Two of the most important problems in cell-based treatments of muscular and neurological diseases and injuries are: i) the regulation of cell proliferation and differentiation, and ii) the control of cell migration. For example, in human myoblast transplant trials for treatment of muscular dystrophies, major problems were the lack of proliferation, migration, and fusion of transplanted cells with existing muscle tissue. In repair of nerve damage, suppressing astrocyte proliferation and promoting neuroblast proliferation, along with guidance of neurite extensions are key issues. Although these cellular behaviors are critically depend on nanoscale adhesive cues in the extracellular matrix (ECM), there is currently a lack of understanding of what these crucial nanostructures are and how dynamic changes in those structures determining cell function. This lack of understanding is due, at least in part, to the lack of efficient, versatile, and convenient methods to engineer the ECM at the nanoscale across biologically relevant areas of micrometers, millimeters, and larger.
The specific aims of this proposal are: i) understand and optimize a technology, called nanocrack patterning, to generate nanoengineered substrates with ECM molecule nanolines of defined widths, lengths, spacings, and orientations, ii) test the hypothesis that stretch-induced, nanoscale substrate reconfiguration can contribute to proliferation and lineage determination of myoblasts and neuroblasts, and iii) perform feasibility studies for discovery-driven research on cellular pathfinding where a microarray of criss-crossing nanopatterns of ECM molecules will be fabricated to rapidly profile cellular spreading/migrating preferences. The initial proof-of-concept studies will use C2C12 myoblasts and N27 neuronal precursor cells. Mesenchymal stems cells and primary myoblasts will be studied in the future. Although the biological problem to be addressed in this proposal is limited to myocyte and neuron behavior, the nanobiomaterials developed will be useful for addressing a much broader range of biological questions. The nanocrack patterning technique that will be developed uses nanoscale fracture mechanics and has the advantages of: (i) rapid nanopatterning over large areas (up to square centimeters and larger), (ii) nanopatterning over 3D substrates and inside microfluidic channels, (iii) generation of nanopattems consisting of multiple types of molecules on the same substrate, and (iv) stretch-induced in situ adjustment of the widths of ECM molecule nanolines generated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB003793-02
Application #
6945199
Study Section
Special Emphasis Panel (ZRG1-BPC-A (50))
Program Officer
Wang, Fei
Project Start
2004-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$177,017
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Dixon, Angela R; Moraes, Christopher; Csete, Marie E et al. (2014) One-dimensional patterning of cells in silicone wells via compression-induced fracture. J Biomed Mater Res A 102:1361-9
Mills, K L; Huh, Dongeun; Takayama, Shuichi et al. (2010) Instantaneous fabrication of arrays of normally closed, adjustable, and reversible nanochannels by tunnel cracking. Lab Chip 10:1627-30
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Uchida, Tomoyuki; Mills, K L; Kuo, Chuan-Hsien et al. (2009) External compression-induced fracture patterning on the surface of poly(dimethylsiloxane) cubes and microspheres. Langmuir 25:3102-7
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Uchida, Tomoyuki; Mills, K L; Kuo, Chuan-Hsien et al. (2009) External Compression-Induced Fracture Patterning on the Surface of Poly(dimethylsiloxane) Cubes and Microspheres. Langmuir :
Lam, Mai T; Clem, William C; Takayama, Shuichi (2008) Reversible on-demand cell alignment using reconfigurable microtopography. Biomaterials 29:1705-12
Mills, K L; Zhu, Xiaoyue; Takayama, Shuichi et al. (2008) The mechanical properties of a surface-modified layer on poly(dimethylsiloxane). J Mater Res 23:37-48
Lee, Donghee; Triantafyllidis, N; Barber, J R et al. (2008) Surface instability of an elastic half space with material properties varying with depth. J Mech Phys Solids 56:858-868

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