Fabrication of carboxymethylcellulose hydrogel containing β-cyclodextrin–eugenol inclusion complexes for promoting diabetic wound healing

Abstract

The difficult healing of wounds caused by diabetes remains a challenging clinical problem. The activation of nuclear factor kappa-B as a key factor contributes to prolonged inflammation and inhibition of angiogenesis. As a natural antioxidant, eugenol may downregulate the lectin-like oxidized low-density lipoprotein receptor-1 and inhibit the activation of nuclear factor kappa-B in endothelial cells. However, eugenol shows poor solubility, pungent odor, and volatility, thus impeding its clinical application as a potential therapeutic agent. This study developed a novel bioactive carboxymethylcellulose hydrogel loaded with inclusion complexes of eugenol with b-cyclodextrin (eugenol-b-cyclodextrin/ carboxymethylcellulose hydrogel) to regulate lectin-like oxidized low-density lipoprotein receptor-1-induced activation of nuclear factor kappa-B to enhance angiogenesis and inhibit inflammation for accelerating diabetic wound healing in vivo. It was found that eugenol-b-cyclodextrin/carboxymethylcellulose hydrogel exhibited remarkable antibacterial activity in vivo and in vitro. Furthermore, it accelerated diabetic wound healing by reducing the lectin-like oxidized low-density lipoprotein receptor-1/nuclear factor kappa-B-induced dysfunction in endothelial cells and promoting angiogenesis.

Fabrication of Cyclodextrin-Based Hydrogels for Wound Healing: Progress, Limitations, and Prospects

“…122 EG is a yellow oily natural liquid extracted from cloves, cinnamon, and nutmeg with good antibacterial, anti-inflammatory, and antioxidation activity. 123,124 However, the applications of EG are limited because of its poor water solubility and volatility. 125,126 Li et al incorporated the inclusion complex of EG-β-CD into the CMC hydrogel to synthesize the EG-β-CD/CMC hydrogel.…”

Antimicrobial and healing-promoting properties of animal and plant oils for the treatment of infected wounds

“…In pre-clinical wound healing studies, the effect of clove oil (eugenol) has also been attributed to accelerated healing of diabetic wounds via its effects on reduced lectinlike oxidised low-density lipoprotein receptor 1/ NF-κB induced dysfunction in endothelial cells and promotion of angiogenesis 32 . Additionally, incorporation of clove oil into a wound dressing has been shown to improve wound healing via increased fibroblast migration and deposition of collagen that resulted in significantly decreased scar formation in preclinical models of wound repair in mice 14 .…”

“…A recent pre-clinical in-vivo study has demonstrated that solubility and stability of eugenol (the main component of clove oil) can be significantly enhanced by the creation of a bioactive carboxy-methylcellulose (CMC) hydrogel loaded with inclusion complexes of eugenol with β-cyclodextrin (β-CD) for accelerating healing in full thickness wounds in a diabetic mouse model 32 . Encapsulating the hydrophobic eugenol with β-CD into its cavity to form inclusion complexes overcame the issues of solubility and stability, allowing slow and sustained release of eugenol (EG) from EG-β-CD/CMC hydrogel into the infected diabetic wounds 32 . Subsequently, this allowed eugenol to reduce the chronic wound inflammation and promote healing by inhibiting the secretion of inflammatory factors (TNF-α and IL-6) and promoting angiogenesis by decreasing MMP-9 and increasing VEGF respectively 32 .…”

“…Encapsulating the hydrophobic eugenol with β-CD into its cavity to form inclusion complexes overcame the issues of solubility and stability, allowing slow and sustained release of eugenol (EG) from EG-β-CD/CMC hydrogel into the infected diabetic wounds 32 . Subsequently, this allowed eugenol to reduce the chronic wound inflammation and promote healing by inhibiting the secretion of inflammatory factors (TNF-α and IL-6) and promoting angiogenesis by decreasing MMP-9 and increasing VEGF respectively 32 . This allowed eugenol to exert its antibacterial effect on S. aureus and E. coli while decreasing inflammation, promoting neovascularisation of the wounds, and consequently improving the rate of wound healing (Figure 2) 32 .…”

“…Subsequently, this allowed eugenol to reduce the chronic wound inflammation and promote healing by inhibiting the secretion of inflammatory factors (TNF-α and IL-6) and promoting angiogenesis by decreasing MMP-9 and increasing VEGF respectively 32 . This allowed eugenol to exert its antibacterial effect on S. aureus and E. coli while decreasing inflammation, promoting neovascularisation of the wounds, and consequently improving the rate of wound healing (Figure 2) 32 . Taken together, these studies clearly demonstrate the feasibility and rationale for using essential and animal oils as potential adjuvant therapies to counteract pathogens with multiple antibiotic resistance or to be used as enhancers of conventional therapy approaches.…”