Biological cover over tissue expander prostheses has been introduced to provide soft-tissue support for tissue expanders during breast reconstruction. However, its impact on mechanically induced skin growth remains unknown. This study investigates the hypothesis that covering the tissue expander with acellular dermal matrix (ADM) affects mechanotransduction without compromising the efficacy of tissue expansion. Tissue expansion, with and without use of ADM, was performed on a porcine model. The tissue expanders were inflated twice with 45 mL of saline, and the full-thickness skin biopsy specimens were harvested from expanded and control unexpanded skin 1 week and 8 weeks after the final inflation. Histologic evaluation, immunohistochemistry staining, and gene expression analysis were performed. Skin growth and total deformation were evaluated using isogeometric analysis. The authors' results demonstrate that use of ADM as a biological cover during tissue expansion does not impede mechanotransduction that leads to skin growth and blood vessel formation. Isogeometric analysis revealed similar total deformation and growth of expanded skin with and without a biological cover, confirming that its use does not inhibit mechanically induced skin growth. In addition, the authors found that use of an ADM cover results in more uniform distribution of mechanical forces applied by the tissue expander. These results suggest that ADM improves mechanically induced skin growth during tissue expansion by facilitating a more uniform distribution of mechanical forces applied by the tissue expander. Therefore, the use of a biological cover has potential to improve outcomes in tissue expansion-based reconstruction.