Opposite Mechanical Preference of Bone/Nerve Regeneration in 3D‐Printed Bioelastomeric Scaffolds/Conduits Consistently Correlated with YAP‐Mediated Stem Cell Osteo/Neuro‐Genesis

Abstract To systematically unveil how substrate stiffness, a critical factor in directing cell fate through mechanotransduction, correlates with tissue regeneration, novel biodegradable and photo‐curable poly(trimethylene carbonate) fumarates (PTMCFs) for fabricating elastomeric 2D substrates and 3D bone scaffolds/nerve conduits, are presented. These substrates and structures with adjustable stiffness serve as a unique platform to evaluate how this mechanical cue affects the fate of human umbilical cord mesenchymal stem cells (hMSCs) and hard/soft tissue regeneration in rat femur bone defect and sciatic nerve transection models; whilst, decoupling from topographical and chemical cues. In addition to a positive relationship between substrate stiffness (tensile modulus: 90–990 kPa) and hMSC adhesion, spreading, and proliferation mediated through Yes‐associated protein (YAP), opposite mechanical preference is revealed in the osteogenesis and neurogenesis of hMSCs as they are significantly enhanced on the stiff and compliant substrates, respectively. In vivo tissue regeneration demonstrates the same trend: bone regeneration prefers the stiffer scaffolds; while, nerve regeneration prefers the more compliant conduits. Whole‐transcriptome analysis further shows that upregulation of Rho GTPase activity and the downstream genes in the compliant group promote nerve repair, providing critical insight into the design strategies of biomaterials for stem cell regulation and hard/soft tissue regeneration through mechanotransduction.