Reconstruction of skeletal defects represents a major clinical challenge with over 1 million surgical procedures performed each year. New strategies of regenerating bone are needed because of limitations with existing techniques. One new strategy is to create a composite graft in which autologous cells are seeded onto a porous, degradable scaffold. The scaffold supports the cells, structurally and biologically, allowing them to grow and secrete new extracellular matrix. Optimally tissue growth occurs concurrent with scaffold degradation. The degree of new bone formation is, however, material dependent and not predictable. We therefore seek to establish material chemistry parameters that could optimize bone cell function. In pursuit of this goal, we have developed: (1) in vitro culture methods in which human bone marrow stromal cells (BMSCs) are expanded; (2) polymer processing techniques to reproducibly fabricate highly porous 3D poly(lactic-co-glycolic) scaffolds, which have been successfully used to engineer a number of tissues including bone; (3) materials science design strategies which enable us to biomimetically modify both the internal microenvironment of a scaffold and the scaffold surface; and (4) a critical size cranial defect model in an immunocompromised mouse which has shown that the human BMSCs are capable of forming new bone in an animal model. The global hypothesis of the proposed research is that the extracellular microenvironment provided by the scaffold modulates the ability of human BMSCs to differentiate toward an osteoblast phenotype, and therefore controls biomineralization and structural integrity of regenerated bone. Results from our and other laboratories support this hypothesis, which is tested by synthesizing a series of model biomimetic materials. First, we synthesize environmentally responsive or """"""""smart"""""""" scaffolds that buffer the microenvironment upon scaffold degradation. Second, we synthesize scaffolds with a surface that self-mineralizes into a biological apatite. Third, we use functionally-graded scaffolds in which mineralization is spatially controlled. The rationale for each of these 3 biomimetic strategies lies in the way nature has designed the skeleton. The skeletal system is able to perform its functions using a minimum amount of mass because biology has utilized design approaches, which include the ability to adapt to environmental cues (i.e. """"""""smartness""""""""), a hierarchical organization consisting of elegant mineral synthesis, and an organization that is optimized for physiological function by having gradients in composition and structure. In the proposed studies, we aim to exploit aspects of each of these 3 biomimetic strategies in an effort to create biomaterials that will modulate biological response in a controlled manner.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013380-03
Application #
6634668
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Drummond, James
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$210,645
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Ramaraju, Harsha; Miller, Sharon J; Kohn, David H (2014) Dual-functioning phage-derived peptides encourage human bone marrow cell-specific attachment to mineralized biomaterials. Connect Tissue Res 55 Suppl 1:160-3
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Luong, Linh N; Ramaswamy, Janani; Kohn, David H (2012) Effects of osteogenic growth factors on bone marrow stromal cell differentiation in a mineral-based delivery system. Biomaterials 33:283-94
Zhang, Nianli; Kohn, David H (2012) Using polymeric materials to control stem cell behavior for tissue regeneration. Birth Defects Res C Embryo Today 96:63-81
Rossello, Ricardo A; H, David (2010) Cell communication and tissue engineering. Commun Integr Biol 3:53-6
Addison, William N; Miller, Sharon J; Ramaswamy, Janani et al. (2010) Phosphorylation-dependent mineral-type specificity for apatite-binding peptide sequences. Biomaterials 31:9422-30
Scheller, E L; Krebsbach, P H; Kohn, D H (2009) Tissue engineering: state of the art in oral rehabilitation. J Oral Rehabil 36:368-89
Segvich, Sharon J; Smith, Hayes C; Kohn, David H (2009) The adsorption of preferential binding peptides to apatite-based materials. Biomaterials 30:1287-98

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