FABRICATION OF MICRO- AND NANOFLUIDIC LAB-ON-A-CHIP DEVICES UTILIZING PROTON BEAM WRITING TECHNIQUE WANG LIPING A THESIS SUBMITTED FOR THE DEGREE OF PhD DEPARTMENT OF PHYSICS NATIONAL UNIVERSITY OF SINGAPORE 2008 © Copyright by Wang Liping, 2008 NATIONAL UNIVERSITY OF SINGAPORE DEPARTMENT OF PHYSICS The undersigned hereby certify that they have read and recommend to the Examination Committee for acceptance a thesis entitled “Fabrication of Micro- and Nanofluidic Lab-on-a-chip Devices Utilizing Proton Beam Writing Technique” by Wang Liping© in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Thesis Submission: Oct 2007 Oral Defense: Feb 2008 Resubmission: Feb 2008 Research Supervisor : ----------------------------------------------Prof. Frank Watt Internal Examiner : ----------------------------------------------A/Prof. Sow Chorng Haur Internal Examiner : ----------------------------------------------A/Prof. Johan R.C. van der Maarel External Examiner : ----------------------------------------------A/Prof. Stuart Victor Springham ii NATIONAL UNIVERSITY OF SINGAPORE Date: Feb 2008 Author: Wang Liping © Title: Fabrication of micro- and nanofluidic lab-on-a-chip devices utilizing Proton Beam Writing technique. Department: Physics Degree: PhD Year: 2008 Permission is herewith granted to National University of Singapore to circulate and to copy for noncommercial purposes, at its discretion, the above title upon the request of individuals or institutions. ------------------------------------------------Signature of author THE AUTHOR RESERVES OTHER PUBLICATION RIGHTS, AND NEITHER THE THESIS NOR EXTENSIVE EXTRACTS FROM IT MAY BE PRINTED OR OTHERWISE REPRODUCED WIHTOUT THE AUTHOR'S WRITTEN PERMISSION. THE AUTHOR ATTESTS THAT PERMISSION HAS BEEN OBTAINED FOR THE USE OF ANY COPYRIGHTED MATERIAL APPEARING IN THIS THESIS (OTHER THAN BRIEF EXCERPTS REQUIRING ONLY PROPER ACKNOWLEDGEMENTS IN SCHOLARLY WRITING) AND THAT ALL SUCH USE IS CLEARLY ACKNOWLEDGED. iii To my dearest parents iv Table of Contents Table of Contents v Synopsis ix Acknowledgements xii Introduction Micro- and Nano-fabrication Technologies 1.1 Optical Lithography . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Deep UV Lithography . . . . . . . . . . . . . . . . . . . . . . . 1.3 Extreme UV Lithography . . . . . . . . . . . . . . . . . . . . . 1.4 X-Ray Lithography . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 Electron Beam Lithography . . . . . . . . . . . . . . . . . . . . 1.6 Ion Beam Lithography . . . . . . . . . . . . . . . . . . . . . . . 1.6.1 Focused Ion Beam . . . . . . . . . . . . . . . . . . . . . 1.6.2 Proton Beam Writing . . . . . . . . . . . . . . . . . . . . 1.6.3 Ion Projection Lithography . . . . . . . . . . . . . . . . 1.7 Polymer materials and replication techniques . . . . . . . . . . . 1.7.1 Polymer material properties . . . . . . . . . . . . . . . . 1.7.2 Hot embossing . . . . . . . . . . . . . . . . . . . . . . . 1.7.3 Injection Molding . . . . . . . . . . . . . . . . . . . . . . 1.7.4 Soft Lithography . . . . . . . . . . . . . . . . . . . . . . 1.8 Proton Beam Writing and methods for lab-on-a-chip production 1.8.1 Physical characteristics of protons . . . . . . . . . . . . . 1.8.2 Application areas of proton beam fabrication . . . . . . . 1.8.3 Strategies for lab-on-a-chip fabrication . . . . . . . . . . 1.9 Objective of the Study . . . . . . . . . . . . . . . . . . . . . . . v . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 12 13 15 19 20 21 23 24 25 26 27 28 29 30 32 33 36 Fast Prototyping of PMMA Nanofluidic Devices 2.1 Descriptive overview of micro- and nanofluidics . . . . . . . . . . 2.1.1 Classification of fluid flow . . . . . . . . . . . . . . . . . . 2.1.2 Reynolds number . . . . . . . . . . . . . . . . . . . . . . . 2.1.3 Fluid property at micro- and nanoscales . . . . . . . . . . 2.1.4 Related issues on micro- and nanofluidic devices . . . . . . 2.2 Instrumentation of PBW technique . . . . . . . . . . . . . . . . . 2.3 Resist materials for PBW . . . . . . . . . . . . . . . . . . . . . . 2.3.1 General properties of PMMA . . . . . . . . . . . . . . . . 2.3.2 Spin-coating of PMMA resist . . . . . . . . . . . . . . . . 2.3.3 PMMA development . . . . . . . . . . . . . . . . . . . . . 