Published applications for imprint lithography fall into a few broad categories:
1)        Microarrays for Genomics and Proteomics
2)       Cell Culture
3)        Separations
4)        Sensors

Microarrays for Genomics and Proteomics
There is a significant market today for identifying specific genes or proteins using
microarrays increasing from $7.8 billion in 2004 to $17.5 billion by 2009. The idea behind
microarrays is to create an array of chemically unique locations that are then
simultaneously treated with a sample fluid. The unique site(s) where there is a reaction
identifies a specific characteristic of the sample

DNA Microarrays
The DNA microarrays are fabricated in two ways either direct synthesis at the target site (in
situ synthesis) or targeted transfer of pre-synthesized molecules by direct spotting.

The following are illustrations of thermal imprinting:
  • The use of nanochannels to stretch individual strands of DNA and subsequently
    identifying  binding sites (Tegenfeldt 2004 Morton  2004).
  • The nano-patterning of DNA immobilized onto poly-L-lysine bound substrates, while
    retaining their functionality, for biodevice fabrication .(Ohtake 2004)

The following are illustrations of microcontact lithography:
  • The in situ synthesis of DNA arrays by stamping oligonucleotide onto glass
    substrates .(Xioa 2002)
  • The synthesis of oligonucleotide probes directly on poly(dimethylsiloxane) (PDMS)
    microchannels  moulded with dimensions <100 um. The results suggest PDMS is a
    feasible alternative to glass substrates in the fabrication and synthesis of DNA
    microarrays  (Moorcroft 2005)
  • The patterning of antibodies onto glass substrates while retaining their antigen-
    binding abilities and selectivity .(Graber 2003)

Protein Microarrays
Most protein arrays are fabricated right before use. Zyomyx’s product that uses a unique 3D
ready-to-use capture biochip system for protein profiling. Their biochips are microfabricated
from silicon substrates to have a 3D surface with posts. The top of each post is coated,
using multi-headed dip pens or inkjet drops, with specific capture agents that prevents non-
specific binding of proteins.  

The following are illustrations of thermal imprinting:
  • The selective patterning of proteins with nanoscale line widths of 75nm with protein
    functionality and specific binding preserved between patterned antibodies and their
    antigen  (Hoff 2004)
  • The use of nanoimprint lithography in conjunction with Molecular Assembly
    Patterning by Lift-off  ( Falconnet 2004)  for fabricating large area, high density
    protein patterns with 25nm feature sizes (Park 2004) while increasing the sensitivity
    and detection levels.

The following are illustrations of microcontact lithography:
  • The multi-component patterning of sixteen different proteins onto a polystyrene
    surface using a stamp inked by means of a microfluidic network (Bénard 2000).
  • The use of micropatterned agarose gel for stamping protein arrays, rather than the
    traditional PDMS stamps. Agarose gel allows printing of protein gradients on the
    same stamp. This method needs only sub-nanomolar amounts of protein and does
    not require a drying step after stamping (Mayer 2004).
  • The use of patterned protein microarrays as a useful platform for sensing
    microorganisms  (Howell 2003)

UV imprint has been used to create gratings with protiens for microarrays (Ho 2005).

A unique use for S-FIL is the mass fabrication of tagged encoded objects. This revolutionary
idea was demonstrated with fabricating physically distinct shapes, where each shape has
a different chemical tag   (Meiring 2004). The shapes are sorted and treated with the
sample solution.  Machine vision is then used to identify the reacted shape and the pattern
identifies which chemical tag reacted.


Cell Culture
Cell Culture or Tissue engineering describes the technology to artificially create tissue for
implantation. Tissue needs to be built on a scaffolding, and the scaffolding needs to have a
surface that promotes and directs cell growth. It has been found that the mechanical texture
of the surface is as critical as the chemical texture, making it an ideal application for imprint.
Reviews of surface micro-patterning on cells include  (Curtis 1997, Ito 1999, Kane 1999) .

The following imprint demonstrations have been published:
  • Scaffolds of biocompatible materials have been created as substrates for tissue
    growth by solvent cast molding (Vozzi 2003).
  • Nerve growth on textured surfaces formed by nanoimprint has been demonstrated
    for mouse axons  (Yeung 2001, Carlberg 2003 and 2005).
  • Controlling cell adhesion on human tissue using microcontact imprint with PDMS
    molds   (Lee 2004).
  • Controlled cell attachment using microcontact imprint  (Zheng 2004).
  • Adhesion of osteoblasts to thermal imprint patterned titanium oxide surfaces  
    (Ketterer 2003).
  • Mouse melanoma cell adhesion to patterned fibronectin produced using
    microcontact imprint and PDMS molds  (Lehnert 2004).
  • Direction of cell division has been controlled by patterning using microcontact
    imprint and PDMS molds  (Théry 2004).
  • Directing growth of nerves for restoring sensory and motor deficits by thermal
    imprint (Montelius 2004).
  • A Georgia Tech team have fabricated surfaces with a combination of both physical
    textures and chemical texture to direct cell growth. They used a combination of both
    thermal  and transfer imprint (Charest 2005)
  • Hitachi have reported on thermally imprinted polystyrene sheets for cell culture
    (Kuwabara 2005)


Filters and Separations
There are two types of separation:
1)        Size separations
2)        Affinity separations

Size Separations
Separating molecules and cells by size is a simple filtering process. The following uses of
imprint lithography have been published:
  • Nanopillar structures were formed by thermal imprinting and was shown to
    separate polystyrene spheres Kuwabara 2004).
  • Microchannels have been used for protein separation (Regnier 1999).
  • Nanopore membranes have been fabricated [(Heyderman 2003).

Affinity Separations
Affinity separations describe classic chromatography in which a mixture of chemicals are
flowed over a sensitized surface (typically a column) so that the chemicals are separated
based on their interaction with the sensitized surface.

The following demonstrations of the use of imprint have been published:
  • Protein patterns have been imprinted and have retained antibody binding (Hoff
    2004).
  • Anitibody patterns have been imprinted by microcontact imprinting and retained
    functionality  (Graber 2003).
  • A cell sorting system based on molded PDMS (Takahashi 2004)
  • Cell adhesion in a microfluidic device ( Zhang 2005)  

Biosensors
The following uses of imprint have been published:
  • A micro-ring resonator built by thermal imprinting into polystyrene was shown to
    change resonant frequency depending on the concentration of glucose in an
    immersion solution (Chao 2003)  
  • Lipid vesicles have been immobilized on a surface via microcontact imprinting (
    Mahajan 2005)  
  • DNA sensors have been fabricated by thermal nanoimprint (Choi 2003, Guo 2004)
  • Thermal imprint structures used to produce protein patterns (Mayer 2004)  

The use of surface plasmon structures in bio sensing has become of great interest:
  • Specific applications using SERS  for chemical probe arrays by a team from
    Imperial College (Cohen 2006) , and  Plasmon enchanced microarray substrates
    from  U. Maryland (Szmacinski 2006) ,
  • Dedicated nanosensors using surface plasmon were described by a team from U
    Rochester (Fauchet 2006),  SUNY (Cartwright 2006) and   Tech U Denmark ( Balslev
    2006).

Microfluidics
Microfluidic systems are often used in Bio applications, they are discussed in more detail
under MEMS.

The help of Van Truscott of MII in preparing the material in this section  is gratefully
acknowledged. A more complete version has been submitted to BioTrends.

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Bio Applications