Regulation of Cell Motility on Polymer Substrates via "Dynamic," Cell Internalizable, Ligand Microinterfaces

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Abstract
In vivo, motile epidermal tissues frequently encounter ligand microinterfaces that are dynamic, owing to rapid cell-mediated substrate phagocytosis. In this study, we have examined cell motility phenomena in response to the adhesion ligand, collagen, which was presented on cell-internalizable 400-nm colloidal gold microcarriers. Normal human keratinocytes were seeded onto collagen-adsorbed poly(lactide-co-glycolide) (PLGA) films that were predeposited with varying densities of the ligand-associated microcarriers (LAMs), such that the overall ligand density and the ligand loading per microcarrier were invariant. Cells seeded on LAMs exhibited rapid and distinct cytoskeletal redistribution resulting in numerous filopodial extensions, indicative of activation of cell motility processes. We report that the population-averaged cell migration rate of cells, μ, was increased from 2 μm2/min on collagen substrates lacking the microcarriers, to ~50 μm2/min on collagen presenting LAMs. An increase in LAM density to 1.2 LAMs per μm2 was found to maximize μ, as well as the directional persistence and speed of cell migration, whereas very high LAM densities saturated cell internalization and diminished migration rates. The cell-LAM interactions essential to enhanced migration were ligand-activated, as μ values were reduced 400% on internalizable microcarriers lacking ligands; moreover, cooperative ligand elicitation was possible, for example, when 10 μg/mL soluble fibronectin was introduced as a costimulant of keratinocytes, yielding the highest reported μ values (80 μm2/min) on collagen LAM-PLGA substrates. Notably, cell migration rates were severely repressed when cell internalization processes were challenged through covalent conjugation of ligand carriers to the substrate, indicating that signals from cell-LAM binding alone were inadequate for elevated levels of cell migration. Further analysis indicated that the presence of LAMs did not alter the protease-resistant adhesivity between the cell and the underlying substrate, suggesting that the activation governing ligand interactions likely arose at the cell-LAM interface rather than the cell-substrate interface. This study highlights the novel use of secondary ligand-presenting microscale/nanoscale depots at polymer substrates to elicit, via dynamic cell internalization processes, significantly enhanced levels of cell migration over traditional interfaces with ligand-bearing substrates.

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