Substance-Based Medical Device in Wound Care: Bridging Regulatory Clarity and Therapeutic Innovation.

Substance-based medical devices (SBMDs) are increasingly used in wound care due to their favorable safety profile, physicochemical mechanisms of action, and therapeutic effectiveness. These products often incorporate biopolymers such as hyaluronic acid or chitosan, alone or in combination with antimicrobial agents like silver nanoparticles (AgNPs) or silver sulfadiazine (SSD), offering hydration, tissue protection, and control of microbial burden in both acute and chronic wounds. Despite their widespread clinical use, the regulatory classification of SBMDs under Regulation (EU) 2017/745 (MDR) remains one of the most challenging and debated areas within the current European framework. This review analyzes the scientific and regulatory context of topical SBMDs, with particular emphasis on borderline products that share similarities with medicinal products in terms of formulation, composition, or claimed effects. The discussion focuses on the application of MDR Annex VIII, specifically Rule 21 for substance-based devices and Rule 14 for devices incorporating medicinal substances with ancillary action, together with interpretative guidance provided by MDCG 2022-5 Rev.1 and the Association of the European Self-Care Industry (AESGP) Position Paper. Particular attention is given to the identification of the critical role of the primary mode of action (MoA) as the determining criterion for regulatory qualification, especially for products containing antimicrobial substances. Through selected examples and case analyses, the review highlights inconsistencies in classification across Member States and underscores the need for a more harmonized, evidence-based, and proportionate regulatory approach. Overall, SBMDs challenge traditional regulatory boundaries and call for a framework capable of accommodating complex, multifunctional products while ensuring patient safety and regulatory coherence.