Diseases and trauma which involve the loss of bony tissue are the most common clinical dental problems, and we propose to develop a new class of polymeric materials for bone tissue engineering. We hypothesize that matrices which regulate both the adhesion of osteoblasts with the matrix (e.g., integrin mediated), and the subsequent ability of the matrix to resist cell-generated tractional forces will regulate the gene expression adherent cells, and the ultimate structure and function of the engineered tissue. A large body of two-dimensional cell culture studies with a variety of cell types supports the importance of this latter interaction in regulating cell phenotype, and this prior work will be used as the basis for the design of three-dimensional tissue engineering matrices. Alginate will be used as a model matrix system to address the hypothesis guiding this proposal. Cells exhibit little to no adhesion or interaction with alginate, and thus alginate provides an ideal ~blank slate~ on which one can confer specific cellular interaction properties in a controlled manner. Alginate also, in contrast to most model systems, is a practical biomaterial for the ultimate clinical application of this work. We specifically aim to: (1) Covalently couple cell adhesion ligands (RGD, and DGEA- containing) to alginate, (2) simultaneously develop matrices with a wide range of mechanical properties by varying covalent cross-linking density and cross linker molecules, and 93) determine the role of matrices with predefined cell binding and mechanical properties in regulating osteoblast gene expression, and new bone formation in vitro and in vivo. The development of these new materials will potentially have a broad impact on the ability of clinicians to treat the loss of bony tissues resulting from a variety of diseases of trauma. More generally, the matrix design approach outlined in this proposal may provide a new paradigm for the design of biomaterials that may find broad application in tissue engineering. In addition to a variety of tissue engineering applications, this class of materials may find broad application as a model system to study the interplay of matrix mechanics and specific receptor-ligand interactions as they together regulate gene expression. This work would have broad impact on developmental biology, wound healing, and other biological processes such as cancer, where this interplay is disrupted.
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