Theoretical and Experimental Framework of Neurite Response to Chemical Gradients in 3D Matrices

During the development of nervous system, various attractive and repulsive signals in the surrounding extracellular matrix (ECM) environment guide the growing neurites along specific directions to reach their intended targets. Neuronal motility is controlled by extracellular signal-sensing via the growth cone at the neurite tip, including chemoattractive and repulsive cues. We quantitatively investigate this response using a combination of mathematical modeling and in vitro experiments, and determine the role of guidance cues and ECM on neurite outgrowth and turning. A microfluidic system was used to show that cortical neurite outgrowth and turning under chemogradients (IGF-1 or BDNF) within 3D scaffolds is highly regulated by the source concentration of the guidance cue and the physical characteristics of the scaffold. A partial differential equation model of neurite outgrowth has been proposed that may be used as a predictive tool. The parameters for the chemotaxis term in the model are determined from experimental data. Resulting model simulations demonstrate how neurite outgrowth was critically influenced by the experimental variables, which was further supported by experimental data on cell-surface-receptor expressions. We demonstrate that our model results are in excellent agreement with experimental findings.