Therapies and delivery systems for diabetic wound care: current insights and future directions

Abstract

The global rise in diabetes mellitus has been paralleled by an increase in associated complications, notably impaired Wound Healing. Non-healing diabetic wounds are driven by multifactorial pathogenesis involving hyperglycemia, immune dysfunction, impaired angiogenesis, bacterial infections, and increased oxidative stress. Traditionally, a variety of plant-derived extracts and phytochemicals such as quercetin, curcumin, and paeoniflorin have been employed in the treatment of diabetic wounds worldwide. These agents exert their therapeutic effects primarily through antioxidant, antibacterial, anti-inflammatory, and pro-angiogenic mechanisms and properties, typically with minimal side effects. Recent advancements have highlighted the potential of integrating phytoconstituents with metal nanoparticles to enhance Wound Healing efficacy. Nanoformulations improve targeted phytochemical delivery and offer synergistic benefits due to intrinsic antimicrobial and antioxidant properties, enhanced antioxidant activity, and high biocompatibility. Similarly, polymeric nanocarrier-based delivery systems have emerged as a promising strategy to address the limitations of conventional wound treatments, promoting faster and more efficient healing in diabetic patients. This review comprehensively discusses the pathophysiology and clinical challenges associated with diabetic Wound Healing, explores the therapeutic potential of key phytochemicals, and presents the current progress in nanoparticle-based delivery systems (metallic and polymeric) for diabetic wound management. Additionally, it provides an update on recent patents and clinical trials involving phytoconstituents and their formulations for the treatment of diabetic wounds.

Keywords: antioxidants; hyperglycemia; nanotechnology; phytopharmaceuticals; topical therapy.

FIGURE 1

A diabetic patient’s Wound Healing process (PDGF-Platelet-Derived Growth Factor, TGF β- Transforming Growth Factor β, TNF α- Tissue Necrosis Factor, EGF- Epidermal Growth Factor, IL- Interleukins, MMPs-matrix metalloproteases, VEGF- Vascular endothelial growth factor, CXCL4-chemokine (C-X-C motif) ligand 4).

FIGURE 2

Differential Mechanisms in normal Wound Healing vs. diabetic Wound Healing.

FIGURE 3

Major factors affecting wound healing in diabetic patients (made using biorender.com).

FIGURE 4

Different phytochemicals, their molecular targets, and pharmacological effects in the context of diabetic wound healing.

FIGURE 5

Plausible mechanism of action of pinitol as an insulin sensitizer (Sánchez-Hidalgo et al., 2021). C/EBPα, CCAAT/enhancer binding protein α; GLUT-4, glucose transporter 4; GPI, glycosyl phosphatidylinositol; GSK-3β, glycogen synthase kinase 3β; IR, insulin receptor; INS-2, insulin second messenger; PDH, pyruvate dehydrogenase; PDHP, pyruvate dehydrogenase phosphatase; PI3K, phosphoinositide 3 kinase; PDK-1, phosphoinositide-dependent kinase 1; PP2Cα, phosphoprotein phosphatase 2C α; PKB/Akt, protein kinase B/Akt; PPARγ, peroxisome proliferator-activated receptor γ; PLD, phospholipase D.