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The use of cell-free scaffolds for the regeneration of clinically relevant volumes of soft tissue has been challenged, particularly in the case of synthetic biomaterials, by the difficulty of reconciling the manufacturing and biological performance requirements. Here, we investigated in vivo the importance of biomechanical and biochemical cues for conditioning the 3D regenerative microenvironment towards soft tissue formation. In particular, we evaluated the adipogenesis changes related to 3D mechanical properties by creating a gradient of 3D microenvironments with different stiffnesses using 3D Poly(Urethane-Ester-ether) PUEt scaffolds. Our results showed a significant increase in adipose tissue proportions while decreasing the stiffness of the 3D mechanical microenvironment. This mechanical conditioning effect was also compared with biochemical manipulation by loading extracellular matrices (ECMs) with a PPAR-γ activating molecule. Notably, results showed mechanical and biochemical conditioning equivalency in promoting adipose tissue formation in the conditions tested, suggesting that adequate mechanical signaling could be sufficient to boost adipogenesis by influencing tissue remodeling. Overall, this work could open a new avenue in the design of synthetic 3D scaffolds for microenvironment conditioning towards the regeneration of large volumes of soft and adipose tissue, with practical and direct implications in reconstructive and cosmetic surgery.

Conditioning the microenvironment for soft tissue regeneration in a cell free scaffold