This study investigates the synthesis and characterization of a model extracellular matrix (ECM) that induces partial regeneration of adult mammalian skin. The researchers found that certain highly porous, crosslinked collagen-glycosaminoglycan copolymers, when seeded with dermal and epidermal cells and grafted on standard, full-thickness skin wounds in adult guinea pigs, could induce the regeneration of a mature epidermis and a nearly physiological dermis over areas up to 16 cm². These chemical analogs of ECMs were morphogenetically active if their average pore diameter ranged between 20 and 125 μm, their resistance to degradation by collagenase exceeded a critical limit, and the density of autologous dermal and epidermal cells inoculated was >5 × 10⁶ cells per cm² of wound area. Unseeded copolymers with physical structures within these limits delayed wound contraction by about 10 days but did not prevent it. Seeded copolymers not only delayed contraction but eventually arrested and reversed it while new skin was being regenerated. The findings suggest that these cell-seeded simple chemical analogs of ECMs induce skin morphogenesis provided their macromolecular network structure is adjusted within highly specific limits. The study also highlights the importance of the ECM's resistance to degradation and its specific physicochemical structure in mediating the interaction between epithelial and mesenchymal cells, thereby inducing normal tissue differentiation and development in an adult mammalian model where such processes do not occur spontaneously.This study investigates the synthesis and characterization of a model extracellular matrix (ECM) that induces partial regeneration of adult mammalian skin. The researchers found that certain highly porous, crosslinked collagen-glycosaminoglycan copolymers, when seeded with dermal and epidermal cells and grafted on standard, full-thickness skin wounds in adult guinea pigs, could induce the regeneration of a mature epidermis and a nearly physiological dermis over areas up to 16 cm². These chemical analogs of ECMs were morphogenetically active if their average pore diameter ranged between 20 and 125 μm, their resistance to degradation by collagenase exceeded a critical limit, and the density of autologous dermal and epidermal cells inoculated was >5 × 10⁶ cells per cm² of wound area. Unseeded copolymers with physical structures within these limits delayed wound contraction by about 10 days but did not prevent it. Seeded copolymers not only delayed contraction but eventually arrested and reversed it while new skin was being regenerated. The findings suggest that these cell-seeded simple chemical analogs of ECMs induce skin morphogenesis provided their macromolecular network structure is adjusted within highly specific limits. The study also highlights the importance of the ECM's resistance to degradation and its specific physicochemical structure in mediating the interaction between epithelial and mesenchymal cells, thereby inducing normal tissue differentiation and development in an adult mammalian model where such processes do not occur spontaneously.