Biomaterial-based mechanical regulation facilitates scarless wound healing with functional skin appendage regeneration. Scar formation from burns or trauma compromises skin structure and leads to loss of skin appendages. Targeted mechanical cues can enhance skin regeneration by influencing the extracellular microenvironment. Biomaterials with distinct physical properties, such as stiffness, topography, magnetism, and conductivity, are being explored for their ability to support cellular activities and promote skin appendage regeneration. These materials can provide a structural framework for stem and progenitor cells, drive their differentiation, and improve immune ecology to enhance neovascularization and tissue repair. The manipulation of mechanical cues using biomaterials holds promise for scarless wound healing and skin appendage restoration. Mechanical forces influence cell phenotypes, including epithelial-mesenchymal transition (EMT), which is critical for fibrosis. TGF-β is a key cytokine involved in fibroblast response to injury and fibrosis. Mechanical forces can alter TGF-β levels, promoting fibroblast transformation into myofibroblasts. Mechanical cues also influence inflammation, with neutrophils and macrophages playing a role in fibrosis. Mechanosensitive proteins, such as integrins, are involved in cell adhesion and signaling. The cytoskeleton, including microfilaments, microtubules, and intermediate filaments, is crucial for cell migration and mechanical responses. The Hippo pathway and its downstream effectors, YAP and TAZ, are key in mechano-transduction. YAP/TAZ regulate gene expression and fibrosis. Biomaterials can be designed to modulate extracellular signaling, cell adhesion, and epigenetic modifications. They can also influence cell migration and tissue ingrowth. The physical properties of biomaterials, such as stiffness and porosity, affect cell behavior and tissue regeneration. Adaptive biomaterials can respond to internal or external stimuli, changing their properties to match the wound environment. The development of biomaterials with specific physical properties is crucial for scarless wound healing and skin appendage regeneration. The review highlights the potential of biomaterial-based mechanical regulation in promoting scarless wound healing and functional skin appendage regeneration.Biomaterial-based mechanical regulation facilitates scarless wound healing with functional skin appendage regeneration. Scar formation from burns or trauma compromises skin structure and leads to loss of skin appendages. Targeted mechanical cues can enhance skin regeneration by influencing the extracellular microenvironment. Biomaterials with distinct physical properties, such as stiffness, topography, magnetism, and conductivity, are being explored for their ability to support cellular activities and promote skin appendage regeneration. These materials can provide a structural framework for stem and progenitor cells, drive their differentiation, and improve immune ecology to enhance neovascularization and tissue repair. The manipulation of mechanical cues using biomaterials holds promise for scarless wound healing and skin appendage restoration. Mechanical forces influence cell phenotypes, including epithelial-mesenchymal transition (EMT), which is critical for fibrosis. TGF-β is a key cytokine involved in fibroblast response to injury and fibrosis. Mechanical forces can alter TGF-β levels, promoting fibroblast transformation into myofibroblasts. Mechanical cues also influence inflammation, with neutrophils and macrophages playing a role in fibrosis. Mechanosensitive proteins, such as integrins, are involved in cell adhesion and signaling. The cytoskeleton, including microfilaments, microtubules, and intermediate filaments, is crucial for cell migration and mechanical responses. The Hippo pathway and its downstream effectors, YAP and TAZ, are key in mechano-transduction. YAP/TAZ regulate gene expression and fibrosis. Biomaterials can be designed to modulate extracellular signaling, cell adhesion, and epigenetic modifications. They can also influence cell migration and tissue ingrowth. The physical properties of biomaterials, such as stiffness and porosity, affect cell behavior and tissue regeneration. Adaptive biomaterials can respond to internal or external stimuli, changing their properties to match the wound environment. The development of biomaterials with specific physical properties is crucial for scarless wound healing and skin appendage regeneration. The review highlights the potential of biomaterial-based mechanical regulation in promoting scarless wound healing and functional skin appendage regeneration.