A Narrative Review of Natural Bioactive Agents for Wound Healing: Mechanistic Insights on Anti-Inflammatory, Angiogenic, Antimicrobial, and Tissue Regeneration Pathways
DOI:
https://doi.org/10.51574/hayyan.v2i3.4211Keywords:
natural bioactives, wound healing, angiogenesis, antibiofilm, anti-inflammatory, extracellular matrix remodelingAbstract
Wound healing is a complex biological process involving the coordinated progression of hemostasis, inflammation, proliferation, and extracellular matrix (ECM) remodeling. Chronic and infected wounds often fail to progress through these stages due to persistent inflammation, oxidative stress, and microbial biofilm formation. In recent years, natural bioactive compounds have gained attention as potential therapeutic agents due to their multi-target biological functions and biocompatibility. This review synthesizes evidence from original in vitro, in vivo, and clinical studies to evaluate the mechanisms of natural compounds, including curcumin, Centella asiatica derivatives, honey-based molecules, flavonoids, and chitosan biomaterials in modulating the wound-healing process. The findings demonstrate that natural compounds can enhance platelet-mediated hemostasis, suppress inflammatory cytokines through NF-κB inhibition and Nrf2 activation, stimulate angiogenesis via VEGF and TGF-β signaling, promote fibroblast proliferation and collagen synthesis, and exert antimicrobial and antibiofilm effects against drug-resistant pathogens. Formulation strategies such as hydrogels and nanoparticle delivery systems were also shown to improve compound stability, tissue penetration, and therapeutic outcomes. These results indicate that natural bioactive wound-healing agents provide a promising avenue for managing both acute and chronic wounds, particularly in contexts where antibiotic resistance or delayed healing presents clinical challenges.
References
Alshaybawee, M. R., Asgari, S., Ghadersoltani, P., Mehrabian, A., & Saniee, P. (2025). Exploring the antibacterial and anti-biofilm activity of two Iranian medical-grade kinds of honey on multidrug-resistant Pseudomonas aeruginosa. BMC Complementary Medicine and Therapies, 25(1). https://doi.org/10.1186/s12906-025-04778-1
Arribas-López, E., Zand, N., Ojo, O., Snowden, M. J., & Kochhar, T. (2022). A Systematic Review of the Effect of Centella asiatica on Wound Healing. In International Journal of Environmental Research and Public Health (Vol. 19, Issue 6). MDPI. https://doi.org/10.3390/ijerph19063266
Assauqi, N. F., Lusiana, R. A., & Masruchin, N. (2025). Optimization of Chitosan-PEG/ZnO Hydrogel Formulation with Pomegranate Peel Extract as an Alternative for Wound Healing. Indonesian Journal of Chemistry, 25(3), 905–918. https://doi.org/10.22146/ijc.105215
Balázs, V. L., Nagy-Radványi, L., Filep, R., Kerekes, E., Kocsis, B., Kocsis, M., & Farkas, Á. (2021). In vitro antibacterial and antibiofilm activity of hungarian honeys against respiratory tract bacteria. Foods, 10(7). https://doi.org/10.3390/foods10071632
Chinko, B. C., & Precious-Abraham, A. D. (2024). Wound healing activity of hydromethanolic Dioscorea bulbifera extract on male wistar rat excision wound models. Pharmacological Research - Modern Chinese Medicine, 11, 100425. https://doi.org/10.1016/J.PRMCM.2024.100425
Deng, X., Ratnayake, J., & Ali, A. (2025). Curcumin-Loaded Drug Delivery Systems for Acute and Chronic Wound Management: A Review. In Bioengineering (Vol. 12, Issue 8). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/bioengineering12080860
Diniz, L. R. L., Calado, L. L., Duarte, A. B. S., & de Sousa, D. P. (2023). Centella asiatica and Its Metabolite Asiatic Acid: Wound Healing Effects and Therapeutic Potential. In Metabolites (Vol. 13, Issue 2). MDPI. https://doi.org/10.3390/metabo13020276
El-Kased, R. F., Amer, R. I., Attia, D., & Elmazar, M. M. (2017). Honey-based hydrogel: In vitro and comparative in vivo evaluation for burn wound healing. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-08771-8
