Associate Member of CIHR Group in Skeletal Development and Remodeling
Department of Anatomy & Cell Biology
Ph.D. University of Glasgow
B.Sc. University of St. Andrews
1. Design of model systems to assess the factors that govern cellular interactions with bio(active) materials.
Since the experiments by Harrison (1911) and Weiss (1945), it has been long recognized that mammalian cells are senstive to the composition of their microenvironment. Surface chemistry and topography have been observed to influence many cellular processes such as adhesion, spreading, morphology, cytoskeletal organization, proliferation, migration and gene expression. As methods of material fabrication and characterization have evolved, it has become possible to identify the limits of cell sensing and how topographical and chemical cues can influence tissue intergration around implanted materials, as well as in vitro tissue development. We are developing new model systems to evaluate cell response to biomaterial surface characteristics, using state of the art microscopy and proteomic techniques.
2. In vitro and in vivo evaluation of biomaterials and cellular response.
To date, the development of biomaterials has often been driven on an empirical basis, rather than on advances made in the understanding of cell and tissue biology/pathophysiology. Our philosophy on biomaterials development is to use biological data from in vitro and in vivo models to re-design materials that will further promote desired cell behaviour, and advantageous gene and protein expression. Through characterization of the material chemistry and topography, as well as the celluar response, materials can be further adapted where applicable, through the incorporation of biologically active molecules on the surfaces. Our philosophy on this area of research is to identify protein changes using western blotting and immunohistochemistry at different time-points, and then to identify those that are changed at the gene level. Many proteins exist stored in the golgi apparatus and endoplasmic reticulum within cells and are activated rather than transcribed. Therefore, our approach allows separation of gene changes and protein activation. Furthermore, identifcation of critical changes in genes and proteins in differentiated cells will be important for the area of stem cell differentiation, where an understanding of more than general differentiation markes will be required. We envisage developing a rigorous screening system for gene and protein changes in newly implanted, as well as end stage failure, biomaterials. Furthermore, such techniques could be used to identify gene changes in pathologies prior to the onset of implant or biomaterial failure.
3. Use of transgenic mice and proteomic/genomic techniques to assess the role of proteins in biomaterial integration in bone and connective tissue
In vitro analyses of the effects of topographical cues on mammalian cell behaviours have correlated relatively well with in vivo observations. Exactly how substratum topography regulates bone and connective tissue formation at the molecular levle remains unknown. Does short-term protein activation and translation influence long-term tissue development? Our approach to address these questions involves the use of gene knockout mice and state of the art proteomics and genomic techniques. Such an approach could lead to the identification of novel diagnostic markers and therapeutic targets that can be applied to other bone and connective tissue diseases.
Hamilton, D. W., Jamshidi, F., and Brunette, D. M. Focal adhesion mediated intracellular signaling, Stat3 activation, and osteoblast differentiation: regulation by substratum topography. (In Press,Materials Science and Engineering Technology)
Hamilton, D. W., and Brunette, D. M. (2007) The effect of substratum topography on osteoblast adhesion mediated signal transduction and phosphorylation. Biomaterials 28(10): 1806-1809.
Schuler, M., Owen, G. Rh., Hamilton, D. W., Wieland, M., Brunette, D. M., Textor, M. and Tosatti, S. (2006) Biomimetic Modification of Titanium Dental Implant Model Surfaces Using the RGDSP-Peptide Sequence: A Preliminary Study for a Cell-Selective Surface. Biomaterials 27(21): 4003-4015.
Hamilton, D. W., Wong, K. S., and Brunette, D. M. (2006) Microfabricated Discontinuous Edge Surface Topographies Influence Osteoblast Adhesion, Migration, Cytoskeletal Organization, Proliferation and Enhance Matrix and Mineral Deposition in vitro. Calcified Tissue International 78(5): 314-325.
Hamilton, D. W., Ghrebi, S., Kim, H., Chehroudi, B., and Brunette, D. M. (2005) Surface Topography and Cell Behaviour. The Encyclopedia of Biomaterials and Biomedical Engineering. Editors, Gary Bowlin and Gary Wnek. Marcel Dekker, New York. P: 1-11.
Hamilton, D. W., Riehle, M., Monaghan, W., and Curtis, A. S. G. (2005) Chonodrocyte passage number: Influence on adhesion, migration, cytoskeletal organization and phenotype in response to nano- and micro-metric topography. Cell Biology International, Volume 29(6): 408-421.
Hamilton, D. W., and Brunette, D. M. (2005) Gap Guidance of Fibroblasts and Epithelial cells by Discontinuous Surface Topography. Experimental Cell Research, Volume 309(2): 429-437.
Hamilton, D. W., Maul, T. M., and Vrop, D. A. (2004) Characterization of the response of Bone Marrow Derived Progenitor Cells to Cyclic Strain: Implications for Vascular Tissue Engineering Applications. Tissue Engineering, Volume 10(34): 361-369.