(594a) Neural Biomimetic Materials for Examining Cell Migration in Disease Progression

Many models have conventionally been used to study neural cell migration in vitro with the goal of creating more effective treatments to brain disease. However, these conventional models lack the mechanical and topographical properties of the brain, which can significantly alter study results. Thus, models are needed that better recapitulate the brain microenvironment. We have demonstrated the ability of aligned electrospun fiber mats (EFMs) to mimic the mechanics and topography of fibrous structures in the brain, such as white matter and radial glia. We have also demonstrated the ability of composite hydrogels to mimic the brain extracellular matrix (ECM). White matter, radial glia and the brain ECM are key migration “highways” for many cell types, be it for migration or development.

Here, we report the use of EFMs and hydrogels to study glioblastoma multiforme (GBM), a highly infiltrative brain tumor., Patient-derived OSU-2 cells cultured on EFMs demonstrated an elongated morphology similar to the in vivo morphology. We examined GBM migration on core-shell EFMs, which allowed independent control over mechanics and chemistry. Cell migration was modulated by the mechanics of the EFMs, with maximum migration speed and feret diameter occurring on PCL EFMs with a stiffness of 7.9 MPa. The surface chemistry of the EFMs did not play as profound an effect on cell migration. Only hyaluronic acid made a significant difference, causing cell migration to decrease. Currently, we are developing an EFM-hydrogel composite to study the effect of mechanics on migration behavior. During development, we discovered a phenomenon where GBM cells can sense the stiffness of a substrate through a 250 µm thick EFM.

Similarly, we have adapted the previous model to study congenital central hypoventilation syndrome (CCHS), a developmental disorder possibly due to a lack of progenitor cell migration. The same advantageous that allow glioma migration can be used to monitor progenitor cell migration, a developmental biomimetic. Patient-derived induced pluripotent stem cells (iPS) were infected with a various HaloTag® viral constructs to create PHOX2B mutant cells, as PHOX2B is implicated in CCHS. An increase in fluorescent intensity of infected neuroblastomas showed an upregulation of PHOX2B. Successful construct design was also further proven through western blotting. In addition, we are utilizing an ink-jet printer to mimic ECM protein (i.e tenascin C, aggrecan, neurocan, and brevican) distribution on the radial glia surface. Future work will include studying PHOX2B mutant migration on these radial glial mimetics.