The Application of hydroxytyrosol in Wound Dressings

Hydroxytyrosol (HT), as an active polyphenol in olive leaf extract, exhibits dual effects of accelerating wound healing and antibacterial activity in wound dressings due to its unique molecular structure (3,4-dihydroxyphenethyl alcohol). Its mechanism of action can be deeply analyzed from three dimensions: cell biology, molecular signaling pathways, and antibacterial activity:

I. Repair Mechanism Promoting Cell Proliferation and Migration

Activation of Fibroblasts and Keratinocytes

Hydroxytyrosol significantly increases the synthesis of type I collagen in fibroblasts by activating the mitogen-activated protein kinase (MAPK) pathway (e.g., ERK1/2 phosphorylation). In vitro experiments show that the synthesis increases by 40% at a concentration of 10 μM. The catechol group in its molecular structure binds to the TGF-β receptor, enhancing Smad2/3 signal transduction and promoting the differentiation of fibroblasts into myofibroblasts, accelerating wound contraction (animal experiments show that HT-containing dressings increase wound contraction rate by 35%).

Meanwhile, HT promotes cell adhesion to the extracellular matrix (ECM) by upregulating the expression of integrin α5β1 in keratinocytes, accelerating cell migration during wound reepithelialization (in vitro scratch assays, the cell migration speed in the 10 μM HT treatment group is twice that of the control group).

Regulation of Angiogenesis

Hydroxytyrosol maintains the biological activity of vascular endothelial growth factor (VEGF) by inhibiting the release of vascular endothelial inhibitory factors (such as soluble VEGF receptor sFlt-1), promoting the formation of endothelial cell tubular structures (the number of lumens formed increases by 60% in vitro). Its antioxidant properties also scavenge excessive ROS (such as superoxide anions) at the wound site, preventing oxidative stress damage to vascular endothelial cells, thereby accelerating the construction of microvascular networks during granulation tissue formation to provide sufficient oxygen and nutrients for the wound (in a rabbit full-thickness wound model, the vascular density in the HT dressing group is twice that of the control group).

II. Optimization of Healing Microenvironment via Anti-Inflammatory and Oxidative Stress Regulation

Precise Inhibition of Inflammatory Signaling Pathways

HT reduces the transcription of pro-inflammatory factors (TNF-α, IL-1β) by inhibiting the nuclear translocation of nuclear factor κB (NF-κB), polarizing macrophages from the M1 (pro-inflammatory) to M2 (anti-inflammatory repair) phenotype during the wound inflammatory phase. Experiments show that treatment with 10 μM HT reduces IL-6 secretion in macrophages by 70% and upregulates the expression of the anti-inflammatory factor IL-10 by 3 times, thus shortening the duration of the inflammatory phase (in a rat wound model, the inflammatory phase is shortened from 72 hours to 48 hours).

Dual Regulation Mechanism of Oxidative Stress

As a strong antioxidant, the catechol structure of HT directly scavenges hydroxyl radicals (・OH) and peroxynitrite anions (ONOO-), with an oxygen radical absorption capacity (ORAC value) of 3000 μmol/g, more than 10 times that of vitamin C. Meanwhile, HT induces the expression of intracellular antioxidant enzymes (such as superoxide dismutase SOD and glutathione peroxidase GPx), enhancing cellular antioxidant capacity by activating the Nrf2/ARE pathway (in vitro experiments show that HT treatment increases Nrf2 nuclear translocation by 2.5 times), reducing oxidative stress damage to wound tissues and providing a suitable microenvironment for cell proliferation.

III. Multi-Target Action Mode of Antibacterial Activity

Disruption and Inhibition of Bacterial Biofilms

Hydroxytyrosol inhibits biofilm formation by interfering with the bacterial quorum sensing (QS) system. In Pseudomonas aeruginosa, HT competitively binds to the LasR receptor protein with the 3-oxo-C12-HSL signaling molecule, downregulating the expression of biofilm-related genes (lasB, rhlA) by more than 50%. In vitro experiments show that 0.5 mg/mL HT reduces the metabolic activity of mature biofilms by 60%. Its lipophilic side chain can also insert into the phospholipid bilayer of the bacterial cell membrane, destroying membrane integrity and causing intracellular substance leakage (after HT treatment, the membrane permeability of E. coli increases by 3 times).

Synergistic Mechanism of Broad-Spectrum Antibacterial Activity

For Gram-positive bacteria (such as Staphylococcus aureus), HT interferes with cell wall cross-linking by inhibiting the activity of peptidoglycan synthase (PBP2a), showing a synergistic effect with β-lactam antibiotics (combined use reduces MIC by 8 times); for Gram-negative bacteria (such as E. coli), it enhances membrane permeability by inhibiting the expression of outer membrane protein OmpF, making antibiotics more likely to enter the bacteria. In addition, the antibacterial activity of HT against drug-resistant bacteria (such as MRSA) is not affected by β-lactamase, and the mechanism may be related to inhibiting the expression of the drug-resistant gene mecA (RT-PCR shows that HT treatment reduces mecA mRNA levels by 70%).

IV. Application Forms and Synergy Strategies in Wound Dressings

Synergy Design of Nano-Drug Delivery Systems

Encapsulating HT in PLGA nanoparticles (particle size 100-200 nm) prolongs the action time through sustained release characteristics (in vitro release experiments show that the cumulative release rate reaches 85% within 72 hours), and the hydroxyl groups on the surface of the nanoparticles form hydrogen bonds with the amino groups of the dressing matrix (such as chitosan), enhancing the adhesion of the dressing to the wound.

Synergistic Effect of Composite Dressings

When HT is combined with hyaluronic acid (HA), the water retention of HA maintains the local concentration of HT (reducing diffusion loss), and the sugar chain structure of HA can adsorb inflammatory factors, forming a synergy with the anti-inflammatory effect of HT (in a pig wound model, the healing speed of the HT/HA dressing group is 15% faster than that of the single HT dressing).

Core Value of the Mechanism of Action

Hydroxytyrosol plays a full-course regulatory role in the inflammatory phase, proliferation phase, and remodeling phase of wound healing through a multi-target synergistic mechanism of "antioxidant - anti-inflammatory - repair-promoting - antibacterial". Its unique polyphenol structure ensures precise regulation of cell signaling pathways and combats bacteria through both physical destruction and metabolic inhibition. Especially in chronic refractory wounds (such as diabetic foot ulcers), it can effectively reverse the healing barriers caused by oxidative stress and persistent inflammation, providing new molecular targets for the development of functional dressings.