Elektrogesponnen alginaat-gebaseerde verbanden voor gecontroleerde stikstofmonoxide-afgifte bij diabetische wonden

Chronic wounds remain a major clinical and socioeconomic challenge, particularly in patients with diabetes mellitus. Among these, diabetic foot ulcers (DFUs) represent one of the most severe complications, affecting one out of three diabetic patients during their lifetime. They are associated with high recurrence, high infection risk, and frequent amputation. Current wound dressings primarily provide protection and moisture balance but do not actively correct the pathophysiological impairments underlying DFUs. One of their key deficiencies is reduced nitric oxide (NO) bioavailability, which contributes to impaired angiogenesis, dysregulated inflammation, and susceptibility to infection. Therefore, the central aim of this dissertation was to develop a multifunctional wound dressing capable of diabetic-specific NO release, while maintaining mechanical stability, biocompatibility, and translational potential. The research followed a stepwise approach to establish a modular, scalable hydrogel platform. In an initial stage, methacrylated alginate hydrogels were reinforced using different photocrosslinking strategies. Covalent crosslinking with ethylene glycol diacrylate yielded hydrogels with improved mechanical integrity and fluid absorption capacity comparable to commercial references, while preserving biocompatibility. Building on this matrix, electrospinning was introduced to generate fibrous scaffolds with extracellular matrix-like architecture. Incorporation of mesoporous silica nanoparticles (MSNs) enhanced mechanical properties while acting as reservoirs for therapeutic agents. Proof-of-concept loading with chlorhexidine confirmed antimicrobial activity but highlighted its known trade-off between efficacy and cytocompatibility. The subsequent focus was on NO delivery. Diazeniumdiolate NO donors were synthesized and loaded into electrospun hydrogels with and without MSNs. A complementary innovation was the adaptation of a hemoglobin-based spectrophotometric assay into a miniaturized, high-throughput format. This assay enabled reproducible, kinetic monitoring of NO release in different donors, scaffold compositions, and loading parameters. Release profiling combined with nonlinear regression modeling revealed that donor chemistry and matrix composition determine release kinetics the most predominantly. This finding conferred flexibility to the system through variation of parameters according to the desired delivery. Integrated evaluation of the system showed that effective NO-releasing dressings require a balanced interplay between four parameters: (i) mechanical stability of the hydrogel matrix, (ii) drug reservoir capacity provided by fibrous and nanoparticle architectures, (iii) donor-specific profiles according to their chemistry, and (iv) reproducible performance monitoring via a standardized assay. Together, these elements resulted in a versatile platform that can be tailored to specific clinical needs while remaining compatible with regulatory expectations. Beyond experimental development, the translational perspectives were also assessed. Valorization analysis highlighted Belgium's strong infrastructure for early clinical evaluation, as well as the broader European regulatory environment. Intellectual property considerations, process scalability, and sterilization challenges were identified as critical steps for future translation. Limitations include donor stability under storage, and the need for validation in preclinical diabetic wound models. In conclusion, this dissertation presents a proof-of-concept for a nitric oxide-releasing wound dressing that integrates advances in polymer chemistry, particle and processing technologies, and analytical techniques. The work demonstrates both technical feasibility and translational potential of a modular hydrogel platform designed to meet a costly medical need. By providing targeted NO delivery combined with structural reinforcement, this system adds to next-generation wound therapies with the potential to reduce amputation rates, improve healing outcomes, and lower healthcare costs in diabetes-related chronic wounds. Keywords: diabetic foot ulcers, nitric oxide delivery, smart biomaterials, release-modulated hydrogels