Dual-Modulated Heparin Delivery from Electrospun PVA Nanofibers for Wound Healing: The Role of Polyelectrolyte Complexes and Fiber Crosslinking

Chronic wounds represent a significant and growing clinical burden, often associated with impaired healing processes, persistent inflammation, and altered local microenvironmental conditions such as pH variations. In this context, the development of advanced topical drug delivery systems able to modulate drug release in response to wound-specific conditions are of considerable therapeutic interest [1]. Heparin, a highly sulphated glycosaminoglycan widely known for its anticoagulant activity, exhibits both anti-inflammatory properties and favourable interactions with growth factors involved in tissue repair, thereby promoting wound healing [2]. The aim of this study was to develop electrospun nanofibrous systems for topical heparin delivery, in which drug release can be modulated through two complementary strategies, i.e. incorporation into polyelectrolyte complexes (PEC) and post-processing crosslinking of the polymeric matrix. Heparin-based binary and ternary PEC, based on chitosan and gelatin, were first designed and optimized to achieve pH-responsive behaviour and controlled drug release. Their physicochemical properties and release profiles were evaluated under different pH conditions (from 5 to 8), being representative of the wound environment. Selected PEC systems were then incorporated into poly(vinyl alcohol) (PVA) electrospun nanofibers, alongside formulations containing free heparin, to enable a comparative assessment of release modulation mechanisms. To further control drug release, PVA nanofibers were loaded with PEC system or free heparin. The latter were subjected to both chemical and thermal crosslinking treatments to reduce PVA solubility in water and burst release of the active agent. The resulting nanofibers were characterized by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) to investigate morphology, molecular interactions, and structural modifications. In vitro release studies, performed in aqueous media under agitation and using Franz diffusion cells, demonstrated that heparin release from nanofibers can be effectively tuned through both PEC formation and crosslinking degree. Specifically, PEC incorporation provided a pH- dependent modulation of drug release, while crosslinking of the PVA matrix was demonstrated to finely tune the rate of nanofiber dissolution, enabling sustained delivery profiles. Overall, this work highlights a novel dual-modulation strategy for controlling heparin release from electrospun nanofibers, combining molecular-level interactions (PEC) with material-level modifications (crosslinking). These findings support the potential of such systems as advanced functional wound dressings for improved management of chronic wounds.