Bioactive sericin scaffolds with allantoin-acetamide eutectic for enhanced wound healing
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Muhammad Naseer
,
Syed Waqar Hussain Shah
,
Abdullah Y. Alzahrani
Abstract
Smart wound dressings that respond to the wound environment have emerged as innovative therapeutic platforms, aiming to control infection, reduce inflammation, and promote vascularization for effective healing. Herein, an innovative eutectic system combining acetamide and allantoin (AAM) integrated with sericin peptides (SS) for enhanced wound healing applications is reported. The binary AAM system exhibited superior physicochemical properties, utilizing acetamide’s anti-inflammatory effects and allantoin’s regenerative capabilities. The binary AAM system exhibited superior physicochemical properties, with molecular modeling revealing optimal donor-acceptor interactions and FTIR confirming complex intermolecular networks in SS-incorporated scaffolds. The SS-containing scaffolds showed significantly enhanced wound healing efficacy in a mouse model compared to non-functionalized AAM systems, with accelerated wound closure through synergistic interactions. This integration of eutectic systems with bioactive peptides presents a promising platform for advanced wound healing therapeutics, offering improved drug delivery and tissue regeneration.
Acknowledgments
The authors extend their appreciation to Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology for valuable Research cooperation.
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Research ethics: Agreed and fulfil the research ethics.
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Informed consent: No consent required.
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Author contributions: MN: Methodology; IB: Conceptualization, Supervision; SWHS: supervision, Conceptualization; NA; methodology; LR: Data Curation; WR: MS Writing, Conceptualization, Validation; AYA: Softaware, data analysis.
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Use of Large Language Models, AI and Machine Learning Tools: No tool used.
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Conflict of interest: No conflict of interest.
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Research funding: No funding.
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Data availability: The data could be made available, if requested.
References
1. Pan, G.; Zhang, J.; Liang, Y.; Guo, B. Latest Findings on Stimuli-Responsive Hydrogel Wound Dressings Applied in Diabetic Chronic Wound Repair. J. Sichuan Univ. Med. Sci. Ed. 2023, 54 (4); https://doi.org/10.12182/20230760206.Search in Google Scholar PubMed PubMed Central
2. Ding, H.; Hao, L.; Mao, H. Magneto-Responsive Biocomposites in Wound Healing: from Characteristics to Functions. J. Mater. Chem. B 2024, 12, 7463–7479; https://doi.org/10.1039/d4tb00743c.Search in Google Scholar PubMed
3. Kaveti, R.; Jakus, M. A.; Chen, H.; Jain, B.; Kennedy, D. G.; Caso, E. A.; Mishra, N.; Sharma, N.; Uzunoğlu, B. E.; Han, W. B.; Jang, T. M.; Hwang, S. W.; Theocharidis, G.; Sumpio, B. J.; Veves, A.; Sia, S. K.; Bandodkar, A. J. Water-Powered, Electronics-free Dressings that Electrically Stimulate Wounds for Rapid Wound Closure. Sci. Adv. 2024, 10 (32), eado7538; https://doi.org/10.1126/sciadv.ado7538.Search in Google Scholar PubMed PubMed Central
