Physiological actions of "medical devices made of natural materials" (such as vegetal matrices) and non-pharmacological actions of "medical devices made of substances" (and as such artificial derivatives) as innovations introduced by Regulation 2017/745.

The European Union's shift from Directive 93/42/EEC to Regulation 2017/745 changes how products made of chemically-defined substances and those made of natural materials should be conceived, evaluated, and regulated. In this study, it is argued that "medical devices made of substances" should be distinguished from "medical devices made of natural materials" (e.g., vegetal matrices) because the regulatory logic linked to "substances" is largely chemistry-centered and may be poorly suited to chemically variable systems whose performance, having the specific medical purpose of restoring a physiological state, emerges from supramolecular, network-level interactions. Regulation 2017/745 provisions addressing devices made of substances require well-defined compositions and identified constituents, consistent with reductionist approaches. In European regulatory practice, "substance" is commonly operationalized through well-defined molecular constituents as key players in pharmacological reasoning. In contrast, devices made of "natural materials" may modulate interconnected biofunctions and regulatory pathways in ways that cannot be reduced to a single constituent or to the sum of isolated constituents. This "matrix effect," associated with redundancy and functional resilience, shifts quality/performance away from compositional markers and pharmacological, immunological or metabolic means toward a network interaction best framed as a physiological mode of action. Under Regulation 2017/745's "New Approach," manufacturers must justify applicable requirements, classification rules, and validation methods for the specific product. Although devices made of "substances" act via non-pharmacological, immunological, or metabolic means, "substance"-oriented requirements should not automatically be extended to natural-material devices whose quality and performance arise from whole-matrix properties. Clear differentiation will support proportionate regulation, innovation, and patient benefit.