Incomplete regeneration and restoration of function in damaged nerves is a major clinical challenge. In this regard, stem cells hold much promise in nerve-tissue engineering, with advantages such as prevention of scar-tissue ingrowth and guidance of axonal regrowth. Engineering three-dimensional and patterned microenvironments using biomaterials with chemical and mechanical characteristics close to those of normal nervous tissue has enabled new approaches for guided differentiation of various stem cells toward neural cells and possible treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Differentiation of stem cells in a neurogenic lineage is largely affected by the signals from surrounding microenvironment (niche). The stem cell niche refers to a specific microenvironment around the stem cells, which provides specific biochemical (soluble factors) and biophysical signals (topography, electrical and mechanical). This specified niche regulates the stem cells' behavior and fate. While the role of chemical cues in neural differentiation is well appreciated, recently, the cues presented by the physical microenvironment are increasingly documented to be important regulators of nerve cell differentiation. The single and synergistic effects of surface topography and electrical signals on neural differentiation of stem cells are reviewed.

A conductive chitosan/polyaniline hydrogel with cell-imprinted topography was used for neural priming of adipose derived stem cells.

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Cell-imprinting technology is a novel method for directing stem cell fate using substrates molded from target cells. Here, we fabricated and studied cell-imprinted substrates for neural priming in human adipose-derived stem cells in the absence of chemical cues. We molded polydimethylsiloxane (PDMS) silicone substrates on fixed differentiated neural progenitor cells (ReNcellTM VM). The ReNcellTM cell line consists of immortalized human neural progenitor cells that are capable to differentiate into neural cells. The fabricated cell-imprinted silicone substrates represent the geometrical micro-and nanotopology of the target cell morphology. During the molding procedure, no transfer of cellular proteins was detectable. In the first test with undifferentiated ReNcellTM VM cells, the cell-imprinted substrates could accelerate neural differentiation. With adipose-derived stem cells cultivated on the imprinted substrates, we observed modifications of cell morphology, shifting from spread to elongated shape. Both immunofluorescence and quantitative gene expression analysis showed upregulation of neural stem cell and early neuronal markers. Our study, for the first time, demonstrated the effectiveness of cell-imprinted substrates for neural priming of adipose-derived stem cells for regenerative medicine applications.

Microfluidic on-chip production of microgels using external gelation can serve numerous applications that involve encapsulation of sensitive cargos. Nevertheless, on-chip production of microgels in microfluidic devices can be challenging due to problems induced by the rapid increase in precursor solution viscosity like clogging. Here, a novel design incorporating a step, which includes a sudden increase in cross-sectional area, before a flow-focusing nozzle was proposed for microfluidic droplet generators. Besides, a shielding oil phase was utilized to avoid the occurrence of emulsification and gelation stages simultaneously. The step which was located before the flow-focusing nozzle facilitated the full shielding of the dispersed phase due to 3-dimensional fluid flow in this geometry. The results showed that the microfluidic device was capable of generating highly monodispersed spherical droplets (CV < 2% for step and CV < 5% for flow-focusing nozzle) with an average diameter in the range of 90–190 μm, both in step and flow-focusing nozzle. Moreover, it was proved that the device could adequately create a shelter for the dispersed phase regardless of the droplet formation locus. The ability of this microfluidic device in the production of microgels was validated by creating alginate microgels (with an average diameter of ~ 100 μm) through an external gelation process with on-chip calcium chloride emulsion in mineral oil.

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