The Wound Healing Effect of Nanoclay, Collagen, and Tadalafil in Diabetic Rats: An In Vivo Study

The diabetic wound is the most challenging one to manage, which is associated with microvascular and macrovascular dysfunction, and novel strategies such as using hydrogels demonstrate their promising prospect in treatment and management approaches of the diabetic wound. This study aimed to investigate the effect of collagen/nanoclay/tadalafil hydrogel on wound healing in diabetic rats under HIIT exercise. Hydrogel was synthesized, and then biocompatibility and antibacterial tests were performed. The therapeutic effect of collagen/nanoclay/tadalafil hydrogel was assessed after induction of diabetes in the rat model, and wound healing was evaluated with macroscopic and microscopic tests. The result of the MTT test showed no significant cytotoxicity of collagen/nanoclay/tadalafil hydrogel. Furthermore, the inhibitory effect of hydrogel was detected on E. coli and S. aureus. The macroscopic results demonstrated that the wound contraction was considerable in the hydrogel/HIIT exercise and hydrogel groups compared with the HIIT exercise and control groups during 21 days. The microscopic results showed that the presence of fibroblasts, the amount of collagen, the epidermis density, and the formation of hair follicles were increased in the hydrogel/HIIT exercise group compared with other groups in the diabetic rate model. It can be concluded that collagen/nanoclay/tadalafil hydrogel with HIIT exercise could accelerate diabetic wound healing and can be an appropriate candidate for skin regeneration in medical applications.

Notoginsenoside R1 Facilitated Wound Healing in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

Diabetic ulcers bring about high morbidity and mortality in patients and cause a great economic burden to society as a whole. Since existing treatments cannot fulfil patient requirements, it is urgent to find effective therapies. In this study, the wound healing effect of topical notoginsenoside R1 (NR1) treatment on diabetic full-thickness wounds in type II diabetes mellitus (T2DM) was induced by the combination of a high-fat diet and streptozotocin (STZ) injection. NR1 significantly increased the wound closure rate, enhanced extracellular matrix (ECM) secretion, promoted collagen growth, increased platelet endothelial cell adhesion molecule-1 (CD31) expression, and decreased cleaved caspase-3 expression. RNA-Seq analysis identified ECM remodeling and inflammation as critical biological processes and Timp1 and Mmp3 as important targets in NR1-mediated wound healing. Further experiments showed that NR1-treated wounds demonstrated higher expression of tissue inhibitor of metalloproteinase 1 (TIMP1) and transforming growth factor-β1 (TGFβ1) and lower expression of matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 3 (MMP3), interleukin-1β (IL-1β), and interleukin-6 (IL-6) than diabetic wounds. These investigations promote the understanding of the mechanism of NR1-mediated diabetic wound healing and provide a promising therapeutic drug to enhance diabetic wound healing.

Evaluation of Effect of Biologically Synthesized Ethanolic Extract of Propolis-Loaded Poly(-Lactic-co-Glycolic Acid) Nanoparticles on Wound Healing in Diabetic Rats

Wound healing is interaction of a complex cascade of cellular/biochemical actions leading to restoration of structural and functional integrity with regain of injured tissues strength. This study was aimed at evaluation of application of ethanolic extract of propolis-loaded poly(-lactic-co-glycolic acid) nanoparticles (EEP-PLGA NPs) on wound healing in diabetic rats. Sixty rats were randomized into four groups of 15 rats each: In control group (Control) diabetic wound was treated with normal saline. In Carrier 1 group diabetic wound was treated with PLGA nanoparticles based solution. In Carrier 2 group the diabetic wound was treated with EEP. In Treatment group animals received EEP-PLGA NPs on the wound. Wound size was measured on 7, 14 and 21 days after surgery. The expression of p53, bcl-2, Caspase III, were evaluated using reverse-transcription PCR and Immunohistochemical staining. The Treatment group had significantly reduced the wound size compared to other groups ( P = 0.001). histological and morphometric studies, and mean rank of the qualitative studies demonstrated that there was significant difference between Treatment group and other groups ( P < .05). Observations demonstrated that ethanolic extract of propolis-loaded PLGA nanoparticles significantly shortened the inflammatory phase and accelerated the cellular proliferation. Accordingly, the animals in Treatment group revealed significantly ( P < .05) higher fibroblast distribution/one mm2 of wound area and rapid re epithelialization. The mRNA levels of bcl-2, p53 and caspase III were remarkably ( P < .05) higher in Treatment group compared to control and animals. The immunohistochemical analyzes confirmed the RT-PCR findings. EEP-PLGA NPs offered potential advantages in wound healing acceleration and improvement through angiogenesis stimulation, fibroblast proliferation and granulation tissue formation in early days of healing phases, acceleration in diabetic wound repair associated with earlier wound contraction and stability of damaged area by rearrangement of granulation tissue and collagen fibers.

