Microscale heterogeneity in implantable biomaterials [electronic resource]

When designing an implantable material, we should consider how the material's microscale structure affects cells that contact the material. Cells respond to microscale structure through mechanisms that are special to that length scale between 100 nanometers and a micron. For example, clusters of molecular receptors can anchor signaling complexes or mechanically transact with other cellular components. For another example, small portions of the cell membrane can deform around microscale features, thereby changing the membrane's lipid thermodynamics. As a technique to engineer implantable materials, the use of protein-engineered polymers complements other techniques that impart microscale structure to these materials. Unlike a synthetic polymer's monomers, each amino acid of a protein can be specified from the chemically diverse set of natural (and a few unnatural) amino acids. Sequences of these amino acids can be made by recombinant organisms; these sequences then fold into complex protein structures. Nature provides a cornucopia of these protein structures, each with a corresponding function tuned by millions of years of evolution. If incorporated into a protein-engineered polymer, protein subsequences derived from these natural protein structures can confer diverse functions. These derived functions can include receptor binding, enzymatic sensitivity, and mechanical responsiveness. Here, I've applied electrospinning and protein-engineered polymers to control the microscale structure of an implantable material. By measuring how a tissue-culture model of vascular endothelium responds to varied microscale structure, my studies have identified two especially interesting forms of microscale structure. One, even if global ligand density—or, average density over the cell-contact area of the material as a whole—is kept constant, local ligand density—or, here, density over a fiber's cell-contact area—is a distinct biomaterials parameter. By restricting bioactive protein subsequences (here, integrin ligands) to some fibers, instead of all fibers, material-cell biochemical signaling can be altered. Here, restricting ligands means increasing their local density on some fibers while making other fiber have no ligands. This approach maintains a defined global density of ligands while increasing their local density. If global ligand density is near the ligand's effective disassociation constant, increasing local ligand density boosts biochemical signals for cell proliferation. Two, cell and monolayer physiology depends of the size of the material's constituent fibers, if these fibers encourage cells to bend around them. Endothelial cells adopt a more invasive phenotype on larger fibers because these fibers trigger increased cellular wrapping around them, as compared to smaller fibers. In other words, fiber size is a necessary, but not sufficient, condition for a shifted endothelial phenotype. This phenotype features greater MAPK phosphorylation, increased cell motility, and weaker cell-cell junctions, which evoke pre-vascular sprouting and other angiogenic processes.

Keywords: Bioengineering.
Advisor: Heilshorn Sarah primary advisor. Thesis advisor
Cochran Jennifer R. advisor. Thesis advisor
Huang Ngan