4. Kolipaka, T.; Pandey, G.; Abraham, N.; Srinivasarao, D. A.; Raghuvanshi, R. S.; Rajinikanth, P. S.; Tickoo, V.; Srivastava, S. Stimuli-Responsive Polysaccharide-based Smart Hydrogels for Diabetic Wound Healing: Design Aspects, Preparation Methods and Regulatory Perspectives. Carbohydr. Polym. 2024, 324, 121537; https://doi.org/10.1016/j.carbpol.2023.121537.Search in Google Scholar PubMed
5. Foroughi, J.; Ruhparwar, A.; Aloko, S.; Wang, C. H. Manufacturing Ulvan Biopolymer for Wound Dressings. Macromol. Mater. Eng. 2024, 309 (2), 2300268; https://doi.org/10.1002/mame.202300268.Search in Google Scholar
6. Joorabloo, A.; Liu, T. Smart Theranostics for Wound Monitoring and Therapy. Adv. Colloid Interface Sci. 2024, 103207; https://doi.org/10.1016/j.cis.2024.103207.Search in Google Scholar PubMed
7. Wang, Y.; Zhai, W.; Cheng, S.; Li, J.; Zhang, H. Surface-Functionalized Design of blood-contacting Biomaterials for Preventing Coagulation and Promoting Hemostasis. Friction 2023, 11 (8), 1371–1394. https://doi.org/10.1007/s40544-022-0710-x.Search in Google Scholar
8. Wang, J.; You, C.; Xu, Y.; Xie, T.; Wang, Y. Research Advances in Electrospun Nanofiber Membranes for Non-invasive Medical Applications. Micromachines 2024, 15 (10), 1226. https://doi.org/10.3390/mi15101226.Search in Google Scholar PubMed PubMed Central
9. Shi, T.; Lu, H.; Zhu, J.; Zhou, X.; He, C.; Li, F.; Yang, G. Naturally Derived Dual Dynamic Crosslinked Multifunctional Hydrogel for Diabetic Wound Healing. Composites, Part B 2023, 257, 110687; https://doi.org/10.1016/j.compositesb.2023.110687.Search in Google Scholar
10. Bin, A.; Yao, W.; Guo, T.; Wang, X.; Zhang, J. Clinical Effectiveness of Tazarotene Betamethasone Cream Combined with Compounded Allantoin Cream in the Treatment of Chronic Hand Eczema. Indian J. Pharm. Sci. 2023, 85, 284–289; https://doi.org/10.36468/pharmaceutical-sciences.spl.810.Search in Google Scholar
11. Huang, B.; An, H.; Chu, J.; Ke, S.; Ke, J.; Qiu, Y.; Zhang, J.; Zhu, H.; Lin, J.; Yang, M.; Yang, D.; Song, X.; Liu, W. Glucose-Responsive and Analgesic Gel for Diabetic Subcutaneous Abscess Treatment by Simultaneously Boosting Photodynamic Therapy and Relieving Hypoxia. Advanced Science 2025, e02830; https://doi.org/10.1002/advs.202502830.Search in Google Scholar PubMed
12. Bao, M.; Li, G.; Huang, X.; Tang, L.; Dong, L.; Li, J. Long Noncoding RNA LINC00657 Acting as a miR-590-3p Sponge to Facilitate Low Concentration Oxidized Low-Density Lipoprotein–Induced Angiogenesis. Mol. Pharmacol. 2018, 93 (4), 368–375; https://doi.org/10.1124/mol.117.110650.Search in Google Scholar PubMed
13. Shah, S. W. H.; Imran, F.; Ahmad, H. S.; Bibi, I.; Pervaiz, S.; Ul Wahab, Z. Allantoin Eutectics with Choline Chloride and Zinc Chloride: Interactions and Wound Healing Applications. J. Taibah Univ. Sci. 2023, 17 (1), 2208727; https://doi.org/10.1080/16583655.2023.2208727.Search in Google Scholar
