Collagen-based dermal regeneration matrices have become synonymous with the treatment of full-thickness burns. These skin replacements provide wound closure, restore barrier function, facilitate correct healing, and manage pain. The aim of this study was to histologically (Picrosirius red, haematoxylin and eosin, and Masson's trichrome stained sections) compare host–cellular interaction in wound healing, mediated through enriched and control collagen-glycosaminoglycan scaffolds, in rats. Control matrices were prepared from collagen-glycosaminoglycan co-precipitates subjected to controlled freezing and lyophilization. Test matrices were enriched with a cosmeceutical formulation containing Niacinamide (0.31 mg/ml), L-carnosine (0.10 mg/ml), hesperidin (0.48 mg/ml) and Biofactor HSP® (5.18 μg/ml). Crosslinking was sequentially achieved through a combination of chemical and physical crosslinking steps. Two full-thickness dorsal wounds were created on female Sprague-Dawley rats (n = 16) and surgically treated through implantation (one control and enriched scaffold per rat). Sample material was collected after termination on day 7 (8 rats) and 28 (8 rats). At day 7, scaffolds were infiltrated by fibroblasts with few lymphocytes observed, and in enriched scaffolds the number of lymphocytes and monocytes were reduced compared to controls. No differences in epithelialization, wound closure, and wound contraction were observed between samples. On day 28, wounds subjected to control and test matrices had densely organized superficial Type I-like collagen fibers with looser, deeper Type III-like collagen fibers revealed under polarized light. The collagen deposition in the deeper regions demonstrated a basket weave appearance. Thus, collagen-based scaffolds have the potential to serve as a delivery system and alter the cellular dynamics associated with the cellular phase of wound healing in vivo.