Effects of epidermal growth factor-loaded mucoadhesive films on wounded oral tissue rafts

Abstract

Current treatments for traumatic oral mucosal wounds include the gold standard of autologous tissue and alternative tissue engineered grafts. While use of autografts has disadvantages of minimal availability of oral keratinized tissue, second surgery, and donor site discomfort, tissue engineered grafts are limited by their unavailability as off-the-shelf products owing to their fabrication time of 4–8 weeks. Hence, the current work aimed to develop a potentially cost-effective, readily available device capable of enhancing native mucosal regeneration. Considering the key role of epidermal growth factor (EGF) in promoting mucosal wound regeneration and the advantages of mucoadhesive delivery systems, mucoadhesive films composed of polyvinylpyrrolidone and carboxymethylcellulose were developed to provide sustained release of EGF for minimum of 6 hours. Bioactivity of released EGF supernatants was then confirmed by its ability to promote proliferation of BALB/3T3 fibroblasts. Efficacy of the developed system was then investigated in vitro using buccal tissues (ORL 300-FT) as a potential replacement for small animal studies. Although the mucoadhesive films achieved their desired role of delivering bioactive EGF in a sustained manner, treatment with EGF, irrespective of its release from the films or solubilized in medium, caused a hyperparakeratotic response from in vitro tissues with distinguishable histological features including thickening of the spinous layer, intra- and intercellular edema, and pyknotic nuclei. These significant morphological changes were associated with no improvements in wound closure. These observations raise questions about the potential of using in vitro tissues as a wound healing model and substitute for small animal studies. The mucoadhesive delivery system developed, however, with its potential for sustained release of bioactive growth factors and small molecules, may be loaded with other desired compounds, with or without EGF, to accelerate the process of wound healing.

In vitro three-dimensional organotypic culture models of the oral mucosa

“…However, the EGF treatment caused a hyperparakeratotic response and induced other structural abnormalities including thickening of the spinous layer, intra-and intercellular edema, and pyknotic nuclei. In addition, no improvements in wound closure were observed (Ramineni et al 2015).…”

“…In addition, the EpiGingival model was used to study the effects of biofilms as they relate to the expression of junctional proteins within the tissue and possible implications of periodontal disease (Belibasakis et al 2015). Ramineni et al 2015 investigated whether mucoadhesive films impregnated with epithelial growth factor (EGF) could be used to treat traumatic oral mucosal wounds. The mucoadhesive films delivered bioactive EGF in a sustained manner to punch biopsy wounds inflicted to the full thickness EpiOral tissue.…”

Local epidermal growth factor delivery using nanopillared chitosan–gelatin films for melanogenesis and wound healing

“…27,30,31 In particular, the report by Ramineni and coworkers successfully demonstrated that a concentration regime between 1-5 ng mL −1 EGF provided maximal cell migration, cellular differentiation and wound healing. 32 Similar EGF levels were attained after 72 hours in our case; hence, this time point was chosen for the following in vitro investigations.…”

Healing kinetics of oral soft tissue wounds treated with recombinant epidermal growth factor: Translation from a canine model

“…The available data suggest the promise of EGF purposed at improving oral wound healing. To recapitulate, stimulation of proliferation and migration of oral keratinocytes, stimulation of gingival fibroblasts mitogenesis and increase of collagen synthesis (Kim et al., ; Pansani et al., ; Ramineni, Fowler, Fisher, Cunningham, & Puleo, ) are among the cellular events through which exogenous EGF is harnessed to facilitate the wound repair in vitro. Nevertheless, whether EGF‐based treatment is able to facilitate the repair of acute injuries healing by secondary intention remains unknown.…”