Microfabrication technologies for plastic microfluidics

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Microfabrication technologies for plastic
microfluidics
Angeliki Tserepi Researcher IMEL - NCSR
Demokritos
Methods in Micro- Nano-technology and
Nano-bio-technology Summer School 08,
NCSR-Demokritos
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Unlike microelectronics, in which the current
emphasis is on reducing the size of transistors,
microfluidics is focusing on making more complex
systems of channels with more sophisticated
fluid-handling capabilities, rather than reducing
the size of the channels. These systems require
the same types of components as larger
fluid-handling systems pumps, valves, mixers,
filters, separators, and the like. Although the
sizes of channels are large relative to the size
of features in microelectronic devices, they are
small enough so that flows in them behave quite
differently than do the large-scale flows that
are familiar from everyday life. The components
needed at small scales are therefore often quite
different from those used at large scales. G.
Whitesides, Dept. of Chemistry Biological
Chemistry, Harvard
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Introduction
Microfluidics science and technologies for
designing/ fabricating devices and processes for
handling and control of minute amounts of fluids
in a miniaturized system
Yole Développment Report Oct. 2004 Emerging
markets for Microfluidics Applications
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Market predictions
Yole Développment Report Nov. 2004 Emerging
markets for Microfluidics Applications
Yole Développment Report May 2007 Emerging
markets for Microfluidics Applications
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Outline

• History
• Miniaturization
• Motivation for using plastics/polymers
• Fabrication (patterning bonding) technologies
  for plastics/polymers
• Examples of plastic microfluidic devices
• Conclusions

Chem Lab-on-a-Chip from Sandia
Lab-on-a-Chip (Bio-analyzer) from Agilent
Technologies
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History

• History of µ-fluidics
• 1975 1st analytical miniaturized device on Si
  (GCA, separation in sec, Stanford)
• 1990 µTAS (Manz), integrated device for sample
  pretreatment, CE separation, detection, on Si
• devices on plastic substrates appeared in
  patents only
• 1993 devices on Si and glass for DNA
  amplification (PCR)
• 1994-1997 growing to critical mass, devices for
  PCR and PCRCE
• 1997 1st miniaturized CE system in PDMS
• commercial companies started investing heavily
  in microfluidics
• interest in plastic substrates begun to increase

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Motivation for miniaturizing applications in
Chemistry and the Life Sciences

• transport controlled by diffusion flow regime
  is laminar
• Scaling laws
• - diffusion time-a molecule needs to travel l by
  diffusive processes
• tD l2 when l ? from cm to 100 µm, timescale
  ? from hours to sec
• - separation efficiency in CE N/t 1/d2 when
  d? 10 separation speed x100
• reduced consumption of reagents and analytes
• reduced time of analysis
• increased resolution
• high throughput (parallel faster analysis)

Example Proteomics 1960 1 protein/day -10-3
mole 2002 10-100 proteins/day 10-13 mole
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Plastics/Polymers as structural materials
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Polymers general properties

• macromolecular (10,000-100,000 Da, gt1000
  monomeric units)
• Tg glass transition temperature
  plastic-viscous, can be molded
• melting temperature highly viscous mass
• decomposition temperature material ceases to
  function

1. Thermoplastic (PA, PC, PE, PMMA, PP, PS, PEEK,
   COC)
2. Elastomers (PDMS)
3. Duroplastic

fabrication of microfluidics
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Plastic/Polymer patterning technologies
Replication methods
Late 1990s

• Injection molding
• Hot embossing
• Casting techniques
• (replica molding)

Common characteristic in all techniques require
use of masters
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Master fabrication I

• Rapid prototyping

• Master in SU(8) photoresist (UV) on a Si wafer
  quite durable, however replication in a hard
  polymer (polyurethane) can further extend its
  lifetime (resolution 5 µm)
• Master fabricated with x-ray sensitive resists
  followed by electroplating (LIGA-technique,
  resolution 0.2 µm)

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Master fabrication II

• Other master fabrication technologies include
• -Si micromachining (high resolution 2 µm
  however subsequent electroplating is
  recommended for increased durability)
• -laser ablation (resolution 5 µm)
• -mechanical micromachining (resolution 50 µm)

Master fabricated by Si micromachining
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Injection molding

• Low viscosity copolymer is injected into a mold
  insert
• Mold by Ni electroform from Si master
• Good contact with the mold is required (low
  viscosity) to result in well resolved feature
  reproduction
• Mold temperature and process time should be
  adjusted for excellent precision
• Mold insert and Ni electroform can be used to
  produce 100,000s parts
• Materials PMMA, PC
• Production of 3D structures
• Inclusion of preformed parts in the molded
  plastic