14. Brahamdutt, B.; Narwal, S.; Kumar, A.; Chaudhary, M.; Budhwar, V. Formulation of Eutectic Mixture of Curcumin with Salicylic Acid for Improving Its Dissolution Profile. Res. J. Pharm. Technol. 2021, 14, 1875–1879; https://doi.org/10.52711/0974-360x.2021.00331.Search in Google Scholar
15. Nica, M.-A.; Anuța, V.; Nicolae, C. A.; Popa, L.; Ghica, M. V.; Cocoş, F.-I.; Dinu-Pîrvu, C. E. Exploring Deep Eutectic Solvents as Pharmaceutical Excipients: Enhancing the Solubility of Ibuprofen and Mefenamic Acid. Pharmaceuticals 2024, 17 (10), 1316; https://doi.org/10.3390/ph17101316.Search in Google Scholar PubMed PubMed Central
16. Liu, Y.; Wang, D.; Lai, Y.; Zou, J.; Yang, P.; Wu, Z.; He, W. Deep Eutectic Solvents for Essential-Oil Delivery and Bacterial-Infected Wound Healing. Langmuir 2024, 40 (45), 23766–23779; https://doi.org/10.1021/acs.langmuir.4c02736.Search in Google Scholar PubMed
17. Liu, S.; Zhan, J.; Liu, Z.; Tan, X.; Huang, J.; Pu, C.; Lin, R.; Chen, Y.; Luo, Q.; Qiu, X.; Hou, H. Versatile Poly(Deep Eutectic Solvents) Electroactive Chitosan Eutectogel for Infected Wound Healing and Monitoring Administration. Carbohydr. Polym. 2025, 352, 123192; https://doi.org/10.1016/j.carbpol.2024.123192.Search in Google Scholar PubMed
18. Wang, F.; Hou, K.; Chen, W.; Wang, Y.; Wang, R.; Tian, C.; Xu, S.; Ji, Y.; Yang, Q.; Zhao, P.; Yu, L.; Lu, Z.; Zhang, H.; Li, F.; Wang, H.; He, B.; Kaplan, D. L.; Xia, Q. Correction: Transgenic PDGF-BB/Sericin Hydrogel Supports for Cell Proliferation and Osteogenic Differentiation. Biomater. Sci. 2021, 9 (11), 4212–4213; https://doi.org/10.1039/d1bm90052h.Search in Google Scholar PubMed
19. Kapoor, D. U.; Garg, R.; Gaur, M.; Pareek, A.; Prajapati, B. G.; Castro, G. R.; Suttiruengwong, S.; Sriamornsak, P. Pectin Hydrogels for Controlled Drug Release: Recent Developments and Future Prospects. Saudi Pharm. J. 2024, 102002; https://doi.org/10.1016/j.jsps.2024.102002.Search in Google Scholar PubMed PubMed Central
20. Silva, A. S.; Costa, E. C.; Reis, S.; Spencer, C.; Calhelha, R. C.; Miguel, S. P.; Ribeiro, M. P.; Barros, L.; Vaz, J. A.; Coutinho, P. Silk Sericin: a Promising Sustainable Biomaterial for Biomedical and Pharmaceutical Applications. Polymers 2022, 14 (22), 4931; https://doi.org/10.3390/polym14224931.Search in Google Scholar PubMed PubMed Central
21. Wanasingha, N.; Balu, R.; Rekas, A.; Mata, J. P.; Dutta, N. K.; Choudhury, N. R. A Controlled Co-Assembly Approach to Tune Temperature Responsiveness of Biomimetic Proteins. J. Mater. Chem. B 2025, 13, 1302–1315; https://doi.org/10.1039/d4tb01737d.Search in Google Scholar PubMed
22. Nadeem Butt, E.; Ali, S.; Summer, M.; Siddiqua Khan, A.; Noor, S. Exploring the Mechanistic Role of Silk Sericin Biological and Chemical Conjugates for Effective Acute and Chronic Wound Repair and Related Complications. Drug Dev. Ind. Pharm. 2024, 50 (7), 577–592; https://doi.org/10.1080/03639045.2024.2387814.Search in Google Scholar PubMed
23. Wang, J.; Liu, H.; Shi, X.; Qin, S.; Liu, J.; Lv, Q.; Liu, J.; Li, Q.; Wang, Z.; Wang, L. Development and Application of an Advanced Biomedical Material—Silk Sericin. Adv. Mater. 2024, 36 (23), 2470178; https://doi.org/10.1002/adma.202311593.Search in Google Scholar PubMed
24. Kim, S.-G.; Choi, J.-Y.; Kweon, H. Biomedical Application of Silk Sericin: Recent Research Trend. Int. J. Ind. Entomol. Biomater. 2024, 48 (1).Search in Google Scholar
