Hyaluronic acid: Evaluation as a potential delivery vehicle for vitronectin:growth factor complexes in wound healing applications

Abstract

We have previously reported that novel vitronectin:growth factor (VN:GF) complexes significantly increase re-epithelialization in a porcine deep dermal partial-thickness burn model. However, the potential exists to further enhance the healing response through combination with an appropriate delivery vehicle which facilitates sustained local release and reduced doses of VN:GF complexes. Hyaluronic acid (HA), an abundant constituent of the interstitium, is known to function as a reservoir for growth factors and other bioactive species. The physicochemical properties of HA confer it with an ability to sustain elevated pericellular concentrations of these species. This has been proposed to arise via HA prolonging interactions of the bioactive species with cell surface receptors and/or protecting them from degradation. In view of this, the potential of HA to facilitate the topical delivery of VN:GF complexes was evaluated. Two-dimensional (2D) monolayer cell cultures and 3D de-epidermised dermis (DED) human skin equivalent (HSE) models were used to test skin cell responses to HA and VN:GF complexes. Our 2D studies revealed that VN:GF complexes and HA stimulate the proliferation of human fibroblasts but not keratinocytes. Experiments in our 3D DED-HSE models showed that VN:GF complexes, both alone and in conjunction with HA, led to enhanced development of both the proliferative and differentiating layers in the DED-HSE models. However, there was no significant difference between the thicknesses of the epidermis treated with VN:GF complexes alone and VN:GF complexes together with HA. While the addition of HA did not enhance all the cellular responses to VN:GF complexes examined, it was not inhibitory, and may confer other advantages related to enhanced absorption and transport that could be beneficial in delivery of the VN:GF complexes to wounds.

Novel curcumin-loaded gel-core hyaluosomes with promising burn-wound healing potential: Development, in-vitro appraisal and in-vivo studies

“…VN: GF was reported to significantly increase re-epithelialization in a porcine deep dermal partial-thickness burn model (Upton et al, 2008). Despite the advantages of HA in wound healing, results obtained from this study (Xie et al, 2011) indicated that, there was no significant difference between the thicknesses of the epidermis treated with VN:GF complexes alone and VN:GF complexes together with HA. Therefore, promising use of HA in burn healing process still needs a step of skin penetration enhancement (El-Refaie et al, 2015).…”

“…This long time might also result in impaired healing. Recently, the potential of HA as a suitable delivery vehicle to facilitate sustained local release and reduced doses of VN:GF (vitronectin:growth factor) was investigated (Xie et al, 2011). VN: GF was reported to significantly increase re-epithelialization in a porcine deep dermal partial-thickness burn model (Upton et al, 2008).…”

Epidermal growth factor, from gene organization to bedside

“…Many studies have suggested that the local concentration of EGF needs to be sufficiently high and prolonged for effective wound healing [126,132,133]. Therefore, different drug delivery systems that are able to protect and stabilize the protein have been investigated, including hydrogels, sponges, polymeric pellets, nanofibers, microspheres, a biomimetic delivery system that incorporated EGF with biocompatible components such as hyaluronic acid, collagen, vitronectin or liposome, and more recently, a poloxamer gel formulation of recombinant low-molecular-weight protamine conjugated EGF (rLMWP-EGF) by conjugating a highly positively charged rLMWP to the N-terminal of EGF [134–140]. The latter has shown better healing effects on burn injuries [139].…”

Drug Delivery Systems for Wound Healing

“…In their first pre-clinical evaluation, vitronectin complexes of IGFs and EGF accelerated healing of partial-thickness burn wounds in pigs, although this approach did require multiple administrations per week [108]. To improve the clinical usefulness, HA was then added as a carrier system for vitronectin:GF complexes [109]. In a clinical pilot study, this therapy demonstrated convincing efficacy at re-epithelializing venous leg ulcers, and also showed promise for treating other types of chronic wounds [110].…”