2.4 Fabrication of PMMA nanofluidic structures . . . . . . . . . . . . 2.4.1 Beam focusing . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2 Adjustment of the focal plane . . . . . . . . . . . . . . . . 2.4.3 Dose normalization . . . . . . . . . . . . . . . . . . . . . . 2.4.4 Dose correction . . . . . . . . . . . . . . . . . . . . . . . . 2.4.5 Single-loop scanning versus multi-loop scanning . . . . . . 2.4.6 Exposure strategies . . . . . . . . . . . . . . . . . . . . . . 2.5 Integration of nanofluidic device . . . . . . . . . . . . . . . . . . . 2.5.1 Bonding techniques . . . . . . . . . . . . . . . . . . . . . . 2.5.2 Nanochannel integration by novel thermal bonding method 2.5.3 Optimization of bonding process . . . . . . . . . . . . . . . 2.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Batch Fabrication of PDMS Micro- and Nanofluidic Devices 3.1 Soft lithography and substrate material . . . . . . . . . . . . . . 3.1.1 Material properties of PMDS . . . . . . . . . . . . . . . 3.1.2 Technical problems of PDMS molding . . . . . . . . . . . 3.2 Polymer replication stamps . . . . . . . . . . . . . . . . . . . . 3.2.1 SU-8 stamp . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Metallic replication stamp . . . . . . . . . . . . . . . . . . . . . 3.3.1 Electroplating principles . . . . . . . . . . . . . . . . . . 3.3.2 Nickel sulfamate electroplating . . . . . . . . . . . . . . . 3.3.3 Fabrication of Ni stamp using PMMA resist template . . 3.4 PDMS fabrication strategies . . . . . . . . . . . . . . . . . . . . 3.4.1 Replication procedure . . . . . . . . . . . . . . . . . . . 3.4.2 Surface dynamic coatings . . . . . . . . . . . . . . . . . . 3.4.3 Hydrophilic treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 . 77 . 78 . 80 . 83 . 83 . 87 . 88 . 91 . 93 . 97 . 98 . 101 . 103 vi . . . . . . . . . . . . . 37 37 37 38 39 40 44 50 51 52 55 56 58 60 61 62 63 64 69 69 69 73 75 3.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Electrokinetic Characterization of PDMS Microfluidic Channels 4.1 Electrokinetic phenomena . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 Electroosmosis . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Electrophoresis . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Characterization of electroosmotic effect . . . . . . . . . . . . . . . 4.2.1 Current monitoring . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Experimental setup and method . . . . . . . . . . . . . . . . 4.2.3 Results and discussion . . . . . . . . . . . . . . . . . . . . . 4.3 Characterization of electrophoretic effect . . . . . . . . . . . . . . . 4.3.1 Micro-particle image velocimetry (µPIV) . . . . . . . . . . . 4.3.2 Experimental setup and procedure . . . . . . . . . . . . . . 4.3.3 Results and discussion . . . . . . . . . . . . . . . . . . . . . 4.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 106 106 111 113 113 114 116 121 122 122 126 132 Investigation of Red Blood Cell (RBC) Deformability in PDMS Microchannels 134 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 5.1.1 Physiological and mechanical properties of RBCs . . . . . . . 135 5.1.2 Inspection techniques . . . . . . . . . . . . . . . . . . . . . . . 138 5.2 Fabrication of microfluidic channel-device . . . . . . . . . . . . . . . . 142 5.3 Experimental instruments and methodology . . . . . . . . . . . . . . 145 5.3.1 Flow generating systems . . . . . . . . . . . . . . . . . . . . . 145 5.3.2 Visualization and data processing systems . . . . . . . . . . . 146 5.3.3 Sample preparation . . . . . . . . . . . . . . . . . . . . . . . . 148 5.4 Deformation of RBCs in micro-capillaries . . . . . . . . . . . . . . . . 148 5.5 Transportation of RBCs in micro-capillaries . . . . . . . . . . . . . . 154 5.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Application of Nanofluidic Devices in Fluorescence Correlation Spectroscopy 160 6.1 Fluorescence Correlation Spectroscopy(FCS) . . . . . . . . . . . . . . 161 6.1.1 FCS setup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 6.1.2 What can be studied using FCS? . . . . . . . . . . . . . . . . 162 6.1.3 How to read FCS results? . . . . . . . . . . . . . . . . . . . . 163 6.1.4 How to improve FCS performance? . . . . . . . . . . . . . . . 165 6.1.5 FCS for single molecule detection . . . . . . . . . . . . . . . . 