25. Yang, C.; Zhang, Z.; Fan, X.; Liu, Y.; Deng, C.; Zhang, M.; Wang, X.; Deng, L.; Gao, H.; Deng, Y.; Song, Y.; Liu, H.; Wang, Z.; Xiong, W.; Wang, L. Sericin-Based 3D High-Precision Biomimetic Microscaffold Fabricated by Laser Direct Writing for Tissue Engineering. Nano Lett. 2025, 25 (20), 8110–8119; https://doi.org/10.1021/acs.nanolett.5c00346.Search in Google Scholar PubMed
26. Khan, A.; Rehman, W.; Alanazi, M. M.; Khan, Y.; Rasheed, L.; Saboor, A.; Iqbal, S. Development of Novel Multifunctional Electroactive, Self-Healing, and Tissue Adhesive Scaffold to Accelerate Cutaneous Wound Healing and Hemostatic Materials. ACS Omega 2023, 8, 39110–39134; https://doi.org/10.1021/acsomega.3c04135.Search in Google Scholar PubMed PubMed Central
27. Butenko, S.; Nagalla, R. R.; Guerrero-Juarez, C. F.; Palomba, F.; David, L.-M.; Nguyen, R. Q.; Gay, D.; Almet, A. A.; Digman, M. A.; Nie, Q.; Scumpia, P. O.; Plikus, M. V.; Liu, W. F. Hydrogel Crosslinking Modulates Macrophages, Fibroblasts, and their Communication, During Wound Healing. Nat. Commun. 2024, 15, 6820; https://doi.org/10.1038/s41467-024-50072-y.Search in Google Scholar PubMed PubMed Central
28. Soleimanpour, M.; Mirhaji, S. S.; Jafari, S.; Derakhshankhah, H.; Mamashli, F.; Nedaei, H.; Karimi, M. R.; Motasadizadeh, H.; Fatahi, Y.; Ghasemi, A.; Nezamtaheri, M. S.; Khajezade, M.; Teimouri, M.; Goliaei, B.; Delattre, C.; Saboury, A. A. Designing a New Alginate-Fibrinogen Biomaterial Composite Hydrogel for Wound Healing. Sci. Rep. 2022, 12, 7213; https://doi.org/10.1038/s41598-022-11282-w.Search in Google Scholar PubMed PubMed Central
29. Parnham, E. R.; Drylie, E. A.; Wheatley, P. S.; Slawin, A. M.; Morris, R. E. Ionothermal Materials Synthesis Using Unstable Deep-Eutectic Solvents as Template-Delivery Agents. Angew. Chem. 2006, 118, 5084–5088; https://doi.org/10.1002/ange.200600290.Search in Google Scholar
30. Dall’Olio, L.. Survey of Methodologies of Pharmaceutical Interest for Quantification of Crystal Form via X-Ray Powder Diffraction. Dissertation Thesis, Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Nanoscienze per la medicina e per l’ambiente, 2021.Search in Google Scholar
31. Li, W.; Kong, L.; Feng, B.; Fu, H.; Li, H.; Zeng, X. C.; Wu, K.; Chen, L. Abnormal Phase Transition Between two-dimensional high-density Liquid Crystal and low-density Crystalline Solid Phases. Nat. Commun. 2018, 9, 198–204; https://doi.org/10.1038/s41467-017-02634-6.Search in Google Scholar PubMed PubMed Central
32. Nasr, S.; Ghédira, M.; Cortes, R. H-bonding in Liquid Acetamide as Studied by x-ray Scattering. J. Chem. Phys. 1999, 110, 10487–10492.10.1063/1.478978Search in Google Scholar
33. Codorniu-Hernández, E.; Boese, A. D.; Schauerte, C.; Rolo-Naranjo, A.; Miranda-Quintana, R.; Montero-Cabrera, L. A.; Boese, R. MMH-2 as a New Approach for the Prediction of Intermolecular Interactions: the Crystal Packing of Acetamide. CrystEngComm 2009, 11, 2358–2370; https://doi.org/10.1039/b905779j.Search in Google Scholar
34. Biovia, D. S. BIOVIA Discovery Studio Visualizer, v16. 1.0. 15350; Dassault Systèmes: San Diego, 2015; pp. 627–628.Search in Google Scholar
