Mounting evidence showing that local nitric oxide (NO) delivery may significantly improve the wound healing process has stimulated the development of wound dressings capable of releasing NO topically. Herein, we describe the preparation of a selfexpandable NO-releasing hydrolyzed collagen sponge (CS), charged with the endogenously found NO donor, S-nitrosoglutathione (GSNO). We show that cold pressed and GSNO-charged CS (CS/GSNO) undergo self-expansion to its original 3D shape upon water absorption to a swelling degree of 2,300 wt%, triggering the release of free NO. Topical application of compressed CS/GSNO on wounds in an animal model showed that exudate absorption by CS/GSNO leads to the release of higher NO doses during the inflammatory phase and progressively lower NO doses at later stages of the healing process. Moreover, treated animals showed significant increase in the mRNA expression levels of monocyte chemoattractant protein-1 (MCP-1), murine macrophage marker (F4/80), transforming growth factor beta (TGF-β), stromal cell-derived factor 1 (SDF-1), insulin-like growth factor-1 (IGF-1), nitric oxide synthase(iNOS), and matrix metalloproteinase(MMP-9). Cluster differentiation 31 (CD31), vascular endothelial growth factor (VEGF), and F4/80 were measured on Days 7 and 12 by immunohistochemistry in the cicatricial tissue. These results indicate that the topical delivery of NO enhances the migration and infiltration of leucocytes, macrophages, and keratinocytes to the wounded tissue, as well as the neovascularization and collagen deposition, which are correlated with an accelerated wound closure. Thus, self-expandable CS/GSNO may represent a novel biocompatible and active wound dress for the topical delivery of NO on wounds. K E Y W O R D S hydrolyzed collagen sponge, nitric oxide, S-nitrosoglutathione, topical application, wound healing Valéria C. O. Póvoa and Giovanna J. V. P. dos Santos contributed equally to this work.
Nitric oxide (NO) donor biomaterials have great potential to promote tissue regeneration and healing. Among the materials that can be used for this purpose, collagen has high biocompatibility, low antigenic activity and is already used commercially in the form of membranes with hemostatic action for the coating of lesions to favor the regeneration of the injured area. NO is directly involved in angiogenic and proliferative activities, stimulating the tissue repair process in healthy individuals or patients suffering from chronic diseases (e.g. diabetes). The collagen membranes were impregnated with S-nitrosoglutathione (GSNO), a NO donor, through absorption from solution and characterized by vibrational spectroscopy, scanning electron microscopy and dispersive energy spectroscopy. NO release was characterized by chemiluminescence. The kinetics of NO release were shown to be dependent on the hydration degree. In vivo experiments showed that collagen/GSNO membranes accelerate wound healing and increase the expression of cytokines associated with cell proliferation in cicatricial tissue of animals compared with control animals. These results show collagen/GSNO membranes exert an effective wound healing action and have potential to treat chronic ulcers.
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