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Hot embossing/imprinting

• Low cost mass production technique
• Stamps can be Si or metal
• Heating of the plastic at its softening
  temperature at lower pressures or at
  room-temperature at elevated pressures
• Materials PS, PMMA, PVC,

Resolution 25 nm
Microplate with 96 CE devices
Metal mechanical micromachined tool
Si stamp Imprinted channel in PMMA
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Casting/Replica molding

• Casting of prepolymer against a master and
  allowed to cure generating a negative replica
  easily detachable from the master
• Materials elastomeric polymers, PDMS
• Masters not subjected to excessive heat or
  pressure, therefore usually produced in
  photoresist but other materials can be used
• Resolution and roughness of the master is
  reproduced
• Advantage easily bonded to most of surfaces (Si,
  SiO2, other plastic)
• facilitates fabrication of multilayered
  structures

Channels of a miniaturized CE device created by
molding PDMS against a lithographic master
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Soft lithography

• Use of elastomeric patterned PDMS stamps to
  generate structures
• Require little capital investment
• Ambient laboratory conditions
• Able to generate features on curved substrates

• MicroContact Printing MicroTransfer Molding
• MIcroMolding In Capillaries Replica Molding

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Soft lithography techniques (I)

• Replica Molding allows duplication of 3D
  topologies in a single step
• Use of elastomers facilitates the release of
  small fragile structures
• Harder polymers are then molded against the
  secondary master

Resolution 30 nm
Master (Au) Replica (PU)
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Soft lithography techniques (II)

• Microtransfer molding
• PDMS stamp is filled with a prepolymer and
  placed on substrate
• Polymer cured and stamp removed
• Able to generate multilayer structures

Resolution 250 nm
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Soft lithography techniques (III)

• Micro-molding in capillaries
• Continuous channels formed upon contact of PDMS
  stamp with substrate
• A polymer precursor fills channels with capillary
  action
• Polymer is cured and stamp is removed

Resolution 1 µm
Membrane of PU
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Soft lithography techniques (IV)

• Micro-contact Printing
• An ink is spread on a patterned PDMS stamp
• The stamp is then brought into contact with the
  substrate
• The ink is then transferred to the substrate
  where it can act as a resist against etching
• Ink can be a SAM or a biological sample

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Soft lithography

• Restrictions
• High resolution registration is problematic due
  to distortion of PDMS
• Multilevel structures necessitate accurate
  placement of many layers, only possible with
  relaxed requirements
• Defects dust particles, bubbles in precursor,
  residual thin polymer film

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Comparison of micro-molding technologies
?
?
?
?
?
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Direct methods (not based on use of a master)

• laser photo-ablation (1997)
• polymer degradation by UV absorption
• direct-write or through mask
• roughness formation
• materials PMMA, PVC, PET, PS, cellulose acetate,
  
• resolution 1 µm

Channel fabricated by laser ablation of PMMA
optical lithography (deep resists, e.g.
SU(8)) stereolithography (with focused laser
beams) micromilling (CNC micromachining,
resolution down to 100 µm) ion milling
(Ar) plasma etching (under development,
appropriate for mass production)
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Summary

• Non-photolithographic patterning methods
• low cost technology
• allows patterning of non-planar surfaces
• can generate 3D structures
• applicable to patterning of a variety of
  materials
• applicable to patterning of functionalities of
  certain chemistry

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Surface modification and sealing (I)

• few methods of stable chemical modification of
  plastic channels (e.g. PMMA)
• modification by amine functionalities,
  polyelectrolytes, protein adsorption
• PDMS exposure to O2 plasma activation creates
  SiOH groups on the surface, thus
• renders the channels hydrophilic (easily
  wettable by aqueous solutions)
• supports strong EOF in contact with neutral or
  basic solutions (CE)
• PDMS easily sealed on materials glass, silica,
  plasma-treated PDMS, pressures 30-50 psi
  (irreversibly)
• conformal sealing with flat surfaces (Van der
  Waals), pressures up to 5 psi (reversibly)

Schematics and photo of a passive micromixer
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Sealing (II)

• Polymer-to-polymer bonding methods include
• adhesives
• solvent-assisted glueing
• thermal bonding (near or above Tg)
• ultrasonic/microwave bonding (small area, 1x1 cm)
• (disadvantage possible deformation of
  substrates and microchannel patterns)
• 5. laser welding
• 6. lamination (with foils)

PET/PE foil J. Rossier et. al., Electrophoresis
23 (2002) 858-867
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Sealing (III)

• polymers as adhesive layers (SU(8), PDMS,..)
• 8. surface activation (e.g. PDMS/plexiglass
  after chemical and plasma modification)

