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Peripheral nerve injuries have become a common clinical disease with poor prognosis and complicated treatments. The development of tissue engineering pointed a promising direction to produce nerve conduits for nerve regeneration. Electrical and mechanical stimulations have been incorporated with tissue engineering, since such external stimulations could promote nerve cell proliferation, migration and differentiation. However, the combination of electrical and mechanical stimulations (electromechanical stimulation) and its effects on neuron proliferation and axon outgrowth have been rarely investigated. Herein, silver nanowires (AgNWs) embedded polydimethylsiloxane (PDMS) electrodes were developed to study the effects of electromechanical stimulation on rat pheochromocytoma cells (PC12 cells) behaviors. AgNWs/PDMS electrodes demonstrated good biocompatibility and established a stable electric field during mechanical stretching. PC12 cells showed enhanced proliferation rate and axon outgrowth under electrical stimulation alone, and the cell number significantly increased with higher electrical stimulation intensity. The involvement of mechanical stretching in electrical stimulation reduced the cell proliferation rate and axon outgrowth, compared with the case of electrical stimulation alone. Interestingly, the cellular axons outgrowth was found to depend on the stretching direction, where the axons prefer to align perpendicularly to the stretch direction. These results suggested that AgNWs/PDMS electrodes provide an in vitro platform to investigate the effects of electromechanical stimulation on nerve cell behaviors and can be potentially used for nerve regeneration in the future.

Breast cancer (BCa) is one of the most common cancers for women and metastatic BCa causes the majority of deaths. The extracellular matrix (ECM) stiffens during cancer progression and provides biophysical signals to modulate proliferation, morphology, and metastasis. Cells utilize mechanotransduction and integrins to sense and respond to ECM stiffness. Chitosan‐alginate (CA) scaffolds have been used for 3D culture, but lack integrin binding ligands, resulting in round cell morphology and limited cell‐material interaction. In this study, 2, 4, and 6 wt% CA scaffolds were produced to mimic the stages of BCa progression and evaluate the BCa response to CA scaffold stiffness. All three CA scaffold compositions highly porous with interconnected pores and scaffold stiffness increased with increasing polymer concentration. MDA‐MB‐231 (231) cells were cultured in CA scaffolds and 2D cultures for 7 d. All CA scaffold cultures had similar cell numbers at 7 d and the 231 cells formed clusters that increased in size during the culture. The 2 wt% CA had the largest clusters throughout the 7 d culture compared with the 4 and 6 wt% CA. The 231 cell migration was evaluated on 2D surfaces after 7 d culture. The 6 wt% CA cultured cells had the greatest migration speed, followed by 4 wt% CA, 2D cultures, and 2 wt% CA. These results suggest that 231 cells sensed the stiffness of CA scaffolds without the presence of focal adhesions. This indicates that a non‐integrin‐based mechanism may explain the observed mechanotransduction response.

Peripheral nerve injuries cause different degrees of nerve palsy and function loss. Due to the limitations of autografts, nerve tissue engineering (TE) scaffolds incorporated with various neurotrophic factors and cells have been investigated to promote nerve regeneration. However, the molecular mechanism is still poorly understood. In this study, we co-cultured Schwann cells (SCs) and rat adrenal pheochromocytoma (PC-12) cells on 50% degrees of methacryloyl substitution gelatin methacrylate (GelMA) scaffold. The SCs were encapsulated within the GelMA, and PC-12 cells were on the surface. A 5% GelMA was used as the co-culture scaffold since it better supports SCs proliferation, viability, and myelination and promotes higher neurotrophic factors secretion than 10% GelMA. In the co-culture, PC-12 cells demonstrated a higher cell proliferation rate and axonal extension than culturing without SCs, indicating that the secretion of neurotrophic factors from SCs can stimulate PC-12 growth and axonal outgrowth. The mRNA level for neurotrophic factors of SCs in 5% GelMA was further evaluated. We found significant upregulation when compared with a 2D culture, which suggested that this co-culture system could be a potential scaffold to investigate the mechanism of how SCs affect neuronal behaviors.

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Prostate cancer (PCa) is one of the most lethal cancers in men worldwide. The tumor microenvironment (TME) plays an important role in PCa development, which consists of tumor cells, fibroblasts, endothelial cells, and extracellular matrix. Hyaluronic acid (HA) and cancer-associated fibroblasts (CAFs) are the major components in the TME and are correlated with PCa proliferation and metastasis, while the underlying mechanism is still not fully understood due to the lack of biomimetic extracellular matrix components and coculture models. In this study, gelatin methacryloyl/chondroitin sulfate-based hydrogels were physically crosslinked with HA to develop a novel bioink for the three-dimensional (3D) bioprinting of a coculture model that can be used to investigate the effect of HA on PCa behaviors and the mechanism underlying PCa-fibroblasts interaction. PCa cells demonstrated distinct transcriptional profiles under HA stimulation, where cytokine secretion, angiogenesis, and epithelial to mesenchymal transition were significantly upregulated. Further coculture of PCa with normal fibroblasts activated CAF transformation, which could be induced by the upregulated cytokine secretion of PCa cells. These results suggested HA could not only promote PCa metastasis individually but also induce PCa cells to activate CAF transformation and form HA-CAF coupling effects to further promote PCa drug resistance and metastasis.