of these scenarios. [1] Migration is influenced by chemotactic, topographical, and mechanotransductive cues from the extracellular matrix. [2] Moreover, cell migration in the context of cancer metastasis is a complex and important factor for understanding tumor progression. [3] The most aggressive form of a primary brain tumor is glioblastoma multiforme (GBM) which are highly invasive heterogenous tumors with a very low survival rate. [4] Surgical resection and chemo-or radiotherapy is commonly used for patient treatment, however, tumor recurrence is very frequent. Importantly, GBM cells invade and migrate along white matter tracts and brain blood vessels which promote tumor dissemination. [5] Hence, it is critical to understand the basic process of tumor migration and progression in order to develop new therapeutic drugs and treatment regimens. While therapeutic approaches that minimize GBM migration are logical, another approach focuses on guiding these cells away from the tumor into biomaterial reservoirs with the goal to reduce tumor size. [6] This diversional approach is based on the placement of a tube filled with a matrix and oriented substrate that provides topographical guidance cues at the tumor site. This results in the attraction and guidance of migration of GBM cells into the tube, effectively reducing overall tumor size. Therefore, in line with this study and the fact that GBM cells have an affinity for white brain matter and blood vessels, it is important to develop new 3D in vitro cell culture models to determine the optimal matrix composition that drives GBM migration. Novel research methods and tools provide an opportunity to study cell migration during cancer metastasis [7] where loss of cell adhesion from the primary tumor along with increased cell motility and invasion occurs. There is evidence from 3D microfluidic devices and microchips that matrix stiffness influences the migratory and invasive capabilities of tumor cells through the structure characteristics. [8] There have been significant advances to understand the process of cell migration using in vitro models, which are cost effective and easier to use compared to in vivo studies. With existing in vitro assays, cell migration conditions are welldefined with many based on the traditional 2D cell culture methods. [9] While simple to use, they are challenged to recapitulate the 3D in vivo microenvironment.
Tunable culture platforms that guide cellular organization and mechanically stimulate skeletal muscle development are still unavailable due to limitations in biocompatibility and actuation triggered without contact. This study reports the rational design and fabrication of magneto-active microfiber meshes with controlled hexagonal microstructures via melt electrowriting (MEW) of a thermoplastic/graphene/iron oxide composite. In situ deposition of iron oxide nanoparticles on oxidized graphene yielded homogeneously dispersed magnetic particles with sizes above 0.5 micrometer and low aspect ratio, preventing cellular internalization and toxicity. With these fillers, homogeneous magnetic composites with very high magnetic filler content (up to 10 wt.%) were obtained and successfully processed in a solvent-free manner for the first time. MEW of magnetic composites enabled the skeletal muscle-inspired design of hexagonal scaffolds with tunable fiber diameter, reconfigurable modularity, and zonal distribution of magneto-active and nonactive material. Importantly, the hexagonal microstructures displayed elastic deformability under tension, mitigating the mechanical limitations due to high filler content. External magnetic fields below 300 mT were sufficient to trigger out-of-plane reversible deformation leading to effective end-to-end length decrease up to 17%. Moreover, C2C12 myoblast culture on 3D Matrigel/collagen/MEW scaffolds showed that the presence of magnetic particles in the scaffolds did not significantly affect viability after 8 days with respect to scaffolds without magnetic filler. Importantly, in vitro culture demonstrated that myoblasts underwent differentiation at similar rates regardless of the presence of magnetic filler. Overall, these innovative microfiber scaffolds were proven as a magnetically deformable platform suitable for dynamic culture of skeletal muscle with potential for in vitro disease modeling.
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