Eriksson, E., Liu, P. Y., Schultz, G. S., Martins-Green, M. M., Tanaka, R., Weir, D., Gould, L. J., Armstrong, D. G., Gibbons, G. W., Wolcott, R., Olutoye, O. O., Kirsner, R. S., & Gurtner, G. C. (2022). Chronic wounds: Treatment consensus. Wound Repair and Regeneration, 30(2), 156–171. https://doi.org/10.1111/wrr.12994
Falcone, M., De Angelis, B., Pea, F., Scalise, A., Stefani, S., Tasinato, R., Zanetti, O., & Dalla Paola, L. (2021). Challenges in the management of chronic wound infections. Journal of Global Antimicrobial Resistance, 26, 140–147. https://doi.org/10.1016/J.JGAR.2021.05.010
Fasiku, V. O., Omolo, C. A., Devnarain, N., Ibrahim, U. H., Rambharose, S., Faya, M., Mocktar, C., Singh, S. D., & Govender, T. (2021). Chitosan-Based Hydrogel for the Dual Delivery of Antimicrobial Agents against Bacterial Methicillin-Resistant Staphylococcus aureus Biofilm-Infected Wounds. ACS Omega, 6(34), 21994–22010. https://doi.org/10.1021/acsomega.1c02547
Firmanda, A., Mahardika, M., Fahma, F., Gozan, M., Pratama, A. W., Mardawati, E., Millar, A., Rahmadanis, Amelia, D., & Ya Habib, A. A. (2024). Honey-loaded 3D bioprinted scaffolds: A promising fabrication with wound healing properties. Biocatalysis and Agricultural Biotechnology, 59, 103247. https://doi.org/10.1016/J.BCAB.2024.103247
Gościniak, A., Attard, E., Malesza, I. J., Kamiński, A., & Cielecka-Piontek, J. (2025). Modern Honey-Based Delivery Systems for Wound Healing: A Review of Current Trends and Future Perspectives. In Applied Sciences (Switzerland) (Vol. 15, Issue 18). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/app15189997
Guedes, G. M. de M., Freitas, A. S., Pinheiro, R. M., Pereira, V. C., Melgarejo, C. M. A., de Araujo, E. S., Ribeiro, K. V. C., Bandeira, S. P., Cordeiro, R. de A., Rocha, M. F. G., Sidrim, J. J. C., & Castelo-Branco, D. de S. C. M. (2023). Antibiofilm activity of promethazine, deferiprone, and Manuka honey in an ex vivo wound model. Letters in Applied Microbiology, 76(10). https://doi.org/10.1093/lambio/ovad119
Larson, D., Neelon, J., Karna, S. L. R., & Nuutila, K. (2025). Local Treatment of Wound Infections: A Review of Clinical Trials from 2013 to 2024. Advances in Wound Care, 14(1), 14–32. https://doi.org/10.1089/wound.2024.0129
Li, Y., Tang, X., Liu, Y., Chen, X., Wang, L., Su, Y., He, W., Li, J., Huang, Q., & Wu, P. (2025). Advanced wound healing with chitosan hydrogels incorporating metabolites from whale-derived Lactiplantibacillus plantarum HJ-S2. Frontiers in Materials, 12. https://doi.org/10.3389/fmats.2025.1573222
Liu, M., Wang, J., Song, Z., & Pei, Y. (2025). Regulation mechanism of curcumin mediated inflammatory pathway and its clinical application: a review. In Frontiers in Pharmacology (Vol. 16). Frontiers Media SA. https://doi.org/10.3389/fphar.2025.1642248
Lu, J., Cokcetin, N. N., Burke, C. M., Turnbull, L., Liu, M., Carter, D. A., Whitchurch, C. B., & Harry, E. J. (2019). Honey can inhibit and eliminate biofilms produced by Pseudomonas aeruginosa. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-54576-2
Millah Shofiah, Husnul Khotimah, & Dhelya Widasmara. (2024). Evaluating the efficacy of topical Centella asiatica in accelerating burn healing in animal models: A systematic review. GSC Biological and Pharmaceutical Sciences, 29(2), 189–201. https://doi.org/10.30574/gscbps.2024.29.2.0415
Mpenda, F. N., Madaha, G., & Jacob, F. (2024). Wound healing and coagulant activity of crude extract metabolites from fungal endophytes . International Journal of Secondary Metabolite, 11(4), 675–686. https://doi.org/10.21448/ijsm.1434379
Nikolić, A., Milošević, I., Janković, A., Prokić, B. B., Nićković, E., Marković, D., Stevanović, M., Vukašinović-Sekulić, M., Mišković-Stanković, V., & Lužajić Božinovski, T. (2025). Poly(vinyl alcohol)/Gentamicin and Poly(vinyl alcohol)/Chitosan/Gentamicin: Promising Materials for Rapid Burn Wound Healing. Gels, 11(5). https://doi.org/10.3390/gels11050352
Oluwole, D. O., Coleman, L., Buchanan, W., Chen, T., La Ragione, R. M., & Liu, L. X. (2022). Antibiotics-Free Compounds for Chronic Wound Healing. In Pharmaceutics (Vol. 14, Issue 5). MDPI. https://doi.org/10.3390/pharmaceutics14051021
Peng, Y., Song, C., Yang, C., Guo, Q., & Yao, M. (2017). Low molecular weight chitosan-coated silver nanoparticles are effective for the treatment of MRSA-infected wounds. International Journal of Nanomedicine, 12, 295–304. https://doi.org/10.2147/IJN.S122357
Pratiwi, D. M. N., Yuliani, S. H., & Samirana, P. O. (2025). Studies on anti-inflammatory activity and wound-healing property of secondary metabolite of Anredera cordifolia (Ten.) Steenis leaves: A review. Journal of Applied Pharmaceutical Science, 15(2), 45–56. https://doi.org/10.7324/JAPS.2025.206872
Samavati, S. S., Kashanian, S., Derakhshankhah, H., Rabiei, M., Sajadimajd, S., Fakhri, S., & Rashidi, Z. (2025). Accelerated wound healing through tannin-rich Jaft extract, concentration-dependent efficacy and mechanistic insights from Quercus brantii ointment formulations. Scientific Reports, 15(1). https://doi.org/10.1038/s41598-025-13832-4
Sen, C. K. (2023). Human Wound and Its Burden: Updated 2022 Compendium of Estimates. In Advances in Wound Care (Vol. 12, Issue 12, pp. 657–670). Mary Ann Liebert Inc. https://doi.org/10.1089/wound.2023.0150
Sharfina, M., Kuswanti, N., & Khaleyla, F. (2025). Effect of African Leaf Extract (Vernonia amygdalina) on Blood Sugar Levels and Wound Healing in Mice with Type 2 Diabetes Mellitus. LenteraBio : Berkala Ilmiah Biologi, 14(2), 204–211. https://doi.org/10.26740/lenterabio.v14n2.p204-211
Shen, A. Z., Taha, M., Ghannoum, M., & Tyring, S. K. (2025). Biofilms and Chronic Wounds: Pathogenesis and Treatment Options. In Journal of Clinical Medicine (Vol. 14, Issue 21). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/jcm14217784
Singhmura, S., Paul, A., Raj, R., Banik, S., & Mandal, A. (2025). Exploring the Hemostatic and Hematological Impact of Butea monosperma Bark Ethanolic Extract in a Rodent Model. https://doi.org/10.21203/rs.3.rs-7934816/v1
Swastini, D. A., Martien, R., Fachiroh, J., & Nugroho, A. E. (2025). Ethnopharmacology and bioactive evidence of medicinal plants for wound healing in Indonesia: A scoping review. Journal of Applied Pharmaceutical Science, 15(6), 10–30. https://doi.org/10.7324/JAPS.2025.211952
Utoyo, F. S., Widowati, W., & Ratnawati, H. (2025). The Potency of Centella asiatica Leaf Extract on VEGF Expression and Angiogenesis in Second-Degree Burn Wound in Mice. HAYATI Journal of Biosciences, 32(1), 140–146. https://doi.org/10.4308/hjb.32.1.140-146
Witkowska, K., Paczkowska-Walendowska, M., Garbiec, E., & Cielecka-Piontek, J. (2024). Topical Application of Centella asiatica in Wound Healing: Recent Insights into Mechanisms and Clinical Efficacy. In Pharmaceutics (Vol. 16, Issue 10). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/pharmaceutics16101252
Wu, J., Deng, L., Yin, L., Mao, Z., & Gao, X. (2023). Curcumin promotes skin wound healing by activating Nrf2 signaling pathways and inducing apoptosis in mice. Turkish Journal of Medical Sciences, 53(5), 1127–1135. https://doi.org/10.55730/1300-0144.5678
Wulandari, D. P., Subronto, Y. W., & Surono, A. (2025). Honey as a Wound Care Modality in Treating Deep Neck Space Abscesses: Protocol for a Randomized Controlled Trial. JMIR Research Protocols, 14, e75475. https://doi.org/10.2196/75475
Xiao, F., Li, Q., Zeng, W., Tang, B., Chen, Q., Wu, C., Duan, Z., Chen, H., Rui, S., & Liu, B. (2025). Centella asiatica enhances diabetic wound healing by decreasing macrophage-driven inflammation via the AKT/MAPK/NF-κB pathway. Frontiers in Pharmacology, 16. https://doi.org/10.3389/fphar.2025.1632573
Yang, Y., Ma, Y., Wang, H., Li, C., Li, C., Zhang, R., Zhong, S., He, W., & Cui, X. (2024). Chitosan-based hydrogel dressings with antibacterial and antioxidant for wound healing. International Journal of Biological Macromolecules, 280, 135939. https://doi.org/10.1016/J.IJBIOMAC.2024.135939
Zainuddin, A. N. Z., Mustakim, N. N., Rosemanzailani, F. A., Fadilah, N. I. M., Maarof, M., & Fauzi, M. B. (2025). A Comprehensive Review of Honey-Containing Hydrogel for Wound Healing Applications. In Gels (Vol. 11, Issue 3). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/gels11030194
