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)
Type
Research Project (R01)
Project #
2R01DE013033-17A1
Application #
8757679
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lumelsky, Nadya L
Project Start
Project End
Budget Start
Budget End
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
Ali, Omar A; Huebsch, Nathaniel; Cao, Lan et al. (2009) Infection-mimicking materials to program dendritic cells in situ. Nat Mater 8:151-8
Kong, Hyun Joon; Kim, Eun Seok; Huang, Yen-Chen et al. (2008) Design of biodegradable hydrogel for the local and sustained delivery of angiogenic plasmid DNA. Pharm Res 25:1230-8
Evangelista, Marta B; Hsiong, Susan X; Fernandes, Rui et al. (2007) Upregulation of bone cell differentiation through immobilization within a synthetic extracellular matrix. Biomaterials 28:3644-55
Kong, Hyun Joon; Polte, Thomas R; Alsberg, Eben et al. (2005) FRET measurements of cell-traction forces and nano-scale clustering of adhesion ligands varied by substrate stiffness. Proc Natl Acad Sci U S A 102:4300-5
Murphy, William L; Hsiong, Susan; Richardson, Thomas P et al. (2005) Effects of a bone-like mineral film on phenotype of adult human mesenchymal stem cells in vitro. Biomaterials 26:303-10
Kong, Hyun Joon; Liu, Jodi; Riddle, Kathryn et al. (2005) Non-viral gene delivery regulated by stiffness of cell adhesion substrates. Nat Mater 4:460-4
Kong, Hyun Joon; Kaigler, Darnell; Kim, Kibum et al. (2004) Controlling rigidity and degradation of alginate hydrogels via molecular weight distribution. Biomacromolecules 5:1720-7
Leach, J Kent; Mooney, David J (2004) Bone engineering by controlled delivery of osteoinductive molecules and cells. Expert Opin Biol Ther 4:1015-27
Lee, Kuen Yong; Bouhadir, Kamal H; Mooney, David J (2004) Controlled degradation of hydrogels using multi-functional cross-linking molecules. Biomaterials 25:2461-6
Simmons, Craig A; Alsberg, Eben; Hsiong, Susan et al. (2004) Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells. Bone 35:562-9

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