Remote Force Guided Assembly Of Complex Orthopaedic Tissues

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Doctor of Philosophy (PhD)
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Animal models
Tissue engineering
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Zlotnick, Hannah Marie

Articular cartilage is a complex orthopaedic tissue with zonal differences in cellularity, cell phenotype, mineralization, and extracellular matrix components. The unique arrangement of these building blocks allows the tissue to withstand cyclic compressive loads over a lifetime of use. In the case of injury or disease, the complex structure of articular cartilage is disrupted, reducing the tissue’s load bearing capacity. To restore the complex structure, and ultimately the function of cartilage, this work establishes and validates both in vitro and in vivo tissue assembly methods utilizing remote fields (i.e., magnetic fields and gravity). First, chondrogenic culture conditions were optimized to promote uniform cartilage growth in vitro. Thereafter, native-like cell gradients were assembled in engineered cartilage tissues using a novel magneto-patterning approach. To do this, a paramagnetic contrast agent, hydrogel precursor solution, and naturally diamagnetic cells were combined above a permanent magnet. After brief exposure to a magnetic field, the cell-laden solution was crosslinked, forming a three-dimensional tissue. The fabricated magneto-patterned tissues were viable, metabolically active over time in culture, and contained depth dependent extracellular matrix, reflecting their cellularity. Moving forward, we established a new nanofracture-based surgical model and advanced cryohistology methods to then assess the therapeutic potential of a novel in vivo tissue assembly method. Previous work in the lab found that awl-based microfracture leads to significant resorption of the subchondral bone, limiting the success of the overlying repair cartilage. To better preserve the osteochondral interface – or the connection between cartilage and bone after marrow stimulation, we designed microcapsules to carry and localize pro-osteogenic agents to the bottom surface of a debrided cartilage defect. Due to their thick shells, these microcapsules sank within a saline carrier solution, enabling gravity-based patterning to the osteochondral interface. We discovered that the therapeutic microcapsules best preserved bone nearest the nanofracture holes, and across the osteochondral interface, as assessed 1- and 2-weeks post-surgery via fluorochrome labeling and alkaline phosphatase staining. Together, these studies push the field of biofabrication forward to consider noncontact methodologies of tissue patterning, and the clinical translation of such approaches.

Robert L. Mauck
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