INTRODUCTION TO BIO-MEMS/NEMS 丁卫平 副教授、博士生导师 电子科学与技术系 电子邮件：wpdings@ustc.edu.cn 电话：18056099696 实验室：科技楼东楼 403/409/416

Dr. Ding’s Course When: 1st to 9th week, Tuesday (6,7) Where: Lectures: 3A109; Experiments: East Tech. Lab Bldg. (Dr. Ding’s Lab Rm 403-410) Assignments and Grading: Total points: 50+5 Class participation (30%): 8+2 Presentation (10%): 1 Final report (10%): 1 Experiments (+5%): 1 Presentation: PPT (review articles), 9 groups (4x9), 10 min/group, 9th week Textbook: 《Introduction to BioMEMS》Albert; Folch CRC Press 2012-07-08 Reference books: 1.《BioMEMS (microsystems)》Gerald Urban Springer，2006 2.《微纳加工科学原理》唐天同、王兆宏 编著，电子工业出版社，2010 3.《图解微流控芯片实验室》林炳承、秦建华 编著，科学出版社，2008

Great Expectations Student Learning Goals Experiment Goals Know the state of the art of BioMEMS (lectures) Learn to design/operate from scratch a microfluidic device (labs) Be able to comprehend a text from the BioMEMS literature (assignments) Experiment Goals Photomask design (computer) Photolithography Soft lithography Microfluidic gradient Quantitative analysis (microscopy, image processing)

Outlines 0: It’s a small world 1: How do we make small things? 2: Micropatterning of substrates and cells 3: Microfluidics 4: Molecular biology on a chip 5: Cell-based chips for biotechnology 6: BioMEMS for cell biology 7: Tissue microengineering 8: Microfabricated implants and sensors 9: The frontiers of BioMEMS

0. It’s a small world Dimensions and scaling in biology Size: from our bodies to our molecules Time: from life’s origin to enzymatic reactions Energy: from body heat to chemical bonds Electric currents: from electronics to ion channels Complexity Why BioMEMS? “A technology that allows us to make small “things” that are useful for biomedicine”

1. How do we make small things? Microfabrication techniques Micropatterning Photolithography Scanning Lithographies Soft Lithography Microstamping (“Microcontact Printing”) Microfluidic Patterning Stencil Patterning (模板构图) Dynamic Substrates Micromachining Micromolding: PDMS, plastics Subtraction: dry/wet etching Addition: deposition/growth

1.1. Benefits of microfabrication

1.2. Photolithography Photoresist (photosensitive organic polymer) 2. Selective illumination through mask Positive / Negative photoresist Contact / Projection 3. Dissolution of photoresist

Discussion on use of photoresist for patterning biological material Clean room requirements: biological solutions? Substrate requirements: plastic? glass? Compatible with proteins? Compatible with cells?

1.3. 3-D photoresist structures

1.4. The SU-8 era Photoplastic “SU-8” Depth = 53 µm photosensitized epoxy negative photoresist 750 rpm ~ 50 µm 30 s exp. @ 365 nm 20 min. dev. aspect ratios > 5:1 vertical sidewalls Depth = 53 µm

1.5. Tilted exposure

1.6. Biocompatible photoresists

1.7. Maskless Photolithography Laser Writer Raster Scanning of SU8

1.8. Maskless Photolithography Digital Micromirror Device Texas Instruments

1.9. Micromachining 1. Photoresist micropattern 2. Chemical etching through photoresist “mask” dry etching (ion plasma) wet etch (acids, bases, etc.) selectivity is an issue 3. Photoresist “stripping”

1.10. Metal deposition and lift-off 1. Photoresist micropattern 2.a. “Blanket” deposition of material Metal evaporation Metal sputtering 2.b. Selective growth Electrochemical growth Self-assembly 3. Photoresist “lift-off”

1.11. Micromachining of a cantilevered tip Deposition of Si3N4 Etch of Si3N4 with reactive plasma Etch of Si with HNO3/HF Three masks Si Si3N4

1.12. Flexible substrates

1.13. Laser-cut laminated devices

1.14. Laser deposition in-situ

1.15. Laser direct writing

Micromolding Duroplastic (“thermoset”) polymers Thermoplastic polymers Elastomeric polymers Injection molding Hot embossing Soft Lithography

1.16. Photolithography vs. Soft Lithography Soft lithography

First paper on microcontact printing First paper on microfluidic patterning Kim, E., Xia, Y., and Whitesides, G.M. Nature 376, 581-584 (1995)

1.17. PDMS micromolding 2. Pour polymer precursor(s) and cure 1. Photolithography 3. Peel off and cut 4. Apply

1.17. PDMS micromolding PDMS replica PDMS Photoresist (SU8) master Inexpensive Multiple replicas

1.17. The magic of PDMS Inexpensive Very elastic and soft Transparent down to 300 nm Surface is hydrophobic Self-seals by conformal contact Inert, but can be oxidized, etched, and derivatized Biocompatible Swells when exposed to solvents High permeability to gases and fluids Expands a lot with temperature

1.18. Structural integrity of PDMS walls

Soft lithography: Microcontact printing Material is added where stamp contacts surface Poly-dimethylsiloxane (PDMS) (transparent rubber) 1. Ink 2. Transfer

Microcontact printing

1.20. Selective inking of a flat stamp

Soft Lithography: Microfluidic Patterning Material is added where stamp does not contact the surface microchannels 1. Fill Inlet fabrication? Seal? Filling method? Uniformity of filling? Types of solutions? 2. Remove microchannels Immobilization of material? Procedure for removal of microchannels?

1.21. Micromolding in capillaries (MIMIC)

1.22. Microfluidically-patterned polyurethane 3D structures

Microfluidic patterning for BioMEMS Science 276, 779 (1997) microchannels filled by capillarity

1.23. Stopped-flow lithography

1.24. Railed microfluidic fabrication

1.25. Lock-release microfluidic lithography

1.26. Lock-release microfluidic lithography

1.27. Fabrication of PDMS stencils

1.28. Fabrication of PDMS stencils by exclusion molding

1.29. Tunable micromolding

1.30. Molding of PDMS from liquid patterns

Traditional photolithography is limited to 2-D Homogeneous photoresist thickness 2. Mask only has 2 levels of opacity 3. Developing is homogeneous

1.31. Microfluidic photomasks for grayscale photolithography

1.32. Agarose stamps（琼脂糖模板）

1.33. Depositing and etching of posts and wells using agarose stamps

1.34. Nanoscale lithography Also: scanning beam deposition: Energetic particles (electrons, ions, photons) break bonds in gas or liquid, resulting in solid remains

1.35. Mesoscale self-assembly