Sustained Release and Therapeutic Evaluation of Simvastatin-Loaded Bioglass–Chitosan Gel Formulation for Skin Regeneration and Wound Healing Potential

Abstract

Chronic wounds pose a major clinical challenge due to a complex pathophysiological condition. It is characterized by persistent inflammation, excessive oxidative stress, and a high risk of bacterial infection, which hinders tissue repair. To address this, a multifunctional hydrogel dressing based on gallic acid conjugated chitosan (G-CHI) and integrated with simvastatin and heparin-functionalized Ag/Zn-doped bioactive glass (HBG). The incorporation of gallic acid improved the structural integrity and viscoelastic behavior of the hydrogel. The release kinetics study demonstrated controlled liberation of Ag⁺ and Zn²⁺ ions within biologically safe limits over 24 h, while simvastatin exhibited diffusion-controlled release behavior. The hydrogel also exhibited desirable adhesive properties, indicating its suitability as a wound dressing material. In vitro biofunctional assays showed enhanced antioxidant activity (~75% free radical scavenging), hemocompatibility (< 5% hemolysis), and effectiveness against both Staphylococcus aureus and Escherichia coli (> 90% efficacy in time kill assay). Further, synergistic release of simvastatin and bioglass showed enhanced proliferation of fibroblast (NIH 3T3), keratinocyte (HaCaT), and endothelial cells (SVEC), accompanied by increased collagen deposition compared to control groups. These findings suggest that the synthesized hydrogel (BSG-CHI) provides a favorable microenvironment for tissue regeneration and wound management applications.

Keywords

antibiotic / bioglass / chronic wound / enhanced angiogenesis / heparin

References

[1] P. Pankongadisak, K. Kiti, J. Yang, L. Grøndahl, and O. Suwantong, “Multifunctional Injectable Self-Healing Hydrogels Based on Quaternized Chitosan-Gallic Acid and Oxidized Pectin for Use in Wound Management,” International Journal of Biological Macromolecules 348 (2026): 150746.

[2] X. Yu, T. Yang, Z. Bei, et al., “Microenvironment-Responsive Injectable Dynamic Hydrogel for Sequential Antioxidant and Tissue Regeneration Therapy of Radiation-Induced Skin Injury,” Bioactive Materials 63 (2026): 778–794.

[3] X. Wu, H. Ye, and X. Wu, “Mechanical Properties of Hydrogel Wound Dressing in Skin Regeneration – A Meta-Analysis of In Vivo Studies,” Regenesis Repair Rehabilitation 2, no. 1 (2026): 35–45.

[4] W. Shen, G. Xie, X. Luan, et al., “Self-Regulating Mechanical Microenvironment Cellulose-Based Hydrogels as Living Scar-Free Wound Healing Materials,” International Journal of Biological Macromolecules 358 (2026): 151612.

[5] T. Lu, Q. Wang, M. Sun, et al., “Light-Driven Switchable Polyacrylamide/Chitosan-Based Hydrogel Dressings for Outdoor Wound Temperature Regulation and Enhanced Skin Regeneration,” Carbohydrate Polymers 378 (2026): 124920.

[6] X. Qi, Y. Li, Y. Xiang, et al., “Hyperthermia-Enhanced Immunoregulation Hydrogel for Oxygenation and ROS Neutralization in Diabetic Foot Ulcers,” Cell Biomaterials 1, no. 3 (2025): 100020.

[7] X. Dang, J. Tang, S. Han, X. Wang, M. Tao, and M. Zheng, “Injectable Self-Healing Biomass-Based Hydrogel Bioadhesive Integrating Skin Bioelectronics and Regenerative Wound Healing,” Advanced Functional Materials 36, no. 36 (2026): e30332.

[8] T. Jiao, Q. Lian, W. Lian, et al., “Properties of Collagen/Sodium Alginate Hydrogels for Bioprinting of Skin Models,” Journal of Bionic Engineering 20, no. 1 (2023): 105–118.

[9] Q. Bai, Q. Gao, F. Hu, et al., “Chitosan and Hyaluronic-Based Hydrogels Could Promote the Infected Wound Healing,” International Journal of Biological Macromolecules 232 (2023): 123271.

[10] H. Yamamoto and M. Amaike, “Biodegradation of Cross-Linked Chitosan Gels by a Microorganism,” Macromolecules 30, no. 13 (1997): 3936–3937.

