Optimized Hesperidin-Loaded Lipid Nanoparticles with Tea Tree Oil for Enhanced Wound Healing: Formulation, Characterization, and Evaluation
Abstract
:1. Introduction
2. Results and Discussion
2.1. Optimization of Factorial Design
2.2. Investigation of HESP-SLNs
2.2.1. Impact of Formulation Variables on PS
2.2.2. Impact of Formulation Variables on PDI
2.2.3. Impact of Formulation Variables on ZP of HESP-SLNs
2.2.4. Impact of Formulation Variables on EE% of HESP-SLNs
2.3. Identifying the Optimized HESP-SLNs
2.4. Improvement of Optimized HESP-SLNs Properties Producing Essential Oil-Loaded HESP-NLCs
2.4.1. Screening and Selecting Essential Oils
Agar Diffusion Assay
2.4.2. Evaluation of the Minimum Inhibitory Concentration (MIC)
2.5. Investigation of HESP-NLCs
2.6. Transmission Electron Microscopy (TEM) of the Optimized HESP-SLNs and HESP-NLCs
2.7. Compatibility Evaluation Optimized HESP-SLNs and HESP-NLCs
2.7.1. Differential Scanning Calorimetry (DSC)
2.7.2. Raman Spectroscopy
2.8. In Vitro Release of Optimized HESP-SLNs and HESP-NLCs
2.9. Storage Stability Studies
2.10. Determination of In Vitro Antibacterial Properties
2.11. Cytotoxicity Assay
2.12. In Vivo Study
2.12.1. Assessment of the Percentage of Wound Closure
2.12.2. Histopathology Study
2.12.3. Assessment of Serum Inflammatory Biomarkers
2.12.4. Investigation of Skin Irritation
3. Materials and Methods
3.1. Materials
3.2. Experimental Design Construction of HESP-SLNs
3.3. Preparation of Hesperidin-Loaded Solid Lipid Nanoparticles
3.4. Investigation of HESP-SLNs
3.4.1. Evaluation of PS, ZP, and PDI of HESP-SLNs
3.4.2. Percentage of Encapsulation Efficiency (EE%)
3.5. Identifying the Optimized HESP-SLNs
3.6. Improvement of Optimized HESP-SLNs Properties Producing Essential Oil-Loaded HESP-NLCs
3.6.1. Screening and Selecting of Essential Oils
Diffusion Agar Method
Evaluation of the Minimum Inhibitory Concentration (MIC)
3.7. Preparation of Essential Oil-Loaded HESP-NLCs
3.8. Investigation of HESP-NLCs
3.8.1. Evaluation of PS, ZP, and PDI of HESP-NLCs
3.8.2. Percentage Encapsulation Efficiency (EE%)
3.9. Transmission Electron Microscopy (TEM) of Optimized HESP-SLNs and HESP-NLCs
3.10. Compatibility Evaluation Optimized HESP-SLNs and HESP-NLCs
3.10.1. Differential Scanning Calorimetry (DSC)
3.10.2. Raman Spectroscopy
3.11. In Vitro Release Study of Optimized HESP-SLNs and HESP-NLCs
3.12. Effect of Storage Conditions on the Optimized HESP-SLNs and HESP-NLCs
3.13. Determination of In Vitro Antibacterial Properties
3.14. Cytotoxicity Assay
3.15. In Vivo Study
3.15.1. Experimental Animals
3.15.2. Wound Excision Induction
3.15.3. Assessment of the Percentage of Wound Closure
3.15.4. Histopathology Study
3.15.5. Assessment of Serum Inflammatory Biomarkers
3.15.6. Investigation of Skin Irritation
3.16. Statistical Analysis
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | (X1) Lipid Type | (X2) Lipid Concentration | (X3) Surfactant Type | (X4) Sonication Amplitude (%) | (Y1) PS (nm) | (Y2) ZP (mV) | (Y3) PDI | (Y4) EE (%) |
---|---|---|---|---|---|---|---|---|
