Despite the wide applications, systematic mechanobiological investigation of 3D porous scaffolds has yet to be performed due to the lack of methodologies for decoupling the complex interplay between structural and mechanical properties. Here, we discover the regulatory effect of cryoprotectants on ice crystal growth and use this property to realize separate control of the scaffold pore size and stiffness. Fibroblasts and macrophages are sensitive to both structural and mechanical properties of the gelatin scaffolds, particularly to pore sizes. Interestingly, macrophages within smaller and softer pores exhibit pro-inflammatory phenotype, whereas anti-inflammatory phenotype is induced by larger and stiffer pores. The structure-regulated cellular mechano-responsiveness is attributed to the physical confinement caused by pores or osmotic pressure. Finally, in vivo stimulation of endogenous fibroblasts and macrophages by implanted scaffolds produce mechano-responses similar to the corresponding cells in vitro, indicating that the physical properties of scaffolds can be leveraged to modulate tissue regeneration.

Porous bioscaffolds are applied to facilitate skin repair since the early 1990s, but a perfect regeneration outcome has yet to be achieved. Until now, most efforts have focused on modulating the chemical properties of bioscaffolds, while physical properties are traditionally overlooked. Recent advances in mechanobiology and mechanotherapy have highlighted the importance of biomaterials' physical properties in the regulation of cellular behaviors and regenerative processes. In skin repair, the mechanical and structural features of porous bioscaffolds are two major physical properties that determine therapeutic efficacy. Here, first an overview of natural skin repair with an emphasis on the major biophysically sensitive cell types involved in this multistage process is provided, followed by an introduction of the four roles of bioscaffolds as skin implants. Then, how the mechanical and structural features of bioscaffolds influence these four roles is discussed. The mechanical and structural features of porous bioscaffolds should be tailored to balance the acceleration of wound closure and functional improvements of the repaired skin. This study emphasizes that decoupling and precise control of the mechanical and structural features of bioscaffolds are significant aspects that should be considered in future biomaterial optimization, which can build a foundation to ultimately achieve perfect skin regeneration outcomes.

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Chronic kidney diseases are widespread and incurable. The biophysical mechanisms underlying them are unclear, in part because material systems for reconstituting the microenvironment of relevant kidney cells are limited. A critical question is how kidney podocytes (glomerular epithelial cells) regenerate foot processes of the filtration apparatus following injury. Recently identified sarcomere-like structures (SLSs) with periodically spaced myosin IIA and synaptopodin appear in injured podocytes in vivo. We hypothesized that SLSs template synaptopodin in the initial stages of recovery in response to microenvironmental stimuli and tested this hypothesis by developing an ex vivo culture system that allows control of the podocyte microenvironment. Results supported our hypothesis. SLSs in podocytes that migrated from isolated kidney glomeruli presented periodic synaptopodin-positive clusters that nucleated peripheral, foot process–like extensions. SLSs were mechanoresponsive to actomyosin inhibitors and substrate stiffness. Results suggest SLSs as mechanobiological mediators of podocyte recovery and as potential targets for therapeutic intervention.