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theses

Global increases in life expectancy are accompanied by an increasing need for bone tissue regeneration. The gold standard for bone repair is the autologous graft (autograft), which enjoys excellent clinical outcomes. However, the autograft suffers from significant drawbacks including donor site morbidity and limited availability. Although collagen sponges delivered with bone morphogenetic protein, type 2 (BMP-2) are a common alternative or supplement to grafts, they do not efficiently retain BMP-2, necessitating extremely high doses to elicit bone formation. As a result, reports of BMP-2 complications are on the rise, including the promotion of cancer and ectopic bone formation, the latter of which induces complications such as breathing difficulties and neurologic impairments. Therefore, efforts to exert spatial control over bone formation are of particular interest. Using the tissue engineering paradigm of scaffolds, biological factors, and cells, several studies have demonstrated the potential of this approach to elicit targeted and controlled bone formation. These approaches include biomaterial scaffolds derived from synthetic sources such as calcium phosphates or polymers, natural sources such as bone or seashell, and biofactors such as BMP-2 that are immobilized within the scaffolds. Although BMP-2 is the only protein clinically approved for use in a surgical device, there are several proteins, small molecules, and naturally derived osteogenic growth factors that show promise in tissue engineering applications. This dissertation presents research directed at achieving control over the location and onset of bone formation (spatiotemporal control) for tissue engineered bone towards avoiding the current complications associated with BMP-2.

Spatiotemporal control over tissue formation is relatively unreported in literature, particularly microspatial control. The first aim of this work seeks elucidate the mineralization capacity of osteogenic growth factors covalently tethered to a substrate via a poly(ethylene glycol) (PEG) linker. This was accomplished by PEGylating growth factors and covalently tethering them to acrylated glass substrates. The results of this study indicated that PEGylated WSM can induce mineralization in acellular solution. Further, the results reveal the presence of sub-micron features within the mineralized matrix. Further work in this dissertation sought elucidate the relationship between cellular and acellular osteogenesis and mineralization induced by osteogenic growth factors. The initial hypothesis was that growth factors capable of directing acellular nucleation would demonstrate the ability to microspatially direct cell-mediated osteogenesis and mineralization. The results revealed that both PEGylated BMP-2 and nacre WSM show some ability to direct osteogenesis when patterned onto PEGDA hydrogel substrates. These findings have broad implications on the design and development of orthopaedic interventions and drug delivery.

ETD_9681

Ph.D.

Includes bibliographical references

doi:10.7282/t3-wkqn-e397

ETD doctoral

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