HESP-SLNs1 | Stearic acid | 2% | Span® 60 | 40% | 275 ± 2.26 | −31.7 ± 2.47 | 0.339 ± 0.132 | 53.6 ± 2.90 |
HESP-SLNs2 | Stearic acid | 2% | Span® 60 | 20% | 252 ± 3.12 | −36.2 ± 1.52 | 0.246 ± 0.155 | 55.2 ± 3.49 |
HESP-SLNs3 | Compritol® ATO 888 | 2% | Span® 60 | 40% | 300.8 ± 5.23 | −23.5 ± 4.25 | 0.366 ± 0.191 | 59.2 ± 2.14 |
HESP-SLNs4 | Compritol® ATO 888 | 2% | Span® 60 | 20% | 267.7 ± 1.89 | −35.4 ± 3.53 | 0.317 ± 0.129 | 65.8 ± 3.02 |
HESP-SLNs5 | Stearic acid | 2% | Pluronic® F127 | 40% | 363.9 ± 3.14 | −25.3 ± 2.59 | 0.476 ± 0.151 | 51.8 ± 0.86 |
HESP-SLNs6 | Stearic acid | 2% | Pluronic® F127 | 20% | 354.4 ± 2.33 | −22.9 ± 2.12 | 0.435 ± 0.129 | 52.4 ± 2.13 |
HESP-SLNs7 | Compritol® ATO 888 | 2% | Pluronic® F127 | 40% | 375.4 ± 2.82 | −23.3 ± 0.52 | 0.571 ± 0.161 | 58.6 ± 1.13 |
HESP-SLNs8 | Compritol® ATO 888 | 2% | Pluronic® F127 | 20% | 369.5 ± 1.42 | −32.3 ± 3.71 | 0.492 ± 0.146 | 62.4 ± 1.27 |
HESP-SLNs9 | Stearic acid | 5% | Span® 60 | 40% | 302.7 ± 1.75 | −33.3 ± 3.85 | 0.294 ± 0.132 | 72.4 ± 1.7 |
HESP-SLNs10 | Stearic acid | 5% | Span® 60 | 20% | 280 ± 1.35 | −39.4 ± 0.92 | 0.239 ± 0.012 | 88.2 ± 2.09 |
HESP-SLNs11 | Compritol® ATO 888 | 5% | Span® 60 | 40% | 354.1 ± 2.81 | −30.4 ± 2.45 | 0.391 ± 0.131 | 79.3 ± 2.87 |
HESP-SLNs12 | Compritol® ATO 888 | 5% | Span® 60 | 20% | 284 ± 2.07 | −36.9 ± 1.03 | 0.248 ± 0.091 | 85.1 ± 2.12 |
HESP-SLNs13 | Stearic acid | 5% | Pluronic® F127 | 40% | 383.5 ± 1.26 | −29.4 ± 3.79 | 0.334 ± 0.174 | 55.8 ± 1.36 |
HESP-SLNs14 | Stearic acid | 5% | Pluronic® F127 | 20% | 370 ± 2.58 | −37.1 ± 2.19 | 0.311 ± 0.231 | 60.4 ± 1.10 |
HESP-SLNs15 | Compritol® ATO 888 | 5% | Pluronic® F127 | 40% | 495 ± 1.70 | −24.4 ± 1.74 | 0.450 ± 0.197 | 64.2 ± 1.34 |
HESP-SLNs16 | Compritol® ATO 888 | 5% | Pluronic® F127 | 20% | 380.3 ± 2.96 | −34.8 ± 0.93 | 0.378 ± 0.143 | 66.3 ± 2.67 |
Response | Y1: PS (nm) | Y2: ZP (Absolutes) | Y3: PDI | Y4: EE (%) |
---|---|---|---|---|
p-value | p < 0.0001 | p < 0.0001 | p < 0.0001 | p < 0.0001 |
R2 | 0.9586 | 0.9091 | 0.9803 | 0.9911 |
Adj. R-squared | 0.9388 | 0.8659 | 0.9708 | 0.9869 |
Pre. R-squared | 0.9038 | 0.7890 | 0.9541 | 0.9794 |
Adequate precision | 23.539 | 16.5419 | 35.5317 | 49.5395 |
Significant factors of the optimized (HESP-SLNs 10) | X1, X2, X3, X4 | X1, X2, X3, X4 | X1, X2, X3, X4 | X1, X2, X3, X4 |
The predicted value of the optimized (HESP-SLNs 10) | 277.97 | 40.8 | 0.229 | 81.8 |
The observed value of the optimized (HESP-SLNs 10) | 280 | 39.4 | 0.239 | 88.2 |
Essential Oils/ Microbial Strains | Diameter of Inhibition Zone (mm) | ||
---|---|---|---|
Escherichia coli ATCC 25922 | Pseudomonas aeruginosa ATCC 27853 | Staphylococcus aureus ATCC 25923 | |
Lavender Oil | 15 ± 1.5 | 22 ± 2.5 | 30 ± 3 |
Eucalyptus Oil | 15 ± 1 | 11 ± 2 | 6 ± 1 |
Thyme Oil | 30 ± 3 | 27 ± 4 | 29 ± 3 |
Tea Tree Oil | 35 ± 2.5 | 37 ± 2 | 45 ± 2 |
Essential Oils/ Microbial Strains | Minimum Inhibitory Concentration (mg/mL) | ||
---|---|---|---|
Escherichia coli ATCC 25922 | Pseudomonas aeruginosa ATCC 27853 | Staphylococcus aureus ATCC 25923 | |
Lavender Oil | 6.1 ± 0.3 | 6.3 ± 0.2 | 2.1 ± 0.7 |
