Diseases and trauma involving the loss of bony tissue are the most common clinical dental problems, and we propose to develop new polymeric materials for bone tissue engineering. We hypothesize that controlling the nanoscale organization of adhesive ligands presented to transplanted cells from the polymer, as well as the susceptibility of these ligands to cell-mediated rearrangement, will regulate the gene expression of the cells. Alginate will be used as a model matrix system to address the hypothesis guiding this proposal. Cells exhibit little to no adhesion or interaction with alginate, and thus alginate provides an ideal """"""""blank slate"""""""" on which one can confer specific cellular interaction properties in a controlled manner. Alginate also, in contrast to most model systems, is a practical biomaterial for in vivo application of this work. We specifically aim to: (1) Control the nanoscale presentation of RGD-containing peptides to a model pre-osteoblast cell line and human mesenchymal stem cells, and determine how this regulates focal adhesion formation and cell phenotype, (2) determine if the stiffness of the ligand presenting gels regulates the cells ability to rearrange the adhesion ligands, and (3) determine if these variables allow one to regulate new bone formation in vivo. The time-frame required for the gel, before it degrades, to present this information in order to regulate the cell response and bone formation will also be determined. Successful completion of these aims will have significant impact in both basic and applied sciences, and may eventually lead to improved therapies for regenerating bone defects. Establishing the mechanism by which nanoscale ligand organization and matrix mechanical properties regulate cell phenotype will provide an important new variable for design of biomaterials in tissue engineering and regeneration. The biomaterials developed in this proposal may be directly useful in therapies utilizing precursor cells to regenerate bony tissues in a variety of clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DE013033-06A1
Application #
6777972
Study Section
Special Emphasis Panel (ZRG1-SSS-M (01))
Program Officer
Kousvelari, Eleni
Project Start
1998-08-01
Project End
2004-07-31
Budget Start
2004-03-15
Budget End
2004-07-31
Support Year
6
Fiscal Year
2004
Total Cost
$104,150
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Klumpers, Darinka D; Smit, Theo H; Mooney, David J (2015) The effect of growth-mimicking continuous strain on the early stages of skeletal development in micromass culture. PLoS One 10:e0124948
Chaudhuri, Ovijit; Gu, Luo; Darnell, Max et al. (2015) Substrate stress relaxation regulates cell spreading. Nat Commun 6:6364
Klumpers, Darinka D; Mooney, David J; Smit, Theo H (2015) From Skeletal Development to Tissue Engineering: Lessons from the Micromass Assay. Tissue Eng Part B Rev 21:427-37
Huebsch, Nathaniel; Lippens, Evi; Lee, Kangwon et al. (2015) Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation. Nat Mater 14:1269-77
Fonseca, Keila B; Gomes, David B; Lee, Kangwon et al. (2014) Injectable MMP-sensitive alginate hydrogels as hMSC delivery systems. Biomacromolecules 15:380-90
Madl, Christopher M; Mehta, Manav; Duda, Georg N et al. (2014) Presentation of BMP-2 mimicking peptides in 3D hydrogels directs cell fate commitment in osteoblasts and mesenchymal stem cells. Biomacromolecules 15:445-55
Arany, P R; Huang, G X; Gadish, O et al. (2014) Multi-lineage MSC differentiation via engineered morphogen fields. J Dent Res 93:1250-7
Klumpers, Darinka D; Mao, Angelo S; Smit, Theo H et al. (2014) Linear patterning of mesenchymal condensations is modulated by geometric constraints. J R Soc Interface 11:20140215
Kolambkar, Yash M; Bajin, Mehmet; Wojtowicz, Abigail et al. (2014) Nanofiber orientation and surface functionalization modulate human mesenchymal stem cell behavior in vitro. Tissue Eng Part A 20:398-409
Klumpers, Darinka D; Zhao, Xuanhe; Mooney, David J et al. (2013) Cell mediated contraction in 3D cell-matrix constructs leads to spatially regulated osteogenic differentiation. Integr Biol (Camb) 5:1174-83

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