This study was designed to investigate the potential of a wound dressing composed of hyaluronic acid (HA) and collagen (Col) spongy sheet containing epidermal growth factor (EGF) and vitamin C derivative (VC). High-molecular-weight HA aqueous solution, hydrolyzed low-molecular-weight HA aqueous solution and heat-denatured Col aqueous solution were mixed, followed by freeze-drying to obtain a spongy sheet. Cross-linkage between Col molecules was induced by UV irradiation of the spongy sheet (C-wound dressing). In a similar manner, three types of spongy sheet containing EGF (EGF-wound dressing), containing VC (VC-wound dressing) or containing EGF and VC (EGF·VC-wound dressing) were prepared by freeze-drying the mixed solution containing the specified components. Cytokine production by fibroblasts was assessed in a wound surface model using a fibroblast-incorporating Col gel sheet (cultured dermal substitute; CDS). CDS was elevated to the air-medium interface, onto which each wound dressing was placed and cultured for 7 days. Fibroblasts in CDS covered with EGF-wound dressing released 3.6 times more VEGF and 3.0 times more HGF, as compared with the C-wound dressing. Fibroblasts in CDS covered with EGF·VC-wound dressing released 4.2 times more VEGF and 6.0 times more HGF, as compared with the C-wound dressing. The efficacy of these wound dressings was evaluated in animal tests using diabetic mice. Each wound dressing was applied to a full-thickness skin defect on the dorsal area measuring 1.5 × 2.0 cm. After 1 week of application, wound conditions were evaluated histologically. The EGF·VC-wound dressing more effectively promoted granulation tissue formation associated with angiogenesis, as compared with other wound dressings.
We developed a novel wound dressing composed of a hyaluronic acid (HA) and collagen (Col) spongy sheet containing epidermal growth factor (EGF) or basic fibrolast growth factor (bFGF) by freeze-drying method (EGF-wound dressing or bFGF-wound dressing, respectively). A wound dressing without any growth factor was prepared as a control in a similar manner as above (C-wound dressing). Intermolecular cross-linkage between Col molecules was induced by UV irradiation. The release behavior of free HA from the wound dressing was investigated using a C-wound dressing. The weight of C-wound dressing after 1 day, 3, 5, and 7 days of incubation on top of a Col gel sheet at the air-water interface (wound surface model) was 55, 36, 30, and 19% of the original weight, respectively. Most free HA and a part of Col was released from the cross-linked Col network in the wound dressing during incubation, as the original Col content in the wound dressing was 33%. Next, fibroblast proliferation was assessed in conventional culture medium preconditioned by immersion of a piece of C-, EGF-, or bFGF-wound dressing, i.e. C-conditioned medium, EGF-conditioned medium, or bFGF-conditioned medium. Cell proliferation in C-conditioned medium increased to approximately the same level as that in conventional medium. Cell proliferation in EGF- and bFGF-conditioned medium was 1.9 times and 2.6 times greater than that in conventional medium after 7 days of cultivation, respectively. Finally, cytokine production of fibroblasts was assessed in a wound surface model using a fibroblast-incorporating Col gel sheet (cultured dermal substitute [CDS]). CDS was elevated to the air-medium interface, on which each wound dressing was placed and cultured for 7 days. Fibroblasts in CDS covered with EGF-wound dressing released 3.6 times more vascular endothelial growth factor (VEGF) and 4.6 times more hepatocyte growth factor (HGF) when compared with the C-wound dressing. Fibroblasts in CDS covered with bFGF-wound dressing released 10.2 times more VEGF and 6.3 times more HGF when compared with the C-wound dressing. This finding indicates that bFGF-wound dressing can facilitate more effectively the VEGF and FGF production compared with EGF-wound dressing.
This study investigated the effect of a wound dressing composed of hyaluronic acid (HA) and collagen (Col) sponge containing epidermal growth factor (EGF) on wound healing in diabetic mice. High-molecular-weight (HMW) HA aqueous solution, hydrolyzed low-molecular-weight (LMW) HA aqueous solution and heat-denatured Col aqueous solution were mixed, followed by freeze-drying to obtain a spongy sheet. Cross-linkage between Col molecules was induced by UV irradiation to the spongy sheet (Type-I wound dressing). In a similar manner, a spongy sheet containing EGF (Type-II wound dressing) was prepared by freeze-drying the mixed solution of HMW-HA, LMW-HA and Col containing EGF. The efficacy of these products was evaluated in type-II diabetic BKS.Cg-+Lepr(db)/+Lepr(db) (db/db) mice. Wound dressings were applied to a full-thickness, dorsal skin defect measuring 1.5 cm × 2.0 cm, showing adipose tissue. In the control group, a commercially available artificial dermis composed of collagen spongy sheet (TERUDERMIS(®)) was used. A commercially available polyurethane film dressing (Bioclusive(®)) was applied over each wound dressing. After 1 week of application, wound conditions were evaluated based on their gross and histological appearances. Type-I and -II wound dressings promoted a decrease in wound size associated with angiogenesis and granulation tissue formation, compared with the artificial dermis. In particular, Type-II wound dressings promoted sufficient re-epithelialization. These findings indicate that the combination of HA, Col and EGF promotes wound healing by stimulating cell activity including cell migration and proliferation on the adipose tissue in a diabetic wound. Type-I and -II wound dressings would be useful to prepare a well-vascularized wound bed acceptable for split-thickness auto-skin grafting.
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