M ICRO VALVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 !F IGURE 4 - PHOTO OF A REAL M ICRO VALVE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 !F IGURE 5 SWITCH COMPONENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 !F IGURE 6 GRAPH ICAL REPRESENTAT ION OF A M IXER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 !F IGURE 7 - PHOTO OF FLU ID M IXER IN A FLOW-BASED M ICROFLU ID IC B IOCHIP

    (V IDEO FROM (TH IES, PROGRAMMABLE M ICROFLU ID IC B IOCHIPS, 2007) ) . 19 !F IGURE 8 - STORAGE COMPONENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 !F IGURE 9 - B IOCHIP ARCHITECTURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 !F IGURE 10 - USE OF A FLOW PATH TABLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 !F IGURE 11 FLOW PATH SET INFORMAT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 !F IGURE 12 - EXAMPLE OF A B IOCHEMICAL APPL ICAT ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 !F IGURE 13 SCHEDULER . . . . . . . . . . . . . . . . . . .