W. Chow et. al., Smart Mater. Struct. 15 (2006)
S112-S116
Bonding method ?. Misiakos, ?. ?serepi, ?.?.
Vlachopoulou, Patent Appl. No.
20060100518/15.9.2006
W. Chow et. al., Smart Mater. Struct. 15 (2006)
S112-S116
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Examples of commercial polymer microfluidic
devices
Lilliput microtiter plate by Steag Microparts
(96 reaction wells, 1.8µl each, injection molding
from PS, for bacteria identification)
Gyrolab by Gyros AB (injection molding from
polyolefin)
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Microfluidic devices for µ-analysis (I)
Devices for capillary electrophoresis
Becker and Lacascio, Talanta, 56 (2002)
Microchannel device that couples with
ESI/MS (PMMA, hot embossing)

• The 1st widely published application of µTAS was
  in CE, 1st to be commercially available
• materials thermoplastic polymers (PMMA, PC) and
  elastomers (PDMS)
• fabrication methods hot embossing, injection
  molding, laser ablation
• detection LIF, electrochemical detection
• results separation speed and resolution
  comparable to glass devices

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Microfluidic devices for µ-analysis (II)
Devices for miniaturized PCR
PCR the most widely used process in biotechnology
for DNA fragments amplification It involves three
Ts, only polymers with higher T-stability can be
used PC, COC, PDMS
Polymer devices for continuous-flow PCR
Kopp et. al. Science, 280 (1998)
Kohler et. al. IMRET (1998)
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Microfluidic devices for µ-analysis (III)

• Lab-on-chip system for bacterial detection and
  identification (on poly-cyclic olefin)
• It integrates
• DNA amplification
• microfluidic valves
• sample injection
• separation by CE
• detection by LIF

ACLARA BioSciences Inc., Anal. Chem. 2003, 75
PCR sample volume 29 nl DNA detection limit 6
copies of target DNA
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Epilogue

• Challenges for research
• integration of more functions
• cheap and mass production processes
• on-chip integration of external controls

Long-term success of µ-fluidic devices is assured
due to broad range of applications

• Key-players in commercialization of (bio)
  analytical devices
• Agilent provider of instrumentation software
  services to life sciences and chemical analysis
  markets
• Caliper LifeSciences liquid handling
  lab-on-chip technologies for accurate drug
  discovery and diagnosis of disease
• ACLARA BioSciences development of advanced
  tools for drug discovery and development by using
  assay platform
• Affimetrix development of state-of-the-art
  technology for acquiring-analyzing genetic
  information
• many more.

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References

• G. Whitesides and A.D. Stroock, Flexible methods
  for Microfluidics, Physics Today
  (www.physicstoday.org/pt/vol-54/iss-6)
• Yole Développment Report Emerging Markets for
  Microfluidics Applications, (Oct./Nov. 2004, May
  2007)
• J.C. McDonalds, et. al. Fabrication of
  microfluidic systems in PDMS, Electrophoresis
  (2000), 21 27-40
• E. Verpoorte and N. de Rooij, Microfluidics
  meets MEMS, Review Proc. IEEE (2003) 91 930-957
• P. Grodzinski et. al. Development of plastic
  microfluidic devices for sample preparation,
  Biomedical Microdevices (2001), 34 275-83
• H. Becker and L. Locascio, Polymer microfluidic
  devices Review Talanta (2002) 56 267-87
• Y. Xia and G. Whitesides Soft Lithography Annu.
  Rev. Mater. Sci. (1998) 28 153-184
• A. Gerlach, et. al. Microfabrication of
  single-use plastic microfluidic devices for
  high-throughput screening and DNA analysis
  Microsystem Technologies (2002) 7 265-68
• R. Linhardt and T. Toida Ultra-high resolution
  separation comes of age Science 298 1441-42
• M.U. Kopp et. al. Chemical amplification
  Continuous-flow PCR on a chip Science (1998) 280
  1046-48
• CG Koh et. al. Integrating polymerase chain
  reaction, valving, and electrophoresis in a
  plastic device for bacterial detection Anal.
  Chem. (2003) 75 4591-98
• O. Geschke, H. Klank, P. Telleman, Microsystem
  Engineering of Lab-on-a-chip Devices (2004)
  Wiley-VCH Verlag
• H. Becker, C. Gartner, Polymer microfabrication
  methods for microfluidic analytical applications
  Electrophoresis (2000) 21, 12-26
• O. Geschke, H. Klank, P. Telleman, Microsystem
  Engineering of Lab-on-a-chip Devices (2004)
  Wiley-VCH Verlag