Sustained Delivery of MMP-9 siRNA via Thermosensitive Hydrogel Accelerates Diabetic Wound Healing

Abstract

Excessive expression of matrix metalloproteinase 9 (MMP-9) impedes healing of diabetic chronic wounds, thus wound dressing that could effectively inhibit the expression of MMP-9 offers significant clinical translation for diabetic wound healing. Herein, a hybrid hydrogel dressing was developed for localized and sustained delivery of MMP-9 siRNA (siMMP-9). siMMP-9 was complexed with Gly-TETA (GT), the GT/siMMP9 complex was then loaded into a thermosensitive hydrogel based on Pluronic F-127 (PF) and methylcellulose (MC). In vitro, this hybrid hydrogel dressing exhibited negligible cytotoxicity, prolonged the release of GT/siMMP-9 for up to 7 days, and significantly reduced MMP-9 expression. In vivo assessment in diabetic rats demonstrated that hydrogel provided localized and sustained delivery via the thermosensitive controlled release of entrapped GT/siMMP-9 into wound tissues for 7 days, resulting in dramatic MMP-9 silencing which significantly improved diabetic wound closure. This hybrid hydrogel dressing exhibited excellent biocompatibility, with no observed systemic toxicity in rats. Taken together, the hybrid hydrogel dressing may constitute an effective and biocompatible means of enhancing diabetic wound healing through effective silencing of the MMP-9 gene, and this hydrogel delivery system also offers a platform for in vivo delivery of siRNA for the treatment of other diseases.

Pre-Formulation Studies: Physicochemical Characteristics and In Vitro Release Kinetics of Insulin from Selected Hydrogels

“…Stalling et al [ 67 ] confirmed that cultured human dermal fibroblasts in the presence of methyl cellulose hydrogels in vitro did not result in significant changes in cell viability after 5 days, indicating the non-cytotoxic of this material. Lan et al [ 68 ] developed hydrogel dressing made of Pluronic F-127 and methyl cellulose for localized and sustained release of siMMP-9 to treat diabetic chronic wounds. Excessive expression of matrix metalloproteinase 9 (MMP-9) impaired the healing of chronic diabetic wounds.…”