Eucalyptus Oil | 3.3 ± 0.4 | 2.7 ± 0.2 | 3.1 ± 0.5 |
Thyme Oil | 1.9 ± 0.4 | 2.2 ± 0.3 | 2.3 ± 0.2 |
Tea Tree Oil | 1.6 ± 0.1 | 1.2 ± 0.2 | 1.2 ± 0.3 |
Parameter | Freshly Prepared | HESP-SLNs After 3 Months of Storage at 4 °C | HESP-SLNs After 3 Months of Storage at 25 °C |
PS (nm) | 280 ± 1.35 | 295 ± 1.74 | 290 ± 2.13 |
ZP (mV) | −39.4 ± 0.92 | −37.23 ± 0.24 | −35.01 ± 1.32 |
PDI | 0.239 ± 0.012 | 0.247 ± 0.56 | 0.251 ± 0.14 |
EE (%) | 88.2 ± 2.09 | 85.2 ± 1.36 | 86.72 ± 1.58 |
Parameter | Freshly Prepared | HESP-NLCs After 3 Months of Storage at 4 °C | HESP-NLCs After 3 Months of Storage at 25 °C |
---|---|---|---|
PS (nm) | 300 ± 5.21 | 315.93 ± 1.84 | 309.5 ± 2.01 |
ZP (mV) | −39.4 ± 0.42 | −38.29 ± 0.62 | −37.21 ± 1.63 |
PDI | 0.272 ± 0.023 | 0.279 ± 0.03 | 0.302 ± 0.15 |
EE (%) | 93.7 ± 1.55 | 88.57± 2.36 | 91.37 ± 1.47 |
Factors (Independent Variable) | Low Levels | High Levels |
X1: Lipid type | Compritol® ATO 888 | Stearic acid |
X2: Lipid conc | 2% | 5% |
X3: Surfactant type | Pluronic® F127 | Span® 60 |
X4: Sonication amplitude | 20% | 40% |
Responses (Dependent Variables) | Desirability Constraints | |
Y1: PS (nm) | Minimize | |
Y2: ZP (absolute values) (mv) | Maximize | |
Y3: PDI | Minimize | |
Y4: EE (%) | Maximize |
Group Name | n | Treatment | Experiment |
---|---|---|---|
GP1 | 5 | HESP-SLNs | Wound-healing assay groups |
GP2 | 5 | HESP-NLCs | |
GP3 | 5 | NLCs without HESP | |
GP4 | 5 | HESP pure drug | |
GP5 | 5 | Positive Control (untreated group) | |
GP6 | 5 | Negative Control (Distilled water) | |
GP7 | 4 | Negative Control (Distilled water) | Investigation of skin irritation groups |
GP8 | 4 | HESP-NLCs |
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Arneth, B.; Abdelmonem, R.; El-Nabarawi, M.A.; Teaima, M.H.; Rashwan, K.O.; Soliman, M.A.; Al-Samadi, I.E.I. Optimized Hesperidin-Loaded Lipid Nanoparticles with Tea Tree Oil for Enhanced Wound Healing: Formulation, Characterization, and Evaluation. Pharmaceuticals 2025, 18, 290. https://doi.org/10.3390/ph18030290
Arneth B, Abdelmonem R, El-Nabarawi MA, Teaima MH, Rashwan KO, Soliman MA, Al-Samadi IEI. Optimized Hesperidin-Loaded Lipid Nanoparticles with Tea Tree Oil for Enhanced Wound Healing: Formulation, Characterization, and Evaluation. Pharmaceuticals. 2025; 18(3):290. https://doi.org/10.3390/ph18030290
Chicago/Turabian StyleArneth, Borros, Rehab Abdelmonem, Mohamed A. El-Nabarawi, Mahmoud Hassan Teaima, Kareem Omar Rashwan, Mohamed A. Soliman, and Inas Essam Ibrahim Al-Samadi. 2025. "Optimized Hesperidin-Loaded Lipid Nanoparticles with Tea Tree Oil for Enhanced Wound Healing: Formulation, Characterization, and Evaluation" Pharmaceuticals 18, no. 3: 290. https://doi.org/10.3390/ph18030290
APA StyleArneth, B., Abdelmonem, R., El-Nabarawi, M. A., Teaima, M. H., Rashwan, K. O., Soliman, M. A., & Al-Samadi, I. E. I. (2025). Optimized Hesperidin-Loaded Lipid Nanoparticles with Tea Tree Oil for Enhanced Wound Healing: Formulation, Characterization, and Evaluation. Pharmaceuticals, 18(3), 290. https://doi.org/10.3390/ph18030290