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To achieve optimal performances, guided bone regeneration membranes should have several properties, in particular, proper stiffness and tear resistance for space maintenance, appropriate resorption time, and non-cytotoxic effect. In this work, polyphenol-rich pomace extract (PRPE), from a selected grape variety (Nebbiolo), rich in proanthocyanidins and flavonols (e.g., quercetin), was used as a rich source of polyphenols, natural collagen crosslinkers, to improve the physical properties of the porcine pericardium membrane. The incorporation of polyphenols in the collagen network of the membrane was clearly identified by infra-red spectroscopy through the presence of a specific peak between 1360–1380 cm−1. Polyphenols incorporated into the pericardium membrane bind to collagen with high affinity and reduce enzymatic degradation by 20% compared to the native pericardium. The release study shows a release of active molecules from the membrane, suggesting a possible use in patients affected by periodontitis, considering the role of polyphenols in the control of this pathology. Mechanical stiffness is increased making the membrane easier to handle. Young's modulus of pericardium treated with PRPE was three-fold higher than the one measured on native pericardium. Tear and suture retention strength measurement suggest favorable properties in the light of clinical practice requirements. [ABSTRACT FROM AUTHOR]