There are a limited number of options for clinical surgeons who are faced with reconstructing bone defects that result from congenital anomalies, trauma, infection, and oncologic resection. Current grafting techniques and materials each have their own limitations and drawbacks. For this reason, we aim to create improved bone grafting materials that will act as scaffolds to recruit cells from surrounding tissues and promote natural bone regeneration processes. Using a versatile and robust thiol-ene polymerization scheme developed in the Anseth and Bowman laboratories, we are able to create 3-dimensional matrices containing simple cell adhesion mimics and enzymatically-degradable linkages. As a result, these materials support cellular infiltration and are replaced as new tissue is formed by the body. The research proposed herein will aim to engineer these grafting materials for bone regeneration purposes, first by increasing the ability of cells from the body to migrate into these materials, and then by incorporating signals that tell the invading cells to become bone.
Three specific aims are outlined:
Aim I : Identify biological epitopes and functionalities that influence the rate of migration of cells into and through thiol-ene polymer scaffolds.
Aim II : Develop thiol-ene polymer scaffolds that promote osteogenic differentiation and deposition of a mineralized matrix.
Aim III : Demonstrate the ability of injectable polymer scaffolds developed in Aims I &II to promote bone regeneration in vivo. Successful completion of these Aims should significantly advance our understanding of how to design synthetic polymer scaffolds to enhance natural bone regeneration processes, and this material platform should be readily tailored for applications towards regenerating tissues beyond bone, as well as providing specific advantages for future directions in the design of cell delivery vehicles.

Public Health Relevance

The Anseth Group aims to develop synthetic materials for repairing bone defects resulting from congenital anomalies, trauma, infection, and cancer. Our approach is to create 3-dimensional matrices that will act as scaffolds to recruit cells from surrounding tissues and promote natural bone regeneration processes, creating an improved and bioactive bone graft material.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016523-07
Application #
8197724
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (03))
Program Officer
Lumelsky, Nadya L
Project Start
2005-05-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$348,027
Indirect Cost
$110,527
Name
University of Colorado at Boulder
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Magin, Chelsea M; Alge, Daniel L; Anseth, Kristi S (2016) Bio-inspired 3D microenvironments: a new dimension in tissue engineering. Biomed Mater 11:022001
Yang, Chun; DelRio, Frank W; Ma, Hao et al. (2016) Spatially patterned matrix elasticity directs stem cell fate. Proc Natl Acad Sci U S A 113:E4439-45
Tibbitt, Mark W; Rodell, Christopher B; Burdick, Jason A et al. (2015) Progress in material design for biomedical applications. Proc Natl Acad Sci U S A 112:14444-51
Sridhar, Balaji V; Dailing, Eric A; Brock, J Logan et al. (2015) A Biosynthetic Scaffold that Facilitates Chondrocyte-Mediated Degradation and Promotes Articular Cartilage Extracellular Matrix Deposition. Regen Eng Transl Med 1:11-21
Kyburz, Kyle A; Anseth, Kristi S (2015) Synthetic mimics of the extracellular matrix: how simple is complex enough? Ann Biomed Eng 43:489-500
Schultz, Kelly M; Kyburz, Kyle A; Anseth, Kristi S (2015) Measuring dynamic cell-material interactions and remodeling during 3D human mesenchymal stem cell migration in hydrogels. Proc Natl Acad Sci U S A 112:E3757-64
Grim, Joseph C; Marozas, Ian A; Anseth, Kristi S (2015) Thiol-ene and photo-cleavage chemistry for controlled presentation of biomolecules in hydrogels. J Control Release 219:95-106
Gandavarapu, Navakanth R; Alge, Daniel L; Anseth, Kristi S (2014) Osteogenic differentiation of human mesenchymal stem cells on α5 integrin binding peptide hydrogels is dependent on substrate elasticity. Biomater Sci 2:352-361
Yang, Chun; Tibbitt, Mark W; Basta, Lena et al. (2014) Mechanical memory and dosing influence stem cell fate. Nat Mater 13:645-52
Leight, Jennifer L; Alge, Daniel L; Maier, Andrew J et al. (2013) Direct measurement of matrix metalloproteinase activity in 3D cellular microenvironments using a fluorogenic peptide substrate. Biomaterials 34:7344-52

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