Severe burns cause extremely serious damage to human skin, disrupting the normal functions of major skin cells, making skin re-epithelialization difficult, and often leading to prolonged wound healing, which brings great pain to patients and affects their prognosis. Among the many research directions in burn wound repair, promoting the activity of key cells to drive the repair process has become a core focus. Keratinocyte Growth Factor-2 (KGF-2), as a cell growth factor that has attracted much attention in the field of wound repair, is gradually demonstrating its unique mechanism of action and huge application potential.
KGF-2 is an important member of the Fibroblast Growth Factor (FGF) family. Its unique protein structure determines its key role in cell signal transduction and tissue repair. KGF-2 is mainly secreted by fibroblasts and exerts its effects by binding to the specific receptor on the surface of target cells, Fibroblast Growth Factor Receptor 2Ⅲb (FGFR2Ⅲb), activating a series of complex intracellular signaling pathways such as the Ras/Raf/MEK/ERK and PI3K/Akt signaling cascades. The activation of these signaling pathways is like turning on the "switch" of cell functions, which can significantly promote the proliferation, migration, and differentiation of epithelial cells, and is crucial for skin re-epithelialization.
Under normal skin physiological conditions, KGF-2 maintains a low level of expression to maintain the steady-state balance of skin cells. However, once the skin suffers trauma such as burns, the body activates an emergency repair mechanism, and fibroblasts around the damaged area quickly respond by synthesizing and secreting a large amount of KGF-2. KGF-2 then specifically binds to the FGFR2Ⅲb receptor on the surface of epithelial cells, triggering the up-regulation of the expression of related genes in epithelial cells, prompting cells to accelerate entry into the cell cycle, achieve rapid proliferation, and provide sufficient cell sources for wound repair. At the same time, it can also enhance the migration ability of epithelial cells, guiding them to migrate towards the center of the wound, gradually covering the damaged area, and achieving re-epithelialization repair of the wound.
In the process of burn wound healing, re-epithelialization is a key link that directly affects the healing speed and quality of the wound. Studies have shown that exogenous administration of KGF-2 can significantly accelerate this process. When KGF-2 acts on burn wounds, it can stimulate the proliferation of epithelial cells such as keratinocytes and basal cells. In vitro cell experiments have shown that in the culture system supplemented with KGF-2, the proliferation rate of epithelial cells is significantly higher than that of the control group, and the expression of cell cycle-related proteins such as Cyclin D1 and PCNA is significantly up-regulated, indicating that the cell cycle process is accelerated and more cells enter the proliferation state.
In in vivo animal experiments, when KGF-2 is applied to the wounds of burn animal models, it can be observed that the number of epithelial cell layers at the wound site increases, the migration speed of epithelial cells towards the center of the wound accelerates, and the new epithelial tissue quickly covers the wound. For example, in a mouse model of deep second-degree burns, after local treatment with KGF-2, the re-epithelialization rate of the wound on the 7th day was significantly higher than that of the control group, and the wound healing time was significantly shortened. This fully demonstrates the excellent efficacy of KGF-2 in promoting re-epithelialization of burn wounds, which helps to quickly close the wound, reduce the risk of infection, and lay a good foundation for subsequent wound repair.
The normal structure and function of the extracellular matrix (ECM) are crucial for maintaining the integrity and normal physiological functions of the skin. After burns, the local ECM of the wound is severely damaged, and its composition and structure undergo significant changes. KGF-2 plays an important regulatory role in this process. On the one hand, KGF-2 can promote fibroblasts to synthesize and secrete ECM components such as collagen and fibronectin, increase the synthesis of ECM, and help repair the damaged ECM network. Studies have found that fibroblasts treated with KGF-2 have significantly increased mRNA expression levels and protein secretion of collagen type I, III, and fibronectin.
On the other hand, KGF-2 can also regulate the expression and activity of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). During burn wound healing, excessive expression of MMPs may lead to excessive degradation of ECM, affecting the quality of wound healing. KGF-2 can down-regulate the expression of MMP-1, MMP-3, etc., and at the same time up-regulate the expression of TIMP-1, maintaining the balance between MMPs and TIMPs, preventing excessive degradation of ECM, promoting the orderly remodeling of ECM, making the skin tissue structure after wound repair more close to normal skin, and reducing the risk of scar formation.
