This systematic review and GRADE-based analysis evaluates the clinical efficacy, mechanistic plausibility, and certainty of evidence supporting a wool-derived keratin-based matrix (Keramatrix®, Biowound Solutions Inc., Las Vegas, NV, USA) for hard-to-heal wounds. Across 32 clinical and translational studies, including one randomized controlled trial and multiple comparative cohorts, Keramatrix consistently accelerated epithelialization, improved closure rates, and demonstrated a favorable safety profile across acute donor-site wounds, chronic diabetic and venous leg ulcers, and epidermolysis bullosa associated skin fragility lesions. Using standardized GRADE methodology, the certainty of evidence was rated High for acute donor-site healing and Moderate for chronic ulcers, equivalent to or exceeding the evidentiary strength underpinning CMS formulary inclusion of comparator biologic matrices such as Dermagraft. Keramatrix meets CMS’s eligibility and evidentiary criteria for a “reasonable and necessary” cellular, acellular, and matrix-like products (CAMPs) under future-effective Local Coverage Determinations (LCDs), providing a biologically active keratin scaffold that promotes keratinocyte migration, dermal–epidermal junction restoration, and tissue repair.

Background: Hard-to-heal wounds impose substantial morbidity, cost, and, in the case of diabetic foot ulcers, elevated mortality risk. Venous leg ulcers (VLUs) and variants of epidermolysis bullosa (EB) likewise impose major chronic-disease burden and healthcare cost. Keratin biomaterials derived from wool have demonstrated regenerative potential by stimulating keratinocyte activation and collagen synthesis