The long-term objective of this project is to develop material systems that promote new bone formation for reconstructive dental and craniofacial applications. The overall hypothesis guiding our research is that material systems may be designed, based on a fundamental and quantitative understanding of cell receptormaterial ligand binding, to provide a selective advantage to specific cell types present in a mixture, and guide tissue formation from these cells. This hypothesis represents a continuation of our current effort to develop materials to promote bone regeneration by understanding and manipulating the role of cell adhesion peptide presentation (type, density, spacing of ligand, and mechanical properties of presenting substrate) in osteoprogenitor differentiation and bone formation. The specific hypothesis to be tested in the extension of this MERIT award is that the mechanical properties and cell adhesion ligand presentation of alginate gels may be tuned to specifically promote mesenchymal stem cell (MSC) adhesion, proliferation and differentiation, and enhance bone regeneration in vivo from transplanted cell populations or induced host cells.
The specific aims will include: (1) Develop a FRET-based technique to perform single cell analysis of receptor-ligand binding dynamics (kon, koff, KD) in order to determine how ligand presentation (density, spacing, gel mechanical properties) regulate bond formation, (2) Analyze kon, koff, and KD with this technique using libraries of synthetic peptides derived from natural extracellular matrix molecules (e.g., fibronectin, collagen, laminin) in order to identify materials with high specificity for MSC adhesion and possibly distinct stages of differentiation, and (3) Test the ability of specific ligands and ligand presentations chosen from the large-scale screening to enhance bone regeneration from transplanted cell populations and host cell populations. Success in these studies will lead to biomaterials that can dramatically enhance bone regeneration by specifically promoting the adhesion, proliferation and differentiation of the small numbers of osteoprogenitors typically present in cell populations, either in vitro or in vivo.

Public Health Relevance

There are many situations in which new bone is required in dentistry to repair or reconstruct facial or oral structures. This project aims to develop biodegradable plastics that can increase the amount and rate at which new bone can be created in our bodies by stimulating stem cells to become bone-forming cells. It will increase our basic understanding of bone biology, may lead to new approaches to help patients who require large volumes of bone tissue, and may also be widely useful in forming other body tissues as well.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Lumelsky, Nadya L
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Harvard University
Engineering (All Types)
Schools of Arts and Sciences
United States
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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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