Tailoring the multiscale mechanics of tunable decellularized extracellular matrix (dECM) for wound healing through immunomodulation

With the discovery of the pivotal role of macrophages in tissue regeneration through shaping the tissue immune microenvironment, various immunomodulatory strategies have been proposed to modify traditional biomaterials. Decellularized extracellular matrix (dECM) has been extensively used in the clinical treatment of tissue injury due to its favorable biocompatibility and similarity to the native tissue environment. However, most reported decellularization protocols may cause damage to the native structure of dECM, which undermines its inherent advantages and potential clinical applications. Here, we introduce a mechanically tunable dECM prepared by optimizing the freeze-thaw cycles. We demonstrated that the alteration in micromechanical properties of dECM resulting from the cyclic freeze-thaw process contributes to distinct macrophage-mediated host immune responses to the materials, which are recently recognized to play a pivotal role in determining the outcome of tissue regeneration. Our sequencing data further revealed that the immunomodulatory effect of dECM was induced via the mechnotrasduction pathways in macrophages. Next, we tested the dECM in a rat skin injury model and found an enhanced micromechanical property of dECM achieved with three freeze-thaw cycles significantly promoted the M2 polarization of macrophages, leading to superior wound healing. These findings suggest that the immunomodulatory property of dECM can be efficiently manipulated by tailoring its inherent micromechanical properties during the decellularization process. Therefore, our mechanics-immunomodulation-based strategy provides new insights into the development of advanced biomaterials for wound healing. [Display omitted] •Cyclic freeze-thaw treatments altered the microstructure and mechanical properties of the dECM across multiple scales.•Enhanced dECM micromechanics significantly promoted M2 macrophage polarization via mechanotransduction pathways.•The immunomodulatory property of dECM with enhanced micromechanical property leads to a superior regenerative performance.•This mechanics-immunomodulation-based strategy offers new insights for for advanced tissue-regeneration biomaterials. A simple and straightforward method was introduced to tailor the mechanics of dECM for enhanced wound healing. The multiscale mechanics of dECM was dissected from macro-to-micro/nano scale, and demonstrated to be the central role in manipulating the immunomodulatory property of dECM and contrib