35. Spittle, S.; Poe, D.; Doherty, B.; Kolodziej, C.; Heroux, L.; Haque, M. A.; Squire, H.; Cosby, T.; Zhang, Y.; Fraenza, C.; Bhattacharyya, S.; Tyagi, M.; Peng, J.; Elgammal, R. A.; Zawodzinski, T.; Tuckerman, M.; Greenbaum, S.; Gurkan, B.; Burda, C.; Dadmun, M.; Maginn, E. J.; Sangoro, J. Evolution of Microscopic Heterogeneity and Dynamics in Choline Chloride-based Deep Eutectic Solvents. Nat. Commun. 2022, 13, 219; https://doi.org/10.1038/s41467-021-27842-z.Search in Google Scholar PubMed PubMed Central
36. Wahlsten, O.; Apell, P. Wounds as Probes of Electrical Properties of Skin. J. Electr. Bioimped. 2010, 1, 63–70; https://doi.org/10.5617/jeb.130.Search in Google Scholar
37. Sasaki, K.; Porter, E.; Rashed, E. A.; Farrugia, L.; Schmid, G. Measurement and Image-based Estimation of Dielectric Properties of Biological Tissues—Past, Present, and Future. Phys. Med. Biol. 2022, 67, 14TR01; https://doi.org/10.1088/1361-6560/ac7b64.Search in Google Scholar PubMed
38. Zhang, X.; Bontozoglou, C.; Chirikhina, E.; Lane, M. E.; Xiao, P. Capacitive Imaging for Skin Characterizations and Solvent Penetration Measurements. Cosmetics 2018, 5, 52; https://doi.org/10.3390/cosmetics5030052.Search in Google Scholar
39. Bakadia, B. M.; Lamboni, L.; Ahmed, A. A. Q.; Zheng, R.; Boni, B. O. O.; Shi, Z. Antibacterial Silk sericin/poly (Vinyl Alcohol) Hydrogel with Antifungal Property for Potential Infected Large Burn Wound Healing: Systemic Evaluation. Smart Mater. Med. 2023, 4, 37–58.10.1016/j.smaim.2022.07.002Search in Google Scholar
40. Gilbert, A. IR and Raman Spectroscopies, Studies of Hydrogen Bonding and Other Physicochemical Interactions. 2017, https://doi.org/10.1016/b978-0-12-803224-4.00339-3,Search in Google Scholar
41. Ersel, M.; Uyanikgil, Y.; Karbek Akarca, F.; Ozcete, E.; Altunci, Y. A.; Karabey, F.; Cavucoglu, T.; Meral, A.; Yigitturk, G.; Oyku Cetin, E. Effects of Silk Sericin on Incision Wound Healing in a Dorsal Skin Flap Wound Healing Rat Model. Med. Sci. Monit. 2016, 22, 1064; https://doi.org/10.12659/msm.897981.Search in Google Scholar PubMed PubMed Central
42. Teramoto, H.; Kameda, T.; Tamada, Y. Preparation of Gel Film from Bombyx mori Silk Sericin and its Characterization as a Wound Dressing. Biosci. Biotechnol. Biochem. 2008, 72, 3189–3196; https://doi.org/10.1271/bbb.80375.Search in Google Scholar PubMed
43. Tao, G.; Cai, R.; Wang, Y.; Zuo, H.; He, H. Fabrication of Antibacterial Sericin Based Hydrogel as an Injectable and Mouldable Wound Dressing. Mater. Sci. Eng. C 2021, 119, 111597; https://doi.org/10.1016/j.msec.2020.111597.Search in Google Scholar PubMed
44. Thomas, A.; Mandale, V.; Wavhale, R.; Chitlange, S. In-silico Screening of Phytoconstituents on Wound Healing Targets-Approaches and Current Status. Curr. Drug Discov. Technol. 2022, 19, 26–39; https://doi.org/10.2174/1570163819666211130141442.Search in Google Scholar PubMed
45. Brahma, B.; Narzary, R.; Baruah, D. C. Acetamide for Latent Heat Storage: Thermal Stability and Metal Corrosivity with Varying Thermal Cycles. Renew. Energy 2020, 145, 1932–1940; https://doi.org/10.1016/j.renene.2019.07.109.Search in Google Scholar
