The long-term objective of this research is to develop materials to enable the regeneration of bony tissues for reconstructive dental and craniofacial applications. The overall hypothesis guiding our work is that the fate of stem cells within an engineered tissue can be regulated by the presentation of appropriate signals in the microenvironment of the cells. The specific hypothesis to be tested in this application is that the viscoelasticity, particularly the rate of stress relaxation and creep, of biomaterials to which cels adhere controls their response to the material stiffness, and will control stem cell differentiatio. This will be studied with the following aims: (1) alginate hydrogels will be fabricated that displa a range of stress relaxation and creep times ranging from seconds-hours, and used to characterize the relation between initial moduli, stress relaxation/creep rate and MSC fate, (2) the impact of stress relaxation on established mechanotransduction pathway will be analyzed, and (3) the role of stress relaxation in the rate and extent of bone formation will be tested in vio from MSCs transplanted in hydrogels of varying initial mechanical properties and rates of stress relaxation. Successful completion of these aims will have significant impact in our understanding of how adhesion substrate mechanical properties regulate stem cell fate, and may lead to improved therapies for regenerating bone defects in the future. The impact of the viscoelastic properties of materials on stem cell fate has been largely ignored to date, and these studies are anticipated to motivate the development of new biomaterials that exploit this relation to drive bone regeneration. The principles and materials that arise from these studies will likely be broadly applicable in a number of biological settings, and many applications of biomaterials in the future.

Public Health Relevance

Craniofacial bone tissue is often required in reconstructive surgery following trauma, resection due to cancer, or correction of genetic defects. This project addresses how the mechanical properties of biomaterials impacts stem cells capable of promoting bone formation. Success in these studies could lead in the future to new clinical strategies to promote craniofacial bone in patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE013033-17A1
Application #
8757679
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lumelsky, Nadya L
Project Start
1998-08-01
Project End
2019-05-31
Budget Start
2014-07-14
Budget End
2015-05-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Chaudhuri, Ovijit; Gu, Luo; Klumpers, Darinka et al. (2016) Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater 15:326-34
Mehta, Manav; Madl, Christopher M; Lee, Shimwoo et al. (2015) The collagen I mimetic peptide DGEA enhances an osteogenic phenotype in mesenchymal stem cells when presented from cell-encapsulating hydrogels. J Biomed Mater Res A 103:3516-25
Chaudhuri, Ovijit; Gu, Luo; Darnell, Max et al. (2015) Substrate stress relaxation regulates cell spreading. Nat Commun 6:6364
Huang, George X; Arany, Praveen R; Mooney, David J (2015) Modeling and Validation of Multilayer Poly(Lactide-Co-Glycolide) Scaffolds for In Vitro Directed Differentiation of Juxtaposed Cartilage and Bone. Tissue Eng Part A 21:2228-40
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
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
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
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
Arany, Praveen R; Cho, Andrew; Hunt, Tristan D et al. (2014) Photoactivation of endogenous latent transforming growth factor-β1 directs dental stem cell differentiation for regeneration. Sci Transl Med 6:238ra69
Lee, Kuen Yong; Mooney, David J (2012) Alginate: properties and biomedical applications. Prog Polym Sci 37:106-126

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