Accelerated diabetic wound healing by topical application of combination oral antidiabetic agents-loaded nanofibrous scaffolds: An in vitro and in vivo evaluation study

Abstract

The combination of oral antidiabetic drugs, pioglitazone, metformin, and glibenclamide, which also exhibit the strongest anti-inflammatory action among oral antidiabetic drugs, were loaded into chitosan/gelatin/polycaprolactone (PCL) by electrospinning and polyvinyl pyrrolidone (PVP)/PCL composite nanofibrous scaffolds by pressurized gyration to compare the diabetic wound healing effect. The combination therapies significantly accelerated diabetic wound healing in type-1 diabetic rats and organized densely packed collagen fibers in the dermis, it also showed better regeneration of the dermis and epidermis than single drug-loaded scaffolds with less inflammatory cell infiltration and edema. The formation of the hair follicles started in 14 days only in the combination therapy and lower proinflammatory cytokine levels were observed compared to single drug-loaded treatment groups. The combination therapy increased the wettability and hydrophilicity of scaffolds, demonstrated sustained drug release over 14 days, has high tensile strength and suitable cytocompatibility on L929 (mouse fibroblast) cell and created a suitable area for the proliferation of fibroblast cells. Consequently, the application of metformin and pioglitazone-loaded chitosan/gelatin/PCL nanofibrous scaffolds to a diabetic wound area offer high bioavailability, fewer systemic side effects, and reduced frequency of dosage and amount of drug.

Glibenclamide Nanocrystal-Loaded Bioactive Polymeric Scaffolds for Skin Regeneration: In Vitro Characterization and Preclinical Evaluation

“…Histological examination of the NC-GL-treated wounds demonstrated accelerated wound healing, and an early appearance of dermal appendages. This result correlates with that of several studies [26,105] that have proven the ability of GL to decrease the recovery time and increase the cellular proliferation of fibroblasts, keratinocytes and endothelial cells. Topical GL was shown to augment epithelialization and regulate granulation tissue formation, leading to the early beginning of the proliferative phase through the induction of the expression of numerous pro-healing factors such as IGF-1, TGF-β and IL-10 [24].…”

“…As shown in Figure 2C, the GL coarse powder displayed characteristic sharp and intense diffraction peaks at 2θ values of 11. [26,30]. The precipitation and nano-crystallization of GL to form NC-GL did not interfere with the GL crystalline state as the diffraction patterns for GL were preserved at 2θ values of 20.84 • , 22.92 • and 30.08 • but with a lower intensity, reduced sharpness and slight broadening of peaks (Figure 2C).…”

“…As shown in Figure 2A, the GL coarse powder showed two characteristic peaks at 3365 and 3309 cm −1 corresponding to the amide stretching bands, a CH=CH band at 2929 cm −1 , C=O stretching vibration at 1713 cm −1 and 1615 cm −1 , C=C stretching bands at 1591 and 1519 cm −1 and symmetric and asymmetric S=O2 stretching at 1340 and 1155 cm −1 , respectively [26]. Additionally, C-N, C-O and C-C had characteristic peaks at 1334, 1154, 924 and 810 cm −1 .…”

“…The sulphonyl urea group including glibenclamide, glimepiride and gliclazide [25] was specifically studied for its healing potential as, in addition to insulin regulation, fat and carbohydrate metabolism is also controlled, providing a better healing environment and stimulating keratinocyte cellular proliferation and formation of granulation tissue [2]. Moreover, they were shown to possess a high anti-inflammatory action [26], especially glibenclamide, as it contains both sulfonyl and benzamido groups [27]. Glibenclamide was shown to decrease the secretion and mRNA expression of pro-inflammatory cytokines such as IL-1β and IL-18 that are predominantly produced by macrophages in the wounded region [27].…”

“…Improvement in the healing cascade was reported upon the combination of these repurposed antidiabetic drugs with natural bioactive polymers for their pivotal role in healing. Cam et al [26] showed accelerated wound healing by topical application of a combination of oral antidiabetic agents loaded in chitosan and gelatin nanofibrous scaffolds. Additionally, loading of glibenclamide and metformin into bacterial cellulose/gelatin fibrous scaffolds offered a high potential for diabetic wound healing with a high bioavailability and fewer systemic side effects [29].…”