Biodegradable Elastomeric Polymers and MEMS in Tissue Engineering 55
3.4 MEMS PRINCIPLES IN TISSUE ENGINEERING
In the past decade, microscale technologies have emerged as a powerful tool for
biological and biomedical applications.
94
MEMS research and development has
remained intense to solve complex problems at the cellular and molecular level.
2,95
Biological or Biomedical MEMS, BioMEMS, can be defined as the application
of micro– and nanotechnology to develop devices or systems that are used for
the processing, delivery, manipulation, analysis, or construction of biological
and chemical modalities.
2,95
The advancement of BioMEMS technologies has pro-
gressed, and will have a broad and significant impact in the fields of biology and
medicine if fully realized.
96
Few other engineering techniques are able to closely match the micro to
millimeter size dimension of tissues in the human body with the precision and
accuracy of BioMEMS techniques.
95
Due to these advantages, BioMEMS holds
great promise in addressing the challenges found in many disciplines such as di-
agnostic, therapeutic, sensing, detection, and tissue engineering applications.
2,97,98
The potential to mimic complex tissue architecture and in vivo conditions makes
BioMEMS a powerful tool for tissue engineering.
3.5 MEMS APPLICATIONS IN TISSUE ENGINEERING
Although BioMEMS based tissue engineering is a rapidly advancing field, research
involving the use of biodegradable elastomers coupled with microfabrication
processes is new and fairly limited. Discussed in the following section are
BioMEMS based techniques involving hydrogels and biodegradable elastomers to
construct 3D structures, control cell adhesion, control cell morphology, and create
microvasculature for 3D constructs.
The recent progress of MEMS based technologies has lead to new approaches
to study in vitro cell culture environments. Many of these new techniques utilize
a soft lithography approach to rapidly produce 3D microstructures. Leclerc
et al. used a photosensitive caprolactone and lactide based polymer to fabricate
biodegradable polymer microstructures down to 50 μm for tissue engineered liver
constructs.
99
As seen in Fig. 3.7, Leclerc et al. successfully created various single and
multistepwise microstructures using a soft lithographic technique. In addition,
the single stepwise microstructures supported the attachment, spreading, and
growth of a variety of mammalian cell types. Other groups have also successfully
created complex 3D polymer constructs for hepatic tissue engineering. In 2007,
Tsang et al. created PEGDA hydrogel constructs for hepatic cell encapsulation.
By combining a PEG based hydrogel with a multilayer fabrication method, Tsang
and co-workers were able to fabricate highly cell–encapsulated scaffolds with
architecture to facilitate nutrient delivery through convective flow.
100
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56 R. Tran et al.
Figure 3.7. SEM photographs of fabricated microstructures. (A) microchambers and mi-
crochannels on pCLLA; (B) a microchannel network on pCLLA; (C) channels fabricated with
direct UV exposure on pCLLA; (D) a single stepwise microstructure on pCLH fabricated by
stamping; (E) a multistepwise microstructure on pCLLA fabricated by stamping; and (F) a
multistepwise microstructure on pCLH fabricated by stamping. Reprinted from Biomateri-
als, 25(19), Leclerc E. et al., Fabrication of microstructures in photosensitive biodegradable
polymers for tissue engineering applications, 4683–4690, 2004, with permission from Else-
vier.
In addition to creating 3D constructs, many research groups have incorporated
micro scale technologies to promote and discourage cell adhesion. Mizutani et
al. showed the ability to control cell adhesion on PLA films using photocured co-
polymers.
101
Coating a PLA surface with a low molecular weight alcohol based co-
polymer promoted endothelial cell adhesion, whereas the PLA surface coated with
PEG–based co-polymer did not support cell adhesion. The different co-polymers
coated on the PLA films were able to change the hydrophobicity of the surface to
either encourage or deter endothelial cell adhesion.
101
Another research group successfully proved to control tissue organization by
immobilizing non-adhesive domains onto a surface. The group of Liu et al. used
a photolithographic technique to immobilize a PEO–terminated triblock polymer
onto various surfaces to deter cell adhesion for up to 4 weeks in vitro.
102
Expanding
upon previous research by Neff et al., the hydrophobic core of the polymer was
modified with adhesive peptides to create non-adhesive domains.
103
This cell
avoidance phenomenon can be explained by the polymer’s ability to also deter
proteins, which are necessary for cell attachment.
102
The ability to control cell and protein behavior using mechanical cues in
addition to chemical cues is critical in understanding tissue development.
102
While
these mechanisms of cell behavior are not yet fully understood, research has shown
that the extracellular matrix proteins of cells possess a 3D surface topography of
sub-micron length scales.
104
The ability to control cellular structure and function
by culturing cells on substrates modified with micron and sub-micron features is
a field termed contact guidance.
105
Contact guidance has been shown to induce
cellular responses in various cell types such as epithelial cells, fibroblasts, oligo-
dendrocytes, and astrocytes.
106
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