{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:19:40Z","timestamp":1788326380758,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014908","name":"Colombian Institute of Educational Credit and Technical Studies Abroad","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014908","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03jctmx41","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministry of Science, Technology, and Innovation"},{"DOI":"10.13039\/501100009087","name":"Industrial University of Santander","doi-asserted-by":"crossref","award":["2022-0645"],"award-info":[{"award-number":["2022-0645"]}],"id":[{"id":"10.13039\/501100009087","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2022-0645"],"award-info":[{"award-number":["2022-0645"]}],"id":[{"id":"https:\/\/ror.org\/00xc1d948","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>We previously demonstrated the therapeutic potential of a 0.5% miltefosine carbopol-based gel (G-MTF) in experimental cutaneous leishmaniasis (CL). To support formulation optimisation before clinical evaluation, this study assessed whether G-MTF retained antileishmanial activity after storage at different temperatures and durations and evaluated its dose\u2013response following topical application to CL lesions in BALB\/c mice infected with Leishmania amazonensis. Storage effects on some physicochemical and morphological properties, sterility, and MTF detection were also assessed. In vitro antileishmanial activity was largely maintained, although prolonged storage at 35\u201345 \u00b0C moderately reduced potency. During 60 days of follow-up, CL lesions reactivated in 17% of the 118 treated mice, with most reactivations occurring after treatment with G-MTF formulations stored for 3\u20136 months at 35\u201345 \u00b0C. Dose\u2013response analysis showed concentration-dependent effects on lesion reduction and parasite burden, with estimated ED50 values of 3.64 and 4.02 mg\/kg, respectively. All carbopol-based gel formulations remained sterile and retained physicochemical characteristics at 8\u201328 \u00b0C, with pH values within the normal skin range. Storage at 8 \u00b0C increased viscosity and reduced spreadability, whereas higher temperatures increased swelling. MALDI-TOF MS demonstrated that MTF remained detectable after prolonged storage, while SEM showed preserved morphology at 8\u201328 \u00b0C. Overall, carbopol-based G-MTF maintained therapeutic activity and acceptable physicochemical characteristics for up to six months at 8\u201328 \u00b0C. Validated quantitative stability-indicating and drug-release methods are needed to confirm MTF chemical stability and drug availability in the carbopol-based gel.<\/jats:p>","DOI":"10.3390\/gels12090779","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimisation of a Topical Miltefosine Carbopol-Based Gel for Cutaneous Leishmaniasis: Antileishmanial Activity After Storage and Drug Response"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6521-9674","authenticated-orcid":false,"given":"Diana Paola","family":"Pe\u00f1a","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales (CINTROP-UIS), Departamento de Ciencias B\u00e1sicas, Escuela de Medicina, Universidad Industrial de Santander, Bucaramanga 680002, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5320-5075","authenticated-orcid":false,"given":"Laura F.","family":"Neira","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales (CINTROP-UIS), Departamento de Ciencias B\u00e1sicas, Escuela de Medicina, Universidad Industrial de Santander, Bucaramanga 680002, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7527-2364","authenticated-orcid":false,"given":"Patricia","family":"Escobar","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales (CINTROP-UIS), Departamento de Ciencias B\u00e1sicas, Escuela de Medicina, Universidad Industrial de Santander, Bucaramanga 680002, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2024, August 06). Fact Sheets\/Detail\/Leishmaniasis. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Azim, M., Khan, S.A., Ullah, S., Ullah, S., and Anjum, S.I. (2021). Therapeutic Advances in the Topical Treatment of Cutaneous Leishmaniasis: A Review. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009099"},{"key":"ref_3","unstructured":"Pan American Health Organization (2022). Guideline for the Treatment of Leishmaniasis in the Americas, Pan American Health Organization. [2nd ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"789","DOI":"10.4269\/ajtmh.18-0949","article-title":"Natural Resistance of Leishmania Infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil","volume":"101","author":"Carnielli","year":"2019","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ijid.2020.11.183","article-title":"Association of Miltefosine with Granulocyte and Macrophage Colony-Stimulating Factor (GM-CSF) in the Treatment of Cutaneous Leishmaniasis in the Amazon Region: A Randomized and Controlled Trial","volume":"103","author":"Mendes","year":"2021","journal-title":"Int. J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1093\/cid\/cit102","article-title":"Increasing Failure of Miltefosine in the Treatment of Kala-Azar in Nepal and the Potential Role of Parasite Drug Resistance, Reinfection, or Noncompliance","volume":"56","author":"Rijal","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Del Mar Castro, M., Gomez, M.A., Kip, A.E., Cossio, A., Ortiz, E., Navas, A., Dorlo, T.P.C., and Saravia, N.G. (2017). Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis. Antimicrob. Agents Chemother., 61.","DOI":"10.1128\/AAC.02198-16"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6262","DOI":"10.1021\/acs.cgd.2c00843","article-title":"Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine","volume":"22","author":"Hall","year":"2022","journal-title":"Cryst. Growth Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1093\/jac\/dks275","article-title":"Miltefosine: A Review of Its Pharmacology and Therapeutic Efficacy in the Treatment of Leishmaniasis","volume":"67","author":"Dorlo","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"106459","DOI":"10.1016\/j.ijantimicag.2021.106459","article-title":"An Update on the Clinical Pharmacology of Miltefosine in the Treatment of Leishmaniasis","volume":"59","author":"Beijnen","year":"2022","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ribeiro, L.R., Silva, S.N., Saliba, M.F., de Pina Carvalho, J., and Cota, G. (2024). Safety Profile of Miltefosine in the Treatment of Cutaneous Leishmaniasis. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0315710"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2457","DOI":"10.1093\/cid\/ciaa1238","article-title":"Efficacy and Tolerability of Miltefosine in the Treatment of Cutaneous Leishmaniasis","volume":"73","author":"Ware","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1093\/jac\/dkz049","article-title":"Anti-Leishmanial Activity of a Topical Miltefosine Gel in Experimental Models of New World Cutaneous Leishmaniasis","volume":"74","author":"Neira","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Neira, L.F., Mantilla, J.C., and Escobar, P. (2023). Monitoring Cutaneous Leishmaniasis Lesions in Mice Undergoing Topical Miltefosine Treatment. Sci. Pharm., 91.","DOI":"10.3390\/scipharm91040054"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16071","DOI":"10.1038\/natrevmats.2016.71","article-title":"Designing Hydrogels for Controlled Drug Delivery","volume":"1","author":"Li","year":"2016","journal-title":"Nat. Rev. Mater."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1039\/C5TB00264H","article-title":"Preparation and Characterization of a Novel PH-Sensitive Salecan-g-Poly(Acrylic Acid) Hydrogel for Controlled Release of Doxorubicin","volume":"3","author":"Hu","year":"2015","journal-title":"J. Mater. Chem. B"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112173","DOI":"10.1016\/j.cclet.2025.112173","article-title":"A Procyanidin\/Fe3O4 Nanoparticle-Reinforced Pullulan\/Chitosan Hydrogel for Treating Diabetic Wounds","volume":"37","author":"Yu","year":"2025","journal-title":"Chin. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Merino-G\u00f3mez, M., Godoy-Gallardo, M., Wendner, M., Mateos-Timoneda, M.A., Gil, F.J., and Perez, R.A. (2023). Optimization of Guanosine-Based Hydrogels with Boric Acid Derivatives for Enhanced Long-Term Stability and Cell Survival. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1147943"},{"key":"ref_19","first-page":"1","article-title":"Comparison of Rheological, Drug Release, and Mucoadhesive Characteristics upon Storage between Hydrogels with Unmodified or Beta-Glycerophosphate-Crosslinked Chitosan","volume":"2018","author":"Winnicka","year":"2018","journal-title":"Int. J. Polym. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s13346-021-00896-8","article-title":"Efficacy of Topical Miltefosine Formulations in an Experimental Model of Cutaneous Leishmaniasis","volume":"12","author":"Peralta","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1111\/jphp.12548","article-title":"Topical Formulations of Miltefosine for Cutaneous Leishmaniasis in a BALB\/c Mouse Model","volume":"68","author":"Yardley","year":"2016","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_22","first-page":"370","article-title":"In Vitro Activity against Leishmania and Human Skin Permeation of Miltefosine Ultradeformable Liposomes","volume":"66","author":"Hernandez","year":"2014","journal-title":"Rev. Cuba. Med. Trop."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1039\/D0MD00343C","article-title":"Pharmacokinetics and Pharmacodynamics in the Treatment of Cutaneous Leishmaniasis - Challenges and Opportunities","volume":"12","author":"Croft","year":"2021","journal-title":"RSC Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00631-18","DOI":"10.1128\/AAC.00631-18","article-title":"Local Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin B","volume":"62","author":"Wijnant","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","unstructured":"Lubrizol Advanced Materials (2023). Carbopol\u00ae Ultrez 10 NF Polymer Technical Data Sheet, The Lubrizol Corporation. Available online: https:\/\/www.lubrizol.com\/solutions\/products\/pharmaceuticals\/detail-pages\/carbopol-ultrez-10-nf-polymer."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1023\/B:PHAM.0000033006.11619.07","article-title":"Rheological Characterization of Topical Carbomer Gels Neutralized to Different PH","volume":"21","author":"Islam","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_27","unstructured":"WHO (2021). Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products: Stability Conditions for WHO Member States by Region, WHO. WHO Technical Report Series, No. 953, Annex 2, Appendix 1 (Update March 2021)."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jnnfm.2012.07.005","article-title":"Thermorheological Properties of a Carbopol Gel under Shear","volume":"183\u2013184","author":"Weber","year":"2012","journal-title":"J. Nonnewton. Fluid Mech."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/j.1467-2494.2006.00344.x","article-title":"Natural Skin Surface PH Is on Average below 5, Which Is Beneficial for Its Resident Flora","volume":"28","author":"Lambers","year":"2006","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Stojkov, G., Niyazov, Z., Picchioni, F., and Bose, R.K. (2021). Relationship between Structure and Rheology of Hydrogels for Various Applications. Gels, 7.","DOI":"10.3390\/gels7040255"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0014-827X(01)01058-8","article-title":"Viscosity and Temperature Relationship in Ethanol\/Water Mixtures Gelified with Carbopol\u00ae UltrezTM 10","volume":"56","year":"2001","journal-title":"Farmaco"},{"key":"ref_32","unstructured":"Rowe, R.C., Sheskey, P.J., and Quinn, M. (2005). Handbook of Pharmaceutical Excipients, American Pharmacists Association."},{"key":"ref_33","unstructured":"(2003). International Council for Harmonisation (ICH). Q1A(R2): Stability testing of new drug substances and products: Guidance for industry 2003. SubStance, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/q1ar2-stability-testing-new-drug-substances-and-products."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/j.polymer.2008.01.027","article-title":"Hydrogels in Drug Delivery: Progress and Challenges","volume":"49","author":"Hoare","year":"2008","journal-title":"Polymer"},{"key":"ref_35","unstructured":"United States Pharmacopeial Convention (2026). <51>Antimicrobial Effectiveness Testing. United States Pharmacopeia and National Formulary (USP-NF), United States Pharmacopeial Convention."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1093\/bfgp\/eln041","article-title":"Quantitative Matrix-Assisted Laser Desorption\/Ionization Mass Spectrometry","volume":"7","author":"Duncan","year":"2008","journal-title":"Brief. Funct. Genom. Proteom."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20150371","DOI":"10.1098\/rsta.2015.0371","article-title":"Critical Factors Determining the Quantification Capability of Matrix-Assisted Laser Desorption\/Ionization-Time-of-Flight Mass Spectrometry","volume":"374","author":"Wang","year":"2016","journal-title":"Philos. Trans. R. Soc. A Math. Phys. Eng. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.chroma.2017.01.040","article-title":"Recommendations for Quantitative Analysis of Small Molecules by Matrix-Assisted Laser Desorption Ionization Mass Spectrometry","volume":"1486","author":"Wang","year":"2017","journal-title":"J. Chromatogr. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"533","DOI":"10.4155\/bio.16.7","article-title":"LC-Coupled ESI MS for Quantification of Miltefosine in Human and Hamster Plasma","volume":"8","author":"Jaiswal","year":"2016","journal-title":"Bioanalysis"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jchromb.2015.06.017","article-title":"Quantification of Miltefosine in Peripheral Blood Mononuclear Cells by High-Performance Liquid Chromatography-Tandem Mass Spectrometry","volume":"998\u2013999","author":"Kip","year":"2015","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5403","DOI":"10.1021\/ac060436i","article-title":"Qualitative and Quantitative Analysis of Pharmaceutical Compounds by MALDI-TOF Mass Spectrometry","volume":"78","author":"Burgers","year":"2006","journal-title":"Anal. Chem."},{"key":"ref_42","unstructured":"World Health Organization (2025). Safe Management of Pharmaceutical Waste from Health Care Facilities: Global Best Practices, WHO."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1289\/ehp.1104477","article-title":"Pharmaceuticals and Personal Care Products in the Environment: What Are the Big Questions?","volume":"120","author":"Boxall","year":"2012","journal-title":"Environ. Health Perspect."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"272","DOI":"10.4269\/ajtmh.2005.73.272","article-title":"The Sensitivity of Clinical Isolates of Leishmania from Peru and Nepal to Miltefosine","volume":"73","author":"Yardley","year":"2005","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lessa, V.L., Gon\u00e7alves, G., Santos, B., Cavalari, V.C., da Costa Vieira, R.F., and Figueiredo, F.B. (2024). In Vitro Evaluation of the Combinatorial Effect of Naringenin and Miltefosine against Leishmania Amazonensis. Pharmaceuticals, 17.","DOI":"10.3390\/ph17081014"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100617","DOI":"10.1016\/j.ijpddr.2025.100617","article-title":"Biological and Molecular Characterisation of in Vitro Selected Miltefosine-Resistant Leishmania Amazonensis Lines","volume":"29","author":"Neira","year":"2025","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.actatropica.2019.05.018","article-title":"Development of Topical Liposomes Containing Miltefosine for the Treatment of Leishmania Major Infection in Susceptible BALB\/c Mice","volume":"196","author":"Kavian","year":"2019","journal-title":"Acta Trop."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.addr.2003.10.025","article-title":"Penetration Enhancers","volume":"56","author":"Williams","year":"2004","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1128\/AAC.01123-06","article-title":"Miltefosine Affects Lipid Metabolism in Leishmania Donovani Promastigotes","volume":"51","author":"Rakotomanga","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1128\/AAC.26.5.745","article-title":"Development of Topical Treatment for Cutaneous Leishmaniasis Caused by Leishmania Major in Experimental Animals","volume":"26","author":"Jacobs","year":"1984","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1128\/AAC.45.6.1872-1875.2001","article-title":"Activities of Hexadecylphosphocholine (Miltefosine), Ambisome, and Sodium Stibogluconate (Pentostam) against Leishmania Donovani in Immunodeficient Scid Mice","volume":"45","author":"Escobar","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1517\/14656566.2015.973850","article-title":"An Update on Pharmacotherapy for Leishmaniasis","volume":"16","author":"Sundar","year":"2015","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_53","first-page":"1","article-title":"ITS1 PCR-RFLP Diagnosis and Characterization of Leishmania in Clinical Samples and Strains from Cases of Human Cutaneous Leishmaniasis in States of the Mexican Southeast","volume":"2014","author":"Nasereddin","year":"2014","journal-title":"Interdiscip. Perspect. Infect. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"100779","DOI":"10.1016\/j.mex.2019.100779","article-title":"Protocol Efficiently Measuring the Swelling Rate of Hydrogels","volume":"7","author":"Zhang","year":"2020","journal-title":"MethodsX"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/S0731-7085(02)00047-X","article-title":"Development of Validated Stability-Indicating Assay Methods\u2014Critical Review","volume":"28","author":"Bakshi","year":"2002","journal-title":"J. Pharm. Biomed. Anal."}],"container-title":["Gels"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/9\/779\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:28:29Z","timestamp":1788323309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/9\/779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":55,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["gels12090779"],"URL":"https:\/\/doi.org\/10.3390\/gels12090779","relation":{},"ISSN":["2310-2861"],"issn-type":[{"value":"2310-2861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}