Bioactive nanocellulose materials for the treatment of chronic wounds

Sammanfattning: Chronic wounds represent a burden for the healthcare system and significantly affect the quality of life of the patients. There is currently a lack of efficient treatments but new, improved therapeutic approaches are under development. Suggested innovative wound care therapies consist on the topical administration of bioactive compounds aimed at restoring the balance in the wound environment and promoting the healing. However, their effectiveness is limited due to the highly oxidative and proteolytic environment in the chronic wound. In the work presented in this thesis, a series of bioactive nanocellulose-based materials were developed with the aim of addressing some of the present demands in chronic wound care. Wood-derived cellulose nanofibrils (CNFs) were functionalized with selected bioactive molecules expected to endow CNFs with the ability to modulate the chronic wound environment. Different chemical approaches were explored to combine CNFs with the following biomolecules: the amino acid cysteine, the peptide oligoproline and the host defense peptide KR-12. Materials were characterized in terms of chemical structure, degree of substitution and bioactivity.The immobilization of cysteine onto CNFs (cys-CNF) provided the material with radical oxygen species (ROS) scavenging properties and the ability to inhibit protease activity, properties that were related to the presence of free thiol groups on the nanofibers. Storage conditions in an inert atmosphere or in the form of aerogel were proposed to assure the long-term activity of the cys-CNF material.  Investigations on the use of the ROS-sensitive oligoproline to crosslink CNFs provided optimized protocols to maximize peptide substitution and the degree of crosslinking. The oligoproline-CNF materials were sensitive to ROS-mediated cleavage and provided a protective effect to cells exposed to oxidative conditions. Moreover, the feasibility of preparing ROS-responsive drug delivery hydrogels based on the oligoproline-CNF was demonstrated, with indications that tuning the length of the oligoproline peptide could be exploited to tailor the release rate of small proteins.  CNF materials with antibacterial properties and the ability to modulate the response of pro-inflammatory macrophages were obtained by immobilizing KR-12 derivatives onto CNFs. This study highlighted the importance in the selection of the conjugation chemistry to preserve the activity of the peptide once immobilized. To conclude, this work has contributed with valuable strategies to develop bioactive CNF-based materials with the potential of paving the way for advanced solutions in the field of chronic wound care.