[11] S. Cheng, H. Wang, X. Pan, et al., “Dendritic Hydrogels With Robust Inherent Antibacterial Properties for Promoting Bacteria-Infected Wound Healing,” ACS Applied Materials & Interfaces 14, no. 9 (2022): 11144–11155.

[12] Y. Xiang, P. Zhuge, X. Qi, et al., “A Cuttlefish Ink Nanoparticle-Reinforced Biopolymer Hydrogel With Robust Adhesive and Immunomodulatory Features for Treating Oral Ulcers in Diabetes,” Bioactive Materials 39 (2024): 562–581.

[13] Y. Liang, J. He, M. Li, et al., “Polymer Applied in Hydrogel Wound Dressing for Wound Healing: Modification/Functionalization Method and Design Strategies,” ACS Biomaterials Science & Engineering 11, no. 4 (2025): 1921–1944.

[14] H. Sang Yoo, J. Eun Lee, H. Chung, I. Chan Kwon, and S. Young Jeong, “Self-Assembled Nanoparticles Containing Hydrophobically Modified Glycol Chitosan for Gene Delivery,” Journal of Controlled Release 103, no. 1 (2005): 235–243.

[15] L. Li, L. Ren, Q. Zhao, et al., “Gallic Acid-Grafted Chitosan Photothermal Hydrogels Functionalized With Mineralized Copper-Sericin Nanoparticles for MRSA-Infected Wound Management,” Carbohydrate Polymers 352 (2025): 123179.

[16] R. Guan, X. Zhang, H. Gao, et al., “Fungal-Derived Chitin and Chitosan: Sustainable Biomaterials for Advanced Wound Management,” ACS Biomaterials Science & Engineering 12 (2026): 2851–2877.

[17] P. Pankongadisak, K. Kiti, J. Yang, L. Grøndahl, and O. Suwantong, “Multifunctional Injectable Self-Healing Hydrogels Based on Quaternized Chitosan-Gallic Acid and Oxidized Pectin for Use in Wound Management,” International Journal of Biological Macromolecules 348 (2026): 150746.

[18] M. Gümüşderelioğlu and S. Aday, “Heparin-Functionalized Chitosan Scaffolds for Bone Tissue Engineering,” Carbohydrate Research 346, no. 5 (2011): 606–613.

[19] A. Cifuentes, V. Gómez-Gil, M. A. Ortega, et al., “Chitosan Hydrogels Functionalized With Either Unfractionated Heparin or Bemiparin Improve Diabetic Wound Healing,” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 129 (2020): 110498.

[20] J. Wu, J. Li, S. Mao, et al., “Heparin-Functionalized Bioactive Glass to Harvest Endogenous Growth Factors for Pulp Regeneration,” ACS Applied Materials & Interfaces 16, no. 24 (2024): 30715–30727.

[21] P. Naruphontjirakul, P. Kanchanadumkerng, and P. Ruenraroengsak, “Multifunctional Zn and Ag Co-Doped Bioactive Glass Nanoparticles for Bone Therapeutic and Regeneration,” Scientific Reports 13, no. 1 (2023): 6775.

[22] J. Zhao, J. Du, Y. Zheng, et al., “Zinc Ions Coordinated Carboxymethyl Chitosan Hydrogel Doped With Ellagic Acid for Accelerative Diabetic Wound Healing,” International Journal of Biological Macromolecules 327 (2025): 147372.

[23] S. Pourshahrestani, I. Unalan, E. Zeimaran, et al., “Tannic Acid-Loaded Zinc- and Copper-Doped Mesoporous Bioactive Glass Nanoparticles: Potential Antioxidant Nanocarriers for Wound Healing,” Bioactive Materials 54 (2025): 71–85.

[24] D. Banerjee, S. Vishwakarma, M. Nayak, et al., “Fabrication of Zinc-Tryptophan Nanoassemblies for Antibacterial and Wound Healing Applications,” ACS Applied Nano Materials 8, no. 8 (2025): 4263–4278.

[25] N. S. Elbialy, S. F. Aboushoushah, N. Mohamed, and S. F. Abaza, “Chitosan-MXene-Silver Nanocomposite Film With Improved Physicochemical and Biological Functionalities to Potentiate Wound Healing Process,” Journal of Drug Delivery Science and Technology 111 (2025): 107133.

[26] Z. Chegini, M. Azizi, M. Safaiee, et al., “Wound Healing Properties and Antibiofilm Activity of Hydrogel Matrix Containing Nitric Oxide, Silver Nanoparticles, and Ciprofloxacin Against Pseudomonas aeruginosa Burn Wound Infection,” Scientific Reports 15, no. 1 (2025): 26508.

