{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:49:16Z","timestamp":1790200156720,"version":"4.1.0"},"reference-count":81,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epidermolysis bullosa (EB) is a group of genetic diseases characterized by skin fragility. Although therapeutic options aim to accelerate wound-healing, improvement is needed; therefore, birch bark and propolis were investigated due to their beneficial biological properties. A representative ethanolic extract was analyzed by reversed-phase high-performance liquid chromatography with diode array detection (RP-HPLC-DAD) for chemical profiling of the raw materials. A hydrophobic natural deep eutectic solvent (HNaDES) for birch bark extraction, as well as a hydrogel and a bigel enriched with propolis and birch bark extract, were prepared and characterized by Fourier transform infrared (FT-IR) spectroscopy. Cytotoxicity and wound-healing potential were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch assays in six human keratinocyte cell lines: two from healthy individuals, two from recessive dystrophic \u0395\u0392 patients (RDEB), and two from laminin-332-deficient junctional EB patients (JEB). RP-HPLC-DAD revealed the presence of phenolic compounds (e.g., chrysin, pinocembrin, pinobanksin) and pentacyclic triterpenes (e.g., betulin and betulinic acid), characteristic of propolis and birch bark, respectively. FT-IR confirmed HNaDES formation and indicated physical interactions within the gels. All systems exhibited no cytotoxicity at 1 \u03bcg\/mL and increased cell vitality. Moreover, in keratinocytes derived from JEB patients, hydrogel improved wound- healing significantly at 24 h, whereas bigel showed significant improvement at 8 h. The developed systems could be promising topical treatments.<\/jats:p>","DOI":"10.3390\/ijms27135746","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:49:23Z","timestamp":1782434963000},"page":"5746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Wound-Healing Effects of Birch Bark and Propolis Extracts on Epidermolysis Bullosa Keratinocytes"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0948-9315","authenticated-orcid":false,"given":"Thomas","family":"Kissas","sequence":"first","affiliation":[{"name":"Department of Food Science and Technology, Faculty of Agriculture, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2331-8981","authenticated-orcid":false,"given":"Dimitra","family":"Kiritsi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, Medical Center\u2014University of Freiburg, University of Freiburg, 79104 Freiburg, Germany"},{"name":"First Department of Dermatology, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5158-673X","authenticated-orcid":false,"given":"Ioannis","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, Medical Center\u2014University of Freiburg, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4666-2240","authenticated-orcid":false,"given":"Alexander","family":"Nystr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, Medical Center\u2014University of Freiburg, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5026-0431","authenticated-orcid":false,"given":"Alexandros","family":"Onoufriadis","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Biology and Genetics, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5688-7136","authenticated-orcid":false,"given":"Ioannis","family":"Mourtzinos","sequence":"additional","affiliation":[{"name":"Department of Food Science and Technology, Faculty of Agriculture, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1111\/exd.13668","article-title":"Inherited Epidermolysis Bullosa: New Diagnostics and New Clinical Phenotypes","volume":"28","author":"Has","year":"2019","journal-title":"Exp. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1111\/bjd.20958","article-title":"The Epidemiology of Epidermolysis Bullosa in England and Wales: Data from the National Epidermolysis Bullosa Database","volume":"186","author":"Petrof","year":"2022","journal-title":"Br. J. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus Reclassification of Inherited Epidermolysis Bullosa and Other Disorders with Skin Fragility","volume":"183","author":"Has","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41572-020-0210-0","article-title":"Epidermolysis Bullosa","volume":"6","author":"Bardhan","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s40257-025-00942-y","article-title":"Long-Term Safety and Tolerability of Beremagene Geperpavec-Svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa","volume":"26","author":"Marinkovich","year":"2025","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1093\/bjd\/ljaf022","article-title":"Long-Term Safety and Efficacy of Oleogel-S10 (Birch Bark Extract) in Epidermolysis Bullosa: 24-Month Results from the Phase III EASE Study","volume":"192","author":"Murrell","year":"2025","journal-title":"Br. J. