Hydrogels have been used as matrices for the topical delivery of nitric oxide (NO) for obtaining vasodilation, wound healing and analgesic actions. More recently, supramolecular hydrogels comprised of poly(acrylic acid)...
Inflammatory processes are related to a wide variety of diseases with high global impact. Nitric oxide (NO) is an excellent candidate for the treatment of such diseases due to its important anti-inflammatory role in living systems, which is related to its concentration in the cellular medium that in turn depends directly on its release rate from NO releasing compounds. In this work, we synthesized a nitrate-terminated dendrimer and evaluated its anti-inflammatory properties. Remarkably, dendrimer bearing 18 NO-releasing groups was nontoxic, and exhibited antiinflammatory activity (13.7−27.9% of IL-8 inhibition) throughout the tested concentrations (6.50 × 10 −2 to 4.17 × 10 3 nM of dendrimer; (1.17−7.50) × 10 4 nM of NO-moiety). On the other hand, the NO-releasing monomer was pro-inflammatory at concentrations higher than 62.5 nM. Investigation of the NO-releasing profiles from monomer and dendrimer using real-time NO analyzer NOA confirmed the slow release of NO from the dendrimer. Our results suggest that the NO release from the dendrimer occurs in a controlled fashion, keeping the anti-inflammatory effect of NO even at high concentrations.
Highlights
Visualization of individual Pluronic® F127 micelles in hydrogels.
Supramolecular structure evolution of micellar hydrogels as a function of concentration.
Plunge-freezing of high viscosity solutions.
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.
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