167 6.2 Nanoscale fluidic channels . . . . . . . . . . . . . . . . . . . . . . . . 167 vii 6.3 6.4 6.5 PMMA nanofluidic devices for FCS measurements . . . . . . . . 6.3.1 Channel design and fabrication . . . . . . . . . . . . . . 6.3.2 FCS instruments . . . . . . . . . . . . . . . . . . . . . . 6.3.3 Perfusion and fluorescence imaging . . . . . . . . . . . . 6.3.4 FCS measurements in confined nanochannels . . . . . . . PDMS nanofluidic devices for FCS measurements . . . . . . . . 6.4.1 Channel design and fabrication . . . . . . . . . . . . . . 6.4.2 Perfusion and fluorescence imaging . . . . . . . . . . . . 6.4.3 FCS measurements in confining micro- and nanochannels Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 170 171 172 176 178 178 178 180 184 Overall conclusions 186 Appendix 190 A PMMA and SU-8 spin-coating curves 190 B Publications 192 Bibliography 193 viii Synopsis Proton Beam Writing (PBW), pioneered at the Center for Ion Beam Applications (CIBA), National University of Singapore, is a novel mask-less lithographic technique. It relies on a focused beam of high energy fast ions e.g. MeV protons or H+ to rapidly pattern resist materials with nanometer scale details. The inherent properties of protons endow the technique with unique advantages, and distinguish it from conventional optical lithography and various Next Generation Lithography (NGL) techniques. Potential applications of the technique are the fabrication of microand nanofluidic devices and biochips by both fast prototyping and batch fabrication methods to fulfill the need for lab-on-a-chip systems. In this thesis, we describe the development of proton beam writing for the fabrication of lab-on-a-chip devices. Chapter introduces alternative micro- and nano-fabrication technologies, including mainstream lithographic techniques and supplementary polymer replication techniques. The principle, application and prospective development to the respective approaches are given. In particular, fabrication strategies based on proton beam writing technique are detailed and the objective of the study is addressed. In Chapter 2, an overview of fluid principles is presented, and then the fast prototyping fabrication of PMMA nanofluidic devices is described. The instrumentation, substrate materials and related processing steps are explained for carrying out proton beam writing, followed by a detailed discussion of exposure procedures ix x and improvement of operation conditions for high-resolution patterning. In addition, a novel thermal bonding technique is presented, which has been demonstrated to be useful for enclosing PMMA nano-structures to construct functional lab-on-a-chip fluidic devices in a fast and direct way. Chapter presents a bulk fabrication strategy using PDMS elastomer. An introduction to the polymer property is given, then the fabrication of SU-8 polymer stamps and Nickel sulfamate bath electroplating of metallic stamps are described. The PDMS replication processes are described in detail, and the surface modifications, which are important to satisfy different application requirements, are explained. Chapter provides a fluidic characterization of PBW fabricated PDMS channels be means of electrokinetic on-chip testings. Current monitoring and µPIV methods are employed to examine the electrokinetic flow in the PDMS microchannels with inner surface treatment. Results from our study suggest further applications in complex bioparticle manipulations relying on electroosmosis and electrophoresis effects, such as DNA/protiens sequencing and separation. Chapter presents a investigation into deformation behaviors of healthy human Red Blood Cells (RBCs) in PDMS simulated micro-capillaries. The precision and fidelity of bulk-produced fluidic microchannels provides good reproducibility in the measured data. 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[...]