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.burns.2018.10.019","article-title":"Betulin Wound Gel Accelerated Healing of Superficial Partial Thickness Burns: Results of a Randomized, Intra-individually Controlled, Phase III Trial with 12-months Follow-up","volume":"45","author":"Frew","year":"2019","journal-title":"Burns"},{"key":"ref_8","first-page":"5068969","article-title":"Betulin-Based Oleogel to Improve Wound Healing in Dystrophic Epidermolysis Bullosa: A Prospective Controlled Proof-of-Concept Study","volume":"2017","author":"Kiritsi","year":"2017","journal-title":"Dermatol. Res. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/jid.2009.248","article-title":"Triterpenes Promote Keratinocyte Differentiation In Vitro, Ex Vivo and In Vivo: A Role for the Transient Receptor Potential Canonical (Subtype) 6","volume":"130","author":"Woelfle","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_10","unstructured":"(2024, April 07). European Medicines Agency Filsuvez (Birch Bark Extract). Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/filsuvez#authorisation-details."},{"key":"ref_11","first-page":"61","article-title":"Applications of Propolis-Based Materials in Wound Healing","volume":"316","author":"Salama","year":"2024","journal-title":"Arch. Dermatol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.phymed.2017.06.001","article-title":"Mechanisms Underlying the Wound Healing Potential of Propolis Based on Its In Vitro Antioxidant Activity","volume":"34","author":"Cao","year":"2017","journal-title":"Phytomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Steinbrenner, I., Houdek, P., Pollok, S., Brandner, J.M., and Daniels, R. (2016). Influence of the Oil Phase and Topical Formulation on the Wound Healing Ability of a Birch Bark Dry Extract. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155582"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1007\/s10311-018-0763-2","article-title":"Cyclodextrins, from Molecules to Applications","volume":"16","author":"Crini","year":"2018","journal-title":"Environ. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Villa, C., Caviglia, D., Robustelli della Cuna, F.S., Zuccari, G., and Russo, E. (2024). NaDES Application in Cosmetic and Pharmaceutical Fields: An Overview. Gels, 10.","DOI":"10.3390\/gels10020107"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Criollo-Mendoza, M.S., Contreras-Angulo, L.A., Leyva-L\u00f3pez, N., Guti\u00e9rrez-Grijalva, E.P., Jim\u00e9nez-Ortega, L.A., and Heredia, J.B. (2023). Wound Healing Properties of Natural Products: Mechanisms of Action. Molecules, 28.","DOI":"10.3390\/molecules28020598"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.foodchem.2009.02.060","article-title":"Chemical Composition, Antioxidant Activity and Antimicrobial Properties of Propolis Extracts from Greece and Cyprus","volume":"116","author":"Kalogeropoulos","year":"2009","journal-title":"Food Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kurek-G\u00f3recka, A., Keskin, \u015e., Bobis, O., Felitti, R., G\u00f3recki, M., Otr\u0119ba, M., Stojko, J., Olczyk, P., Kolayli, S., and Rzepecka-Stojko, A. (2022). Comparison of the Antioxidant Activity of Propolis Samples from Different Geographical Regions. Plants, 11.","DOI":"10.3390\/plants11091203"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13765-021-00608-3","article-title":"Determination of Antioxidant Activity and Phenolic Compounds for Basic Standardization of Turkish Propolis","volume":"64","author":"Keskin","year":"2021","journal-title":"Appl. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"697390","DOI":"10.1155\/2013\/697390","article-title":"Recent Progress of Propolis for Its Biological and Chemical Compositions and Its Botanical Origin","volume":"2013","author":"Toreti","year":"2013","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.foodchem.2005.07.042","article-title":"Phenolic Compounds in Plants and Agri-Industrial by-Products: Antioxidant Activity, Occurrence, and Potential Uses","volume":"99","author":"Balasundram","year":"2006","journal-title":"Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"\u0160uran, J., Cepanec, I., Ma\u0161ek, T., Radi\u0107, B., Radi\u0107, S., Gajger, I.T., and Vlaini\u0107, J. (2021). Propolis Extract and Its Bioactive Compounds\u2014From Traditional to Modern Extraction Technologies. Molecules, 26.","DOI":"10.3390\/molecules26102930"},{"key":"ref_23","first-page":"e12983","article-title":"Mechanism of Oleogel-S10: A Triterpene Preparation for the Treatment of Epidermolysis Bullosa","volume":"32","author":"Ott","year":"2019","journal-title":"Dermatol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s11101-019-09623-1","article-title":"Betulin and Betulinic Acid: Triterpenoids Derivatives with a Powerful Biological Potential","volume":"18","author":"Hordyjewska","year":"2019","journal-title":"Phytochem. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"99","DOI":"10.15835\/nbha4027967","article-title":"Evaluation of Betulin and Betulinic Acid Content in Birch Bark from Different Forestry Areas of Western Carpathians","volume":"40","author":"Holonec","year":"2012","journal-title":"Not. Bot. Horti Agrobot. Cluj-Napoca"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1515\/gps-2021-0083","article-title":"Valorization of Birch Bark Using a Low Transition Temperature Mixture Composed of Choline Chloride and Lactic Acid","volume":"10","year":"2021","journal-title":"Green Process. Synth."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00226-026-01752-z","article-title":"Optimized Ultrasound-Assisted Extraction of Betulin from Betula Pendula Bark: A Sustainable Approach to Forest Residue Valorization","volume":"60","author":"Chinchilla","year":"2026","journal-title":"Wood Sci. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Giotopoulou, I., Stamatis, H., and Barkoula, N.M. (2024). Encapsulation of Thymol in Ethyl Cellulose-Based Microspheres and Evaluation of Its Sustained Release for Food Applications. Polymers, 16.","DOI":"10.3390\/polym16233396"},{"key":"ref_29","first-page":"1031","article-title":"Development and Evaluation of Thymol Microparticles Using Cellulose Derivatives as Controlled Release Dosage Form","volume":"14","author":"Zamani","year":"2015","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.apenergy.2018.03.134","article-title":"Design of a Novel Nanocomposite with C-S-H@LA for Thermal Energy Storage: A Theoretical and Experimental Study","volume":"220","author":"Jiang","year":"2018","journal-title":"Appl. Energy"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kyriakoudi, A., Tsiouras, A., and Mourtzinos, I. (2022). Extraction of Lycopene from Tomato Using Hydrophobic Natural Deep Eutectic Solvents Based on Terpenes and Fatty Acids. Foods, 11.","DOI":"10.3390\/foods11172645"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"576","DOI":"10.3390\/suschem2040032","article-title":"Natural Deep Eutectic Solvents (NaDESs) as Alternative Green Extraction Media for Ginger (Zingiber Officinale Roscoe)","volume":"2","author":"Tzani","year":"2021","journal-title":"Sustain. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s12231-017-9369-z","article-title":"Identification of an Ancient Birch Bark Quiver from a Tang Dynasty (A.D. 618\u2013907) Tomb in Xinjiang, Northwest China","volume":"71","author":"Rao","year":"2017","journal-title":"Econ. Bot."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/1752-153X-6-67","article-title":"Evaluation and Differentiation of the Betulaceae Birch Bark Species and Their Bioactive Triterpene Content Using Analytical FT-Vibrational Spectroscopy and GC-MS","volume":"6","author":"Dehelean","year":"2012","journal-title":"Chem. Cent. J."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ostapiuk, A., Kurach, \u0141., Strzemski, M., Kurzepa, J., and Hordyjewska, A. (2021). Evaluation of Antioxidative Mechanisms in Vitro and Triterpenes Composition of Extracts from Silver Birch (Betula Pendula Roth) and Black Birch (Betula Obscura Kotula) Barks by Ft-Ir and Hplc-Pda. Molecules, 26.","DOI":"10.3390\/molecules26154633"},{"key":"ref_36","first-page":"767","article-title":"An\u00e1lise Por FTIR e Quantifica\u00e7\u00e3o de Fen\u00f3is e Flavon\u00f3ides de Cinco Produtos Naturais Dispon\u00edveis Comercialmente Utilizados No Tratamento de Feridas","volume":"21","author":"Oliveira","year":"2016","journal-title":"Rev. Mater."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sve\u010dnjak, L., Marijanovi\u0107, Z., Oki\u0144czyc, P., Ku\u015b, P.M., and Jerkovi\u0107, I. (2020). Mediterranean Propolis from the Adriatic Sea Islands as a Source of Natural Antioxidants: Comprehensive Chemical Biodiversity Determined by GC-MS, Ftiratr, UHPLC-DAD-QQTOF-MS, DPPH and FRAP Assay. Antioxidants, 9.","DOI":"10.3390\/antiox9040337"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5533","DOI":"10.1007\/s11696-022-02245-6","article-title":"Detection of Sunflower Oils Adulteration by ATR-FTIR Spectra","volume":"76","author":"Bunaciu","year":"2022","journal-title":"Chem. Pap."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Say\u0131n, B., Bozkurt, A.G., and Kaban, G. (2024). Assessing Waste Sunflower Oil as a Substrate for Citric Acid Production: The Inhibitory Effect of Triton X-100. Fermentation, 10.","DOI":"10.3390\/fermentation10070374"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1900245","DOI":"10.1002\/ejlt.201900245","article-title":"Identification and Quantification of Single and Multi-Adulteration of Beeswax by FTIR-ATR Spectroscopy","volume":"121","author":"Tanner","year":"2019","journal-title":"Eur. J. Lipid Sci. Technol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Vitolina, S., Berzins, R., Rizhikovs, J., Godina, D., Horv\u00e1th, Z.M., Logviss, K., Teresko, A., and Paze, A. (2023). Evaluation of Oleogels Stabilized by Particles of Birch Outer Bark Extract through a Novel Approach. Gels, 9.","DOI":"10.3390\/gels9110911"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.carbpol.2014.10.070","article-title":"Characterization of Hydroxypropyl-\u03b2-Cyclodextrins with Different Substitution Patterns via FTIR, GC-MS, and TG-DTA","volume":"118","author":"Yuan","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rojas-Mu\u00f1oz, Y.V., Santagapita, P.R., and Quintanilla-Carvajal, M.X. (2023). Probiotic Encapsulation: Bead Design Improves Bacterial Performance during In Vitro Digestion. Polymers, 15.","DOI":"10.3390\/polym15214296"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ishfaq, B., Khan, I.U., Khalid, S.H., and Asghar, S. (2023). Design and Evaluation of Sodium Alginate-Based Hydrogel Dressings Containing Betula Utilis Extract for Cutaneous Wound Healing. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1042077"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"131942","DOI":"10.1016\/j.ijbiomac.2024.131942","article-title":"On the Structural and Mechanical Properties of Mixed Coconut and Olive Oil Oleogels and Bigels","volume":"268","author":"Zampouni","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e01648","DOI":"10.1016\/j.heliyon.2019.e01648","article-title":"In Vitro Wound Healing Potency of Methanolic Leaf Extract of Aristolochia Saccata Is Possibly Mediated by Its Stimulatory Effect on Collagen-1 Expression","volume":"5","author":"Bolla","year":"2019","journal-title":"Heliyon"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3390\/jfb5020043","article-title":"HaCaT Keratinocytes Response on Antimicrobial Atelocollagen Substrates: Extent of Cytotoxicity, Cell Viability and Proliferation","volume":"5","year":"2014","journal-title":"J. Funct. Biomater."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpb.2021.11.004","article-title":"Lecithin-Based Nanoemulsions of Traditional Herbal Wound Healing Agents and Their Effect on Human Skin Cells","volume":"170","author":"Vater","year":"2022","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chen, H., Xiao, H., and Pang, J. (2020). Parameter Optimization and Potential Bioactivity Evaluation of a Betulin Extract from White Birch Bark. Plants, 9.","DOI":"10.3390\/plants9030392"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.sajb.2020.10.003","article-title":"Evaluation of the Potential In Vitro Effects of Propolis and Honey on Wound Healing in Human Dermal Fibroblast Cells","volume":"137","author":"Ebadi","year":"2021","journal-title":"S. Afr. J. Bot."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Valverde, T.M., Soares, B.N.G.d.S., Nascimento, A.M.d., Andrade, \u00c2.L., Sousa, L.R.D., Vieira, P.M.d.A., Santos, V.R., Seibert, J.B., Almeida, T.C.S.d., and Rodrigues, C.F. (2023). Anti-Inflammatory, Antimicrobial, Antioxidant and Photoprotective Investigation of Red Propolis Extract as Sunscreen Formulation in Polawax Cream. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065112"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Martinotti, S., Pellavio, G., Laforenza, U., and Ranzato, E. (2019). Propolis Induces AQP3 Expression: A Possible Way of Action in Wound Healing. Molecules, 24.","DOI":"10.3390\/molecules24081544"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/ics.12781","article-title":"Impact of Portuguese Propolis on Keratinocyte Proliferation, Migration and ROS Protection: Significance for Applications in Skin Products","volume":"44","author":"Saraiva","year":"2022","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"P\u00e2rv\u0103nescu, R.D., Watz, C.G., Moac\u0103, E.A., Vlaia, L., Marcovici, I., Maca\u0219oi, I.G., Borcan, F., Olariu, I., Coneac, G., and Dr\u0103ghici, G.A. (2021). Oleogel Formulations for the Topical Delivery of Betulin and Lupeol in Skin Injuries-Preparation, Physicochemical Characterization, and Pharmaco-Toxicological Evaluation. Molecules, 26.","DOI":"10.3390\/molecules26144174"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1007\/s13233-019-7014-7","article-title":"Transdermal Hydrogel Composed of Polyacrylic Acid Containing Propolis for Wound Healing in a Rat Model","volume":"26","author":"Kim","year":"2018","journal-title":"Macromol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e28621","DOI":"10.1016\/j.heliyon.2024.e28621","article-title":"Insight into the Influence of Natural Deep Eutectic Solvents on the Extraction of Phenolic Compounds from Poplar Type Propolis: Composition and in Vitro Biological Activity","volume":"10","author":"Trusheva","year":"2024","journal-title":"Heliyon"},{"key":"ref_57","unstructured":"Cigna Healthcare (2026, June 22). Coverage Policy: FilsuvezTM (Birch Triterpenes) Topical Gel. Available online: https:\/\/static.cigna.com\/assets\/chcp\/pdf\/coveragePolicies\/cnf\/cnf_850_coveragepositioncriteria_filsuvez_pa.pdf."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"465","DOI":"10.3109\/09546634.2015.1021663","article-title":"Triterpenes with Healing Activity: A Systematic Review","volume":"26","author":"Agra","year":"2015","journal-title":"J. Dermatol. Treat."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ebeling, S., Naumann, K., Pollok, S., Wardecki, T., Vidal-y-Sy, S., Nascimento, J.M., Boerries, M., Schmidt, G., Brandner, J.M., and Merfort, I. (2014). From a Traditional Medicinal Plant to a Rational Drug: Understanding the Clinically Proven Wound Healing Efficacy of Birch Bark Extract. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086147"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"183383","DOI":"10.1016\/j.bbamem.2020.183383","article-title":"Effect of Betulin and Betulonic Acid on Isolated Rat Liver Mitochondria and Liposomes","volume":"1862","author":"Dubinin","year":"2020","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Hunt, M., Torres, M., Bachar-Wikstr\u00f6m, E., and Wikstr\u00f6m, J.D. (2023). Multifaceted Roles of Mitochondria in Wound Healing and Chronic Wound Pathogenesis. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1252318"},{"key":"ref_62","first-page":"5798941","article-title":"Research Progress on Therapeutic Effect and Mechanism of Propolis on Wound Healing","volume":"2022","author":"Yang","year":"2022","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s10787-023-01318-6","article-title":"Natural Agents as Wound-Healing Promoters","volume":"32","author":"Akhtari","year":"2024","journal-title":"Inflammopharmacology"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Jacob, A., Parolia, A., Pau, A., and Davamani Amalraj, F. (2015). The Effects of Malaysian Propolis and Brazilian Red Propolis on Connective Tissue Fibroblasts in the Wound Healing Process. BMC Complement. Altern. Med., 15.","DOI":"10.1186\/s12906-015-0814-1"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Miraldi, E., Giordano, A., Cappellucci, G., Vaccaro, F., Biagi, M., and Baini, G. (2024). Phytochemical Characterization and Assessment of the Wound Healing Properties of Three Eurasian Propolis. Pharmaceuticals, 17.","DOI":"10.20944\/preprints202410.0303.v1"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"109855","DOI":"10.1016\/j.foodhyd.2024.109855","article-title":"Enrichment of Sunflower Oil with Tomato Carotenoids and Its Encapsulation in Ca-Alginate Beads: Preparation, Characterization and Chemical Stability upon In Vitro Digestion","volume":"151","author":"Kyriakoudi","year":"2024","journal-title":"Food Hydrocoll."