[27] Z. Hadzhieva, E. Feyles, M. A. Akhtar, et al., “Silver Nitrate and Bioactive Glass Containing Chitosan Coatings: Comparison of Antimicrobial and Antiviral Properties,” ACS Applied Materials & Interfaces 18 (2026): 13290–13304.

[28] N. Manjubaashini, P. Bargavi, N. G. Thomas, N. Krishnan, and S. Balakumar, “Chitosan Bioactive Glass Scaffolds for In Vivo Subcutaneous Implantation, Toxicity Assessment, and Diabetic Wound Healing Upon Animal Model,” International Journal of Biological Macromolecules 256 (2024): 128291.

[29] J. Zhu, G. Jiang, G. Song, et al., “Incorporation of ZnO/Bioactive Glass Nanoparticles Into Alginate/Chitosan Composite Hydrogels for Wound Closure,” ACS Applied Bio Materials 2, no. 11 (2019): 5042–5052.

[30] M. Zhang, Z. Fan, J. Zhang, et al., “Multifunctional Chitosan/Alginate Hydrogel Incorporated With Bioactive Glass Nanocomposites Enabling Photothermal and Nitric Oxide Release Activities for Bacteria-Infected Wound Healing,” International Journal of Biological Macromolecules 232 (2023): 123445.

[31] T. Mehrabi, A. S. Mesgar, and Z. Mohammadi, “Bioactive Glasses: A Promising Therapeutic Ion Release Strategy for Enhancing Wound Healing,” ACS Biomaterials Science & Engineering 6, no. 10 (2020): 5399–5430.

[32] R. Sergi, D. Bellucci, R. Salvatori, and V. Cannillo, “Chitosan-Based Bioactive Glass Gauze: Microstructural Properties, In Vitro Bioactivity, and Biological Tests,” Materials 13, no. 12 (2020): 2819.

[33] Y. Kureishi, Z. Luo, I. Shiojima, et al., “The HMG-CoA Reductase Inhibitor Simvastatin Activates the Protein Kinase Akt and Promotes Angiogenesis in Normocholesterolemic Animals,” Nature Medicine 6, no. 9 (2000): 1004–1010.

[34] M. Yu, W. Liu, J. Li, et al., “Exosomes Derived From Atorvastatin-Pretreated Msc Accelerate Diabetic Wound Repair by Enhancing Angiogenesis via AKT/eNOS Pathway,” Stem Cell Research & Therapy 11, no. 1 (2020): 350.

[35] H. Wu, D. Lu, H. Jiang, et al., “Simvastatin-Mediated Upregulation of VEGF and BDNF, Activation of the PI3K/Akt Pathway, and Increase of Neurogenesis Are Associated With Therapeutic Improvement After Traumatic Brain Injury,” Journal of Neurotrauma 25, no. 2 (2008): 130–139.

[36] O. Neuhaus, S. Strasser-Fuchs, F. Fazekas, et al., “Statins as Immunomodulators,” Neurology 59, no. 7 (2002): 990–997.

[37] Y. Wang, Y. Wu, L. Long, et al., “Inflammation-Responsive Drug-Loaded Hydrogels With Sequential Hemostasis, Antibacterial, and Anti-Inflammatory Behavior for Chronically Infected Diabetic Wound Treatment,” ACS Applied Materials & Interfaces 13, no. 28 (2021): 33584–33599.

[38] G. Chen, Z. Fan, M. Jia, et al., “Simvastatin Administration Prohibits Staphylococcus aureus Anti-ROS Adaptation In Vivo and Alleviates Bone Infections,” ACS Infectious Diseases 11, no. 9 (2025): 2466–2475.

[39] H. Amoozegar, A. Ghaffari, M. Keramati, et al., “A Novel Formulation of Simvastatin Nanoemulsion Gel for Infected Wound Therapy: In Vitro and In Vivo Assessment,” Journal of Drug Delivery Science and Technology 72 (2022): 103369.

[40] M. O. Gallinari, E. A. F. Bordini, E. M. A. Furquim, et al., “Chitosan–Calcium–Simvastatin Scaffold for Bone Repair Under Inflammation,” International Journal of Biological Macromolecules 350 (2026): 151039.

[41] M. Kheirallah and H. Almeshaly, “Simvastatin, Dosage and Delivery System for Supporting Bone Regeneration, