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Cell Interactions within Biomimetic Apatite Microenvironments


Bioactive ceramics, such as calcium phosphate-based materials, have been studied extensively for the regeneration of bone tissue. Accelerated apatite coatings prepared from biomimetic methods is one approach that has had a history of success in both in vitro and in vivo studies for bone regeneration [1]-[4]. However, how cells interact within the apatite microenvironment remains largely unclear, despite the vast literature available today. In response, this thesis evaluates the in vitro interactions of a well-characterized osteoblast cell line with the apatite microenvironment. For this, the cellular response to several aspects of the apatite microenvironment was separately examined in order to piece together a more simplified picture of a complex and dynamic system: (1) the influence of accelerated apatite on local calcium and phosphate concentration, (2) the role of protein adsorption onto apatite surfaces, and (3) apatite surface charge. Furthermore, the immunopotentiating properties of apatite were also characterized by examining monocyte response to 2D and 3D apatite-coated model culture systems in vitro.

A rapid "pull-down" of extracellular Ca2+and PO43- ions onto the apatite surface could be measured upon the incubation of apatites in cell culture medium, suggesting that cells may be subject to changing levels of Ca2+and PO43- within their microenvironment. Changing levels of Ca2+and PO43- are likely to have large implications for the biological response to apatites as increasing concentrations above a certain threshold were confirmed to be cytotoxic. Proteins were found to be critical in the mediation of cell-apatite interactions, as adherence of MC3T3-E1 cells to apatite surfaces without protein coatings resulted in significant levels of cell death within 24 hours in serum-free media. In the absence of protein-apatite interaction, cell viability could be restored upon treatment of the cells with inhibitors to PO43- transport, suggesting that PO43- uptake may play a role in viability. In contrast, rescue was not observed upon treatment with calcium channel inhibitors. The apatite surface charge could be modulated by treating the apatite surface with biomolecular coatings (proteins, polyamino acids), or with non-biological coatings of carbon or gold. In general, surface treatments that resulted in a more negatively-charged apatite surface, relative to that of bare apatite, promoted cell survival in a dose-dependent manner. A potential immunomodulatory role for apatite may contribute to its overall pro-osteogenic capacity, as apatite coatings could enhance monocyte adhesion in the absence of activation factors. Moreover, the presence of monocytes or monocyte conditioned media was shown to promote osteoblastic differentiation on apatite-coated substrates in vitro. Taken together, this investigation provides an initial understanding of the cellular response to various elements within the apatite microenvironment, and may provide the foundation for furthering the development of apatite materials for bone tissue engineering.

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