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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Lumelsky, Nadya L
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Harvard Medical School
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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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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