46. Svetlichny, G.; Külkamp-Guerreiro, I.; Dalla Lana, D.; Bianchin, M.; Pohlmann, A.; Fuentefria, A. Assessing the Performance of Copaiba Oil and Allantoin Nanoparticles on multidrug-resistant Candida parapsilosis. J. Drug Deliv. Sci. Technol. 2017, 40, 59–65.10.1016/j.jddst.2017.05.020Search in Google Scholar
47. Stenekes, R.; Talsma, H.; Hennink, W. Formation of Dextran Hydrogels by Crystallization. Biomaterials 2001, 22, 1891–1898; https://doi.org/10.1016/s0142-9612-00-00375-6.Search in Google Scholar
48. Srinivasan, H.; Sharma, V.; Sakai, V. G.; Embs, J. P.; Mukhopadhyay, R.; Mitra, S. Transport Mechanism of Acetamide in Deep Eutectic Solvents. J. Phys. Chem. B 2020, 124, 1509–1520; https://doi.org/10.1021/acs.jpcb.9b11137.Search in Google Scholar PubMed
49. Araújo, L. U.; Grabe-Guimarães, A.; Mosqueira, V. C. F.; Carneiro, C. M.; Silva-Barcellos, N. M. Perfil Do Processo De Cicatrização Induzido Pela Alantoína. Acta Cir. Bras. 2010, 25, 460–461; https://doi.org/10.1590/s0102-86502010000500014.Search in Google Scholar PubMed
50. Grenier, J.; Duval, H.; Lv, P.; Barou, F.; Le Guilcher, C.; Aid, R.; David, B.; Letourneur, D. Interplay Between Crosslinking and Ice Nucleation Controls the Porous Structure of freeze-dried Hydrogel Scaffolds. Biomater. Adv. 2022, 139, 212973; https://doi.org/10.1016/j.bioadv.2022.212973.Search in Google Scholar PubMed
51. Fahr, A. Voigt’s Pharmaceutical Technology; John Wiley & Sons: USA, 2018.Search in Google Scholar
52. Rajab, A. A.; Al-Wattar, W. T.; Taqa, G. A. The Roles of Apigenin Cream on Wound Healing in Rabbits Model. J. Appl. Vet. Sci. 2022, 7, 1–5.Search in Google Scholar
53. Ravishankar, K.; Kiranmayi, G. V. N.; Prasad, Y. R.; Devi, L. Wound Healing Activity in Rabbits and Antimicrobial Activity of Hibiscus hirtus Ethanolic Extract. Braz. J. Pharm. Sci. 2019, 54; https://doi.org/10.1590/s2175-97902018000417075.Search in Google Scholar
54. Gelsi, P. R. F. Uso Tópico De Componentes Da Matriz Extracelular Canina Provenientes De Derme Para Cicatrização De Ferimentos; Universidade de São Paulo: Brazil, 2022.Search in Google Scholar
55. Sanka, I.; Bartkova, S.; Pata, P.; Smolander, O.-P.; Scheler, O. Investigation of Different Free Image Analysis Software for high-throughput Droplet Detection. ACS Omega 2021, 6, 22625–22634; https://doi.org/10.1021/acsomega.1c02664.Search in Google Scholar PubMed PubMed Central
56. Chavez-Esquivel, G.; Cervantes-Cuevas, H.; Ybieta-Olvera, L.; Castañeda Briones, M. T.; Acosta, D.; Cabello, J. Antimicrobial Activity of Graphite Oxide Doped with Silver Against Bacillus subtilis, Candida albicans, Escherichia coli, and Staphylococcus aureus by Agar Well Diffusion Test: Synthesis and Characterization. Mater. Sci. Eng. C 2021, 123, 111934; https://doi.org/10.1016/j.msec.2021.111934.Search in Google Scholar PubMed
57. Kolken, H.; Garcia, A. F.; Du Plessis, A.; Rans, C.; Mirzaali, M. J.; Zadpoor, A. Fatigue Performance of Auxetic meta-biomaterials. Acta Biomater. 2021, 126, 511–523; https://doi.org/10.1016/j.actbio.2021.03.015.Search in Google Scholar PubMed
58. Khalid, K. L. Modification, Characterization and Evaluation of Anti-microbial Property of Ag-TiO2 Nanoparticles Coated Traditional Leather. Bayero J. Pure Appl. Sci. 2022, 13, 53–59.Search in Google Scholar
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