This study evaluated the effects of two therapeutic approaches using a Bovine Collagen Matrix (BCM) and an innovative Amniotic Membrane Dressing (hAM-pe) in wound healing, integrating both clinical and mechanistic perspectives. Both treatments are collagen-based biomaterials, which play a crucial role in modulating the wound mi-croenvironment, supporting cellular adhesion, and delivering bioactive molecules. While collagen-based therapies have been extensively studied in vitro and in small animal models, clinical translation remains limited. This study’s approach involved the simul-taneous application of both treatments within a single patient, allowing a direct com-parison of therapeutic outcomes. Clinically, hAM-pe demonstrated superior outcomes, accelerating wound closure, re-ducing inflammation, and eliminating the need for surgical intervention. Its practical advantages, including ease of application in outpatient settings, further enhance its translational potential. Mechanistically, hAM-pe treatment was associated with reduced expression of inflammatory markers (IL-1β, TNF-α, and CXCL-10), enhanced vascular-ization (VEGF, CD34), and a shift toward a regenerative macrophage phenotype (Ar-ginase-1 expression). Conversely, BCM treatment led to prolonged inflammation, de-layed tissue remodeling, and an adverse granulomatous response. These findings underscore the potential of hAM-pe as an alternative, non-invasive therapy for chronic wounds. Further investigations into its immunoregulatory mecha-nisms, particularly its influence on macrophage subsets and extracellular matrix re-modeling, will provide valuable insights for optimizing regenerative wound care strategies.