...xi application of PDMS nanochannel systems in single molecule detection and nano uidic analysis The final chapter gives an overall conclusion of the research projects Both the results of the fabrication and the characterization/application of the micro- and nano uidic devices are evaluated In addition, prospective developments of the fabrication strategies utilizing proton beam writing technique, and. .. complexity and the interdisciplinary nature of this area, it is crucial 4 to include a diverse range of expertise in both the fabrication and application areas to address issues relating to lab- on- a- chip devices This is one of the prime reasons for carrying out the research presented in this thesis Chapter 1 Micro- and Nano -fabrication Technologies The design and application of micro- and nano uidic devices. .. sample materials, and new chip designs Many next generation lithography (NGL) methods have been developed which will lead to great advancements in the area of lab- on- a- chip devices In this chapter, a variety of micro and nano -fabrication techniques are discussed This discussion starts from an array of conventional lithographic techniques which have attained an adequate level of maturity to allow for... device applications is the rapid evolution of miniaturized micro- and nano uidic systems, so-called micro total analysis systems (µTAS) or lab- on- a- chip devices, which have become 3 a dominant trend in emerging nano- science and nano- technologies The miniaturization of devices leads to many practical benefits including decreased analysis time, reduced volume of analytes and reagents, increased operation... detection systems, micro- reactors and micro- mixers, micro- arrays or combinations of the above Analytical operations of the devices involve sample preparation, sample injection, micro uid and microparticle handling, cell culture, separation and detection of biological particles, such as cells, proteins and DNA molecules These are carried out by means of chromatography, electrochemistry, fluorescence, optical... the labon -a- chip concept In this area, many existing technologies are being optimized, and many new micro- and nano -fabrication approaches are simultaneously being explored Though it is believed that the long-term impact of lab- on- a- chip technology in our lifetime will be similar to the impact made by the microelectronics and computer technologies, lab- on- a- chip science and engineering, as well as the... Synchrotron radiation(SR) represents a combination of bright short wavelength radiation with good collimation and hence provides X-ray lithography with an ideal radiation source [26] A main challenge in X-ray technology is the fragility and dimensional instability of 15 the mask [32] As most materials attenuate X-rays rapidly with increasing thickness, the X-ray mask can no longer be made on thick plates... bio-compatible properties which are desirable in biological operations In contrast, polymers offer an attractive alternative to Si and glass, because they are bio-compatible, disposable, optically transparent and inexpensive [6] Another particular advantage for polymers is that a wide range of fabrication technologies are available to construct polymer-based fluidic devices, either to fast prototype an experimental... devices are dedicated by the availability of technologies to construct and employ them into functional analytical systems with various detection modes Since the lab- on- a- chip concept has been conceived to be a powerful tool capable of performing versatile sample detection and analysis, it is important to improve the existing technology as well as to explore new fabrication and integration strategies, sample... 2.12 Proton- induced secondary electron image from a free-standing nickel grid The grid has been fabricated by a combination of proton beam writing and nickel electroplating The secondary electron image has been taken by a 2 MeV proton beam at 0.5 pA current 59 2.13 SEM image showing nano uidic channel system in 2 µm PMMA reisist 65 2.14 Detailed geometries of nanochannels: a minimum feature . they have read and recommend to the Examination Committee for acceptance a thesis entitled Fabrication of Micro- and Nanofluidic Lab-on-a-chip Devices Utilizing Proton Beam Writing Technique . FABRICATION OF MICRO- AND NANO- FLUIDIC LAB-ON-A-CHIP DEVICES UTILIZING PROTON BEAM WRITING TECHNIQUE WANG LIPING A THESIS SUBMITTED FOR THE DEGREE OF. Date: Feb 2008 Author: Wang Liping © Title: Fabrication of micro- and nanofluidic lab-on-a-chip devices utilizing Proton Beam Writing technique. Department: Physics Degree: PhD