Enhancing diabetic wound healing: advances in electrospun scaffolds from pathogenesis to therapeutic applications

Abstract

Diabetic wounds are a significant subset of chronic wounds characterized by elevated levels of inflammatory cytokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). They are also associated with impaired angiogenesis, persistent infection, and a high likelihood of hospitalization, leading to a substantial economic burden for patients. In severe cases, amputation or even mortality may occur. Diabetic foot ulcers (DFUs) are a common complication of diabetes, with up to 25% of diabetic patients being at risk of developing foot ulcers over their lifetime, and more than 70% ultimately requiring amputation. Electrospun scaffolds exhibit a structural similarity to the extracellular matrix (ECM), promoting the adhesion, growth, and migration of fibroblasts, thereby facilitating the formation of new skin tissue at the wound site. The composition and size of electrospun scaffolds can be easily adjusted, enabling controlled drug release through fiber structure modifications. The porous nature of these scaffolds facilitates gas exchange and the absorption of wound exudate. Furthermore, the fiber surface can be readily modified to impart specific functionalities, making electrospinning nanofiber scaffolds highly promising for the treatment of diabetic wounds. This article provides a concise overview of the healing process in normal wounds and the pathological mechanisms underlying diabetic wounds, including complications such as diabetic foot ulcers. It also explores the advantages of electrospinning nanofiber scaffolds in diabetic wound treatment. Additionally, it summarizes findings from various studies on the use of different types of nanofiber scaffolds for diabetic wounds and reviews methods of drug loading onto nanofiber scaffolds. These advancements broaden the horizon for effectively treating diabetic wounds.

Keywords: diabetic foot ulcers; electrospinning; nanofiber; nanostructures; wound dressing.

FIGURE 1

Epidemiological survey of diabetes in China and worldwide (Aschner et al., 2021).

FIGURE 2

(A) Wound healing and its major cellular components. The repair of wounds begins with the coagulation phase, where platelet embolization prevents blood loss and the formation of the initial fibrin matrix. This is followed by the inflammation stage, which serves to remove debris and prevent infection. The influx of neutrophils is promoted by the release of histamine by mast cells. Monocytes then migrate to the site of injury and differentiate into tissue macrophages, which help clear residual cell debris and neutrophils. During the proliferation phase, keratinocytes migrate to close the wound space, angiogenesis occurs to reconstruct blood vessels, and fibroblasts replace the initial fibrin clot with granulation tissue. Macrophages and regulatory T cells play critical roles in this stage of healing. Finally, in the remodeling stage, fibroblasts further remodel the deposited matrix, while vascular degeneration and myofibroblasts contribute to overall wound contraction. (B) Factors influencing wound healing in diabetes. Diabetic wound keratinocytes display abnormal activation, leading to impaired hyperproliferation and migration. Additionally, a significant number of chronic inflammatory cells, such as macrophages and fibroblasts, undergo senescence and exhibit a senescence-associated secretory phenotype (SASP). This perpetuates senescence, triggers the release of reactive oxygen species (ROS), and exacerbates inflammation.

FIGURE 3

Schematic diagram of electrospinning equipment.

FIGURE 4

Schematic diagram illustrating quadriaxial electrospinning, with the inset in the upper right corner displaying a photograph of the concentric spinneret (Zhang et al., 2021).

FIGURE 5

(A) A schematic diagram illustrating the development of a drug delivery wound dressing by incorporating methaqualone into the matrix of an electrospun chitosan/carboxymethyl cellulose (CMC)-based scaffold (Abdelbasset et al., 2022). (B) Schematic diagram depicting the construction of biodegradable core-shell nanofibers for the continuous and localized delivery of BIBR-277 to the wall of a balloon-injured artery in the abdominal aorta of diabetic rabbits (Lee et al., 2022). (C) Microscopic sections of skin samples from wounds following an 18-day treatment period, stained with Hematoxylin and eosin (H&E) and Masson’s trichrome (MT). Black arrows indicate crusty scabs, white arrows indicate the epithelial layer, yellow arrow indicates hair follicle, and asterisks indicate Sebaceous gland (Derakhshan et al., 2022).

FIGURE 6

(A) Representative wound images from each group on days 0, 3, 7, 10, and 14 after wound creation. On day 3, mild visible wound closure was observed in the treated rats compared to the untreated rats. The treatment groups with drug-loaded scaffolds exhibited significantly faster wound closure on days 7 and 10 compared to the untreated groups and the treatment groups with pure scaffolds (Cam et al., 2021). (B) The effect of composite scaffolds containing NAG bioceramic particles on diabetic wound healing. Overview of the size change of excision wounds created in the dorsal skin of diabetic mice over different time periods and traces of wound bed closure for each treatment group in vivo. The light brown area indicates the wound area on day 0, and the blue area indicates the wound area on day n (n = 5, 7, 9, 11, and 13) (Fan et al., 2022).

FIGURE 7

(A) Histopathological images comparing normal control, toxic control, F1 (non-crosslinked), and F2 (crosslinked) (Anand et al., 2022). (B) Evaluation of wound healing in diabetic C57/BL6 mice treated with different electrospun nanofibrous scaffolds (panels from left to right represent the progression of wound healing over a 12-day period). Group 1: no treatment (negative control); group 2: 0.1% GS ointment (positive control); group 3: Eudragit RL/RS 100 scaffold without GS and rhEGF; group 4: Eudragit RL/RS 100 scaffold with GS and rhEGF; group 5: Eudragit RL/RS 100 scaffold with GS without rhEGF. (B) Percentage of open wound area (as a percentage of the initial area) over the 12-day treatment period for each group (Dwivedi et al., 2018). (C) Representative histology images of wound sites on day 10. DES: Drug-eluting scaffold; NES: Non-eluting scaffold; Control. The DES group exhibited the most favorable recovery from the cutaneous wound, characterized by a thick epithelial layer (Yin et al., 2016).