<p>Preparation and in vivo evaluation of a topical hydrogel system incorporating highly skin-permeable growth factors, quercetin, and oxygen carriers for enhanced diabetic wound-healing therapy</p>

Abstract

Purpose We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site. Methods To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model. Results The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively. Conclusion LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.

Surface refined AuQuercetinnanoconjugate stimulates dermal cell migration: possible implication in wound healing

“…TGFb1 and SMAD-signalling cascade have intricate actions during broblast migration in wound healing. 16,46 The opposite action of native quercetin and Au Qur NP towards the cell can be explained by absorption kinetics and bioavailability of trapped quercetin material. 47 Our data is consistent with earlier report of accelerated wound healing by quercetin loaded chitosan NPs through TGFb1-dependent mechanism, 48 and we believe it can be used as topical agent for dermal wound healing.…”

“…Rapid hydrolysis due to extreme gastric pH condition in gastrointestinal tract is another bottle neck that decreases its bioactivity index. Recently various attempts, such as incorporating it into NPs, [7][8][9][10][11][12][13] apoferritin loaded system, 14 and hydrogel formulation 15,16 have been made to increase its biopotencies.…”

Lipid Nanoparticles for Enhancing the Physicochemical Stability and Topical Skin Delivery of Orobol

“…Female human cadaver skin (2 × 2 cm 2 ) was purchased from a skin and tissue bank (Hans Biomed Co., Seoul, Korea). Studies that use human cadaver skin from a tissue bank do not require approval from the Institutional Review Board (IRB) or ethics committee (Article 33, Enforcement Rule of the Bioethics and Safety Act in the Republic of Korea) [ 22 ].…”

Hydrogels for the Delivery of Plant-Derived (Poly)Phenols

“…Recent papers demonstrated the possibility to use HGs while taking advantage of the synergic interaction occurring among the intrinsic healing properties of different components. For example, Jee J.-P. et al studied in a diabetic mouse model a Carbopol HG system for topical use containing skin-permeable GFs, Q and oxygen carriers in order to increase re-epithelialization and granulation tissue of diabetic wounds, by rising the concentrations of GFs and antioxidants, and the oxygen delivery in the wound acting in a synergic way [ 32 ]. Gallelli G. et al evaluated both the clinical efficacy and the safety of a HA nano-HG embedded with Q and oleic acid (an unsaturated fatty acid known to accelerate the wound healing process) in the treatment of lower limb skin wounds in fifty-six patients with diabetes mellitus and unsuccessfully treated with mechanical compression [ 33 ].…”

“…All components were then incorporated into a Carbopol 981 HG matrix. This system turned out to be effective in the acceleration of the re-epithelialization and granulation tissue formation in diabetic wounds due to the prolonged skin infiltration of the bioactive components [ 32 ]. GFs were employed since impaired chronic wound healing is characterized by their deficiency [ 65 ]; 1-bromoperfluorooctane has been used as a source of oxygen because tissue repair requires increased metabolic activity, then a high demand of oxygen, which also prevents microbial infections at the wound site, stimulates phagocytes, promotes neovascularization, degradation of necrotic tissue and collagen production [ 66 ].…”