Beneficial Effects of a Blended Fibroin/Aloe Gel Extract Film on the Biomolecular Mechanism(s) via the MAPK/ERK Pathway Relating to Diabetic Wound Healing

Abstract

In diabetic patients, the process of wound healing is usually delayed or impaired. A diabetic environment could be associated with dermal fibroblast dysfunction, reduced angiogenesis, the release of excessive proinflammatory cytokines, and senescence features. Alternative therapeutic treatments using natural products are highly demanded for their high potential of bioactive activity in skin repair. Two natural extracts were combined to develop fibroin/aloe gel wound dressing. Our previous studies revealed that the prepared film enhances the healing rate of diabetic foot ulcers (DFUs). Moreover, we aimed to explore its biological effects and underlying biomolecular mechanisms on normal dermal, diabetic dermal, and diabetic wound fibroblasts. Cell culture experiments showed that the γirradiated blended fibroin/aloe gel extract film promotes skin wound healing by enhancing cell proliferation and migration, vascular epidermal growth factor (VEGF) secretion, and cell senescence prevention. Its action was mainly linked to the activation of the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway known to regulate various cellular activities, including proliferation. Therefore, the findings of this study confirm and support our previous data. The blended fibroin/aloe gel extract film displays a biological behavior with favorable properties for delayed wound healing and can be considered as a promising therapeutic approach in the treatment of diabetic nonhealing ulcers.

Biomaterials for immunomodulation in wound healing

“…During the initial stages of wound healing, pro-inflammatory cells, such as neutrophils and macrophages, recruited to the site of the injury can help in the clearance of debris, dead cells and pathogens, creating an optimal microenvironment for the healing process to commence. In this case, some biomaterials induce pro-inflammatory reactions by activating pathways, such as NF-κB [ 126 ], MAPK [ 127 ] and Janus kinase/signal transducer and activator of transcription (JAK/STAT) [ 128 ], leading to the release of pro-inflammatory cytokines, such as TNF-α [ 129 ], IL-6 [ 130 ], IL-1β [ 129 ], CXCL2, MMPs [ 131 ], CXCL8 [ 132 ] and monocyte chemoattractant protein-1 as well as the recruitment of immune cells crucial for early-stage processes like debris clearance and infection prevention. As Tamada et al .…”

“…Fibroblasts exhibit a remarkable sensitivity to the influence of TGF-β, a molecule predominantly secreted by wound-associated pro-repair macrophages, which facilitate collagen production and provide mechanical strength to the wound. In another example, the combined fibroin/aloe gel wound dressing, developed from natural extracts, promotes skin wound healing by enhancing VEGF secretion linked to the activation of the MAPK signaling pathway [ 127 ]. These findings suggest that biomaterials have the potential to enhance pro-inflammatory cytokines and cells, thereby accelerating wound healing and tissue reconstruction, making them promising candidates for functional wound dressings.…”

“…Excessive suppression may compromise the immune system’s ability to defend against invading microorganisms, resulting in persistent infections that hinder the healing process [ 138 ]. In addition, suppressing pro-inflammatory signals excessively may hinder the activation of macrophages, fibroblasts and angiogenesis, leading to the disturbance of matrix synthesis [ 129 ], inadequate blood supply [ 127 ] and affecting the structural integrity of the healed tissue [ 60 ]. In summary, achieving the optimal and dynamic balance in biomaterial design is an ongoing challenge, with researchers exploring strategies such as incorporating anti-inflammatory agents, manipulating surface properties, and fine-tuning release kinetics to guide the immune response effectively through the phases of wound healing.…”

Highly Absorbent Egg White/Carbomer‐940 Hydrofilm as a Potential Diabetic Wound Dressing

“…[21,22] Considering the mentioned cons and pros, engineering the composition and structure of the traditional film dressings in order to increase their swelling capacity can significantly improve their wound exudate absorption, where they can present some desirable features of hydrogel dressing. [21,23] Materials used in wound dressings include natural, modified, and synthetic polymers and their combinations. Recently, the use of natural materials and biopolymers in the design of diabetic wound dressings is increasingly growing.…”

“…[ 21,22 ] Considering the mentioned cons and pros, engineering the composition and structure of the traditional film dressings in order to increase their swelling capacity can significantly improve their wound exudate absorption, where they can present some desirable features of hydrogel dressing. [ 21,23 ]…”