Nanofiber/hydrogel core–shell scaffolds with three-dimensional multilayer patterned structure for accelerating diabetic wound healing

Impaired angiogenesis is one of the predominant reasons for non-healing diabetic wounds. Herein, a nanofiber/hydrogel core–shell scaffold with three-dimensional (3D) multilayer patterned structure (3D-PT-P/GM) was introduced for promoting diabetic wound healing with improved angiogenesis. The results showed that the 3D-PT-P/GM scaffolds possessed multilayered structure with interlayer spacing of about 15–80 μm, and the hexagonal micropatterned structures were uniformly distributed on the surface of each layer. The nanofibers in the scaffold exhibited distinct core–shell structures with Gelatin methacryloyl (GelMA) hydrogel as the shell and Poly (d, l-lactic acid) (PDLLA) as the core. The results showed that the porosity, water retention time and water vapor permeability of the 3D-PT-P/GM scaffolds increased to 1.6 times, 21 times, and 1.9 times than that of the two-dimensional (2D) PDLLA nanofibrous scaffolds, respectively. The in vitro studies showed that the 3D-PT-P/GM scaffolds could significantly promote cell adhesion, proliferation, infiltration and migration throughout the scaffolds, and the expression of cellular communication protein-related genes, as well as angiogenesis-related genes in the same group, was remarkably upregulated. The in vivo results further demonstrated that the 3D-PT-P/GM scaffolds could not only effectively absorb exudate and provide a moist environment for the wound sites, but also significantly promote the formation of a 3D network of capillaries. As a result, the healing of diabetic wounds was accelerated with enhanced angiogenesis, granulation tissue formation, and collagen deposition. These results indicate that nanofiber/hydrogel core–shell scaffolds with 3D multilayer patterned structures could provide a new strategy for facilitating chronic wound healing. Graphical Abstract

Diabetic wound healing approaches: an update

Diabetic wounds are of profound clinical importance. Despite immense efforts directed towards its management, it results in the development of amputations, following a diagnosis of diabetic foot. With a better understanding of the complexities of the microbalance involved in the healing process, researchers have developed advanced methods for the management of wounds as well as diagnostic tools (especially, for wound infections) to be delivered to clinics sooner. In this review, we address the newer developments that hope to drive the transition from bench to bedside in the coming decade.

Green Synthesis of Silver Nanoparticles by the Cyanobacteria Synechocystis sp.: Characterization, Antimicrobial and Diabetic Wound-Healing Actions

Green nanotechnology is now accepted as an environmentally friendly and cost-effective advance with various biomedical applications. The cyanobacterium Synechocystis sp. is a unicellular spherical cyanobacterium with photo- and hetero-trophic capabilities. This study investigates the ability of this cyanobacterial species to produce silver nanoparticles (AgNPs) and the wound-healing properties of the produced nanoparticles in diabetic animals. Methods: UV–visible and FT-IR spectroscopy and and electron microscopy techniques investigated AgNPs’ producibility by Synechocystis sp. when supplemented with silver ion source. The produced AgNPs were evaluated for their antimicrobial, anti-oxidative, anti-inflammatory, and diabetic wound healing along with their angiogenesis potential. Results: The cyanobacterium biosynthesized spherical AgNPs with a diameter range of 10 to 35 nm. The produced AgNPs exhibited wound-healing properties verified with increased contraction percentage, tensile strength and hydroxyproline level in incision diabetic wounded animals. AgNPs treatment decreased epithelialization period, amplified the wound closure percentage, and elevated collagen, hydroxyproline and hexosamine contents, which improved angiogenesis factors’ contents (HIF-1α, TGF-β1 and VEGF) in excision wound models. AgNPs intensified catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities, and glutathione (GSH) and nitric oxide content and reduced malondialdehyde (MDA) level. IL-1β, IL-6, TNF-α, and NF-κB (the inflammatory mediators) were decreased with AgNPs’ topical application. Conclusion: Biosynthesized AgNPs via Synechocystis sp. exhibited antimicrobial, anti-oxidative, anti-inflammatory, and angiogenesis promoting effects in diabetic wounded animals.