Cells in various tissues are subjected to mechanical stress and strain that have profound effects on cell architecture and function. The specific response of the cell to applied strain depends on multiple factors, including cell contractility, spatial and temporal strain pattern, and substrate dimensionality and rigidity. Recent work has demonstrated that the cell response to applied strain depends on a complex combination of these factors, but the way these factors interact to elicit a specific response is not intuitive. We submit that an understanding of the integrated response of a cell to these factors will provide new insight into mechanobiology and contribute to the effective design of deformable engineered scaffolds meant to provide appropriate mechanical cues to the resident cells.

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Additive manufacturing is a promising method for producing customized three-dimensional (3D) bioactive constructs for regenerative medicine. Here, we report 3D printed highly osteogenic scaffolds using nanoengineered ionic-covalent entanglement ink (NICE) for bone tissue engineering. This NICE ink consists of ionic-covalent entanglement reinforced with Laponite, a two-dimensional (2D) nanosilicate (nSi) clay, allowing for the printing of anatomic-sized constructs with high accuracy. In addition, the 3D printed structure is able to maintain high structural stability in physiological conditions without any significant swelling or deswelling. While the presence of nSi imparts osteoinductive characteristics to the NICE scaffolds, this was further augmented by depositing pluripotent stem cellderived extracellular matrix (ECM) on the surface of the scaffolds. This was achieved by stimulating human induced pluripotent stem cell-derived mesenchymal stem cells (iP-hMSCs) with 2-chloro-5nitrobenzanilide, a PPARγ inhibitor that enhances Wnt pathway, resulting in the deposition of an ECM characterized by high levels of collagens VI and XII found in anabolic bone. The osteoinductive characteristics of these bioconditioned NICE (bNICE) scaffolds is demonstrated through osteogenic differentiation of bone marrow derived human mesenchymal stem cells (hMSCs). A significant increase in the expression of osteogenic gene markers including bone morphogenic protein-2, osteocalcin and osteopontin was observed on ECM-coated scaffolds compared to bare scaffolds, as well as improved mineralization. This approach of augmenting the bioactivity of 3D printed scaffolds by depositing an anabolic bone ECM will provide a unique strategy to design personalized bone graft geometries for in situ bone regeneration.Received: ((will be filled in by the editorial staff))Revised: ((will be filled in by the editorial staff))