Burn wounds are often in a harsh microenvironment, with many factors that are not conducive to wound healing, such as excessive inflammatory response, ischemia and hypoxia, and oxidative stress. KGF-2 also plays a positive role in improving the wound microenvironment. Firstly, in terms of inflammation regulation, KGF-2 can inhibit the excessive infiltration and activation of inflammatory cells, reduce the release of inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thereby reducing the further damage of the inflammatory response to the wound tissue. Studies have shown that after local application of KGF-2 on burn wounds, the expression levels of inflammatory factors such as TNF-α and IL-6 in the wound tissue are significantly reduced, and the number of infiltrating inflammatory cells is decreased.
Secondly, KGF-2 can promote angiogenesis and improve the blood supply to the wound. By up-regulating the expression of vascular endothelial growth factor (VEGF) and its receptors, KGF-2 stimulates the proliferation and migration of vascular endothelial cells, guides the growth of new blood vessels towards the wound, provides sufficient oxygen and nutrients for wound repair, and improves the ischemic and hypoxic state of the wound. In addition, KGF-2 also has a certain ability to resist oxidative stress, which can enhance the activity of intracellular antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), reduce the level of reactive oxygen species (ROS), alleviate the damage of oxidative stress to cells and tissues, and create a relatively favorable microenvironment for wound repair.
At present, KGF-2 has achieved significant results in preclinical studies on burn wound repair, showing good application prospects. In animal experiments, local application of KGF-2 can effectively promote wound healing and improve healing quality in both superficial second-degree and deep second-degree burn models. However, there are still some challenges in moving from basic research to clinical application. Firstly, as a protein biological product, KGF-2 has poor stability, is easily degraded by proteases in vivo, and has a short biological half-life, which limits its effective action time in the local wound. How to improve the stability of KGF-2 and extend its action time in vivo has become an urgent problem to be solved.
Secondly, the complexity of burn wounds and individual differences make it difficult to accurately determine the optimal administration method, dosage, and treatment timing of KGF-2. Burn wounds of different degrees and locations may have different responses to KGF-2. In addition, large-scale preparation of high-purity and stable KGF-2 also has certain technical difficulties and cost issues, which to a certain extent hinders its wide clinical application.
In order to overcome the limitations of KGF-2 when used alone, researchers have begun to explore combined treatment strategies in recent years. Among them, the combined application with other growth factors has become a research hotspot. For example, acidic Fibroblast Growth Factor (aFGF) is a key mediator of fibroblast and endothelial cell growth and differentiation, and has a synergistic effect with KGF-2. A research team led by Professor Wu Jiang and Professor He Huacheng from the academician team of Li Xiaokun of Wenzhou Medical University has developed a new type of microneedle patch, in which aFGF is encapsulated in nanoparticles (NPaFGF), and then KGF-2 and NPaFGF are fixed together in the microneedle patch (KGF-2/NPaFGF@MN). This microneedle patch can smoothly penetrate the eschar of burn wounds to achieve transdermal sequential delivery of KGF-2 and aFGF.
The research results show that KGF-2/NPaFGF@MN can achieve faster wound healing when used on scald wounds, reduce necrotic tissue, promote wound re-epithelialization, increase collagen deposition, and enhance new blood vessel formation. Further studies have found that the expression levels of hypoxia-inducible factor-1α (HIF-1α) and heat shock protein 90 (Hsp90) in the wound area of the KGF-2/NPaFGF@MN group are significantly increased, and these two factors play important roles in promoting wound healing. This combined treatment strategy exerts their respective advantages in different stages of wound repair through different growth factors, synergistically promoting wound healing, and provides new ideas and methods for improving the efficacy of KGF-2 in burn wound repair.
Keratinocyte Growth Factor-2 (KGF-2) has shown great application potential in the field of burn wound repair due to its unique mechanism of action in promoting epithelial cell proliferation, regulating extracellular matrix remodeling, and improving the wound microenvironment. Although there are still some challenges in clinical application, with the deepening of research on the mechanism of action of KGF-2 and the continuous development and improvement of related technologies such as new drug delivery systems and combined treatment strategies, it is expected to overcome these obstacles and apply KGF-2 more effectively in clinical burn wound treatment, bringing better therapeutic effects to a large number of burn patients, improving the quality of wound healing, reducing complications such as scar formation, and improving the quality of life of patients. In the future, KGF-2 will surely play a more important role in the field of burn wound repair, becoming an important means in the field of burn treatment and promoting the further development of burn wound repair medicine.
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