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3109\/07388551.2013.794413","article-title":"Cyclodextrin-Based Hydrogels toward Improved Wound Dressings","volume":"34","author":"Pinho","year":"2014","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Ferreira, L.M.d.M.C., Cruz, N.F.d., Lynch, D.G., Costa, P.F.d., Salgado, C.G., Silva-J\u00fanior, J.O.C., Rossi, A., and Ribeiro-Costa, R.M. (2024). Hydrogel Containing Propolis: Physical Characterization and Evaluation of Biological Activities for Potential Use in the Treatment of Skin Lesions. Pharmaceuticals, 17.","DOI":"10.3390\/ph17101400"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Kapare, H.S., Giram, P.S., Raut, S.S., Gaikwad, H.K., and Paiva-Santos, A.C. (2023). Formulation Development and Evaluation of Indian Propolis Hydrogel for Wound Healing. Gels, 9.","DOI":"10.3390\/gels9050375"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Boudesocque-Delaye, L., Ardeza, I.M., Verger, A., Grard, R., Th\u00e9ry-Kon\u00e9, I., Perse, X., and Munnier, E. (2024). Natural Deep Eutectic Solvents as a Novel Bio-Based Matrix for Ready-to-Use Natural Antioxidants-Enriched Ingredients: Extraction and Formulation Optimization. Cosmetics, 11.","DOI":"10.3390\/cosmetics11010017"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cofs.2019.03.002","article-title":"Bioavailability and Biological Effects of Bioactive Compounds Extracted with Natural Deep Eutectic Solvents and Ionic Liquids: Advantages over Conventional Organic Solvents","volume":"26","author":"Murador","year":"2019","journal-title":"Curr. Opin. Food Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"961","DOI":"10.5650\/jos.ess14101","article-title":"Development and Physical Characterization of Polymer-Fish Oil Bigel (Hydrogel\/Oleogel) System as a Transdermal Drug Delivery Vehicle","volume":"63","author":"Rehman","year":"2014","journal-title":"J. Oleo Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"112815","DOI":"10.1016\/j.lwt.2021.112815","article-title":"Crystalline Microstructure and Physicochemical Properties of Olive Oil Oleogels Formulated with Monoglycerides and Phytosterols","volume":"154","author":"Zampouni","year":"2022","journal-title":"LWT"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.colsurfb.2014.09.056","article-title":"Guar Gum and Sesame Oil Based Novel Bigels for Controlled Drug Delivery","volume":"123","author":"Singh","year":"2014","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"122900","DOI":"10.1016\/j.indcrop.2026.122900","article-title":"Ultrasound-Assisted Deep Eutectic Solvent Extraction and Bioactivity Evaluation of Phenolic Compounds from White Birch Bark","volume":"242","author":"Wu","year":"2026","journal-title":"Ind. Crops Prod."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.jpba.2006.09.026","article-title":"Simultaneous Determination of Betulin and Betulinic Acid in White Birch Bark Using RP-HPLC","volume":"43","author":"Zhao","year":"2007","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ebiom.2019.04.062","article-title":"Treatment of Keratinocytes with 4-Phenylbutyrate in Epidermolysis Bullosa: Lessons for Therapies in Keratin Disorders","volume":"44","author":"Prochnicki","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_78","unstructured":"American Type Culture Collection (ATCC) (2026, June 22). MTT Cell Proliferation Assay Instruction Guide (30-1010K). Available online: https:\/\/www.atcc.org\/products\/30-1010k."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1016\/j.jid.2024.06.425","article-title":"409 Mechanism of Action of Triterpene Extract in Epidermolysis Bullosa: Induction of Migration-Stimulating Inflammation in Keratinocytes","volume":"144","author":"Gretzmeier","year":"2024","journal-title":"J. Investig. Dermatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/7651_2019_259","article-title":"Scratch Wound Healing Assay","volume":"Volume 2109","author":"Martinotti","year":"2020","journal-title":"Methods in Molecular Biology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1016\/j.jid.2016.11.020","article-title":"Research Techniques Made Simple: Analysis of Collective Cell Migration Using the Wound Healing Assay","volume":"137","author":"Grada","year":"2017","journal-title":"J. Investig. Dermatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5746\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:58:49Z","timestamp":1782435529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5746"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":81,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135746"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135746","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}