Enhancing wound repair with marine natural products and nanoparticles
Creators: name: Aloe, Christian
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 310102
subject: Cell development, proliferation and death
classificationCode: 340502
subject: Natural products and bioactive compounds
classificationCode: 401807
subject: Nanomaterials

description: Wound repair is a highly ordered biological process that is essential for the maintenance of the skin’s barrier function. For optimal healing, the inflammatory, proliferative and remodelling phases of repair must occur in the correct sequence with appropriate stimuli to prevent insufficient or excessive activity at critical stages. The inflammatory and proliferative phases of repair can influence both the rate of wound resolution and the skin physiology of newly resolved tissue and subsequent remodelling. Optimisation of these processes has the potential to both enhance closure rate and minimise microorganism colonisation, reduce scarring and enhance wound tensile strength. There are many local and systemic factors that can severely impede healing and promote wound progression from an acute to a chronic state. This is particularly evident in the elderly whom are prone to various comorbidities that can influence the immune, circulatory and respiratory systems and often rely on medical intervention to assist healing.<br><br>In recent decades the anti-inflammatory and antioxidant properties of marine natural products (MNPs) have attained global attention due to their potential implications for human health. Omega-3 fatty acid enriched oils (carbon dioxide and dimethyl ether extracted oils; CO2 and DME oil) extracted from the New Zealand green lipped mussel, Perna canaliculus, have demonstrated potent anti-inflammatory properties. 5β-scymnol, a shark bile sterol, is another MNP with beneficial health implications due to its potent antioxidant abilities. However, the wound healing potential of these MNPs remains broadly unknown. In this study, the effects of these three MNPs on the inflammatory and proliferative phase of repair were explored in vitro. Results indicated that the two marine oils demonstrated inhibition of the pro-inflammatory metabolites of the 5-lipoxygenase and cyclooxygenase pathways in a dose-dependent manner, but did not stimulate keratinocyte or fibroblast growth. Similarly, 5β-scymnol displayed no effect on the growth of keratinocytes and fibroblasts, but was also shown to inhibit cyclooxygenase metabolite production. <br><br>Of equal interest is the recent application of natural and synthetic biomaterials in tissue engineering and wound healing. Wound healing products containing nano-silver – primarily used for its antimicrobial properties – are currently utilised for wound management. However, other metal oxide nanoparticles (NPs), including zinc oxide (ZnO), have not been sufficiently tested for their ability to aid healing. In the second arm of this study, the effects of the ZnO NPs were similarly assessed in vitro. The ZnO NPs significantly enhanced scratch closure in human keratinocyte monolayer cultures in a dose- and particle size-dependent manner, while larger ZnO particulates were less effective. Furthermore, examination of surfactant-dispersed ZnO NPs revealed that the agglomeration state of the material was an important characteristic. Additionally, titanium dioxide (TiO2) NPs similarly enhanced keratinocyte re-epithelialisation, while fibroblasts were unaffected by nanomaterial exposure. These results suggest that the observed scratch closure enhancement effects were dependent on agglomerate size and cell type, and may not be nanomaterial specific. Furthermore, ZnO exhibited 5-lipoxygenase and cyclooxygenase modulating activity.<br><br>The effects of ZnO NPs were further examined in an in vivo model of wound repair as these were the most potent in the in vitro test systems. Nanoparticulate ZnO was directly compared to its surfactant-dispersed equivalent, bulk ZnO particulate and the TiO2 NP, after application to skin biopsy punch wounds on the shaved backs of C57BL/6 female mice. Enhanced wound healing was evident in undispersed ZnO NP-treated wounds only. Histology of skin wounds at day 7 revealed a markedly reduced epidermal thickness and decreased cytokeratin-14 and Ki-67 expression in ZnO NP-treated wounds compared to saline-only controls. A reduced proportion of type-III to type-I collagen was also evident in the dermis of ZnO NP-treated wounds. However, no differences were seen in the amount of immune cell infiltrate or angiogenesis. ZnO NP-treated wounds showed more-ordered healing and were further along the healing process at day 7 compared to untreated controls. However, by day 14 no differences were detectable between ZnO NP treatment and controls in fully-healed skin. These results suggest that ZnO NP-treated wounds heal at an accelerated rate, and in a more organised fashion.<br><br>Taken together, these findings show that MNPs and NPs show potential for modulating both the inflammatory response and the rate of epidermal cell re-epithelialisation in healing wounds, both of which are rate-limiting factors for efficient repair of human skin.