Cellular responses to thermoresponsive stiffness memory elastomer nanohybrid scaffolds by 3D-TIPS.

Increasing evidence suggests the contribution of the dynamic mechanical properties of the extracellular matrix (ECM) to regulate tissue remodeling and regeneration. Following our recent study on a family of thermoresponsive 'stiffness memory' elastomeric nanohybrid scaffolds manufactured via an indirect 3D printing guided thermally-induced phase separation process (3D-TIPS), this work reports in vitro and in vivo cellular responses towards these scaffolds with different initial stiffness and hierarchically interconnected porous structure. The viability of mouse embryonic dermal fibroblasts in vitro and the tissue responses during the stiffness softening of the scaffolds subcutaneously implanted in rats for three months were evaluated by immunohistochemistry and histology. Scaffolds with a higher initial stiffness and a hierarchical porous structure outperformed softer ones, providing initial mechanical support to cells and surrounding tissues before promoting cell and tissue growth during stiffness softening. Vascularization was guided throughout the digitally printed interconnected networks. All scaffolds exhibited polarization of the macrophage response from a macrophage phenotype type I (M1) towards a macrophage phenotype type II (M2) and down-regulation of the T-cell proliferative response with increasing implantation time; however, scaffolds with a more pronounced thermo-responsive stiffness memory mechanism exerted higher inflammo-informed effects. These results pave the way for personalized and biologically responsive soft tissue implants and implantable device with better mechanical matches, angiogenesis and tissue integration. Statement of Significance This work reports cellular responses to a family of 3D-TIPS thermoresponsive nanohybrid elastomer scaffolds with different stiffness softening both in vitro and in vivo rat models. The results, for the first time, have revealed the effects of initial stiffness and dynamic stiffness softening of the scaffolds on tissue integration, vascularization and inflammo-responses, without coupling chemical crosslinking processes. The 3D printed, hierarchically interconnected porous structures guide the growth of myofibroblasts, collagen fibers and blood vessels in real 3D scales. In vivo study on those unique smart elastomer scaffolds will help pave the way for personalized and biologically responsive soft tissue implants and implantable devices with better mechanical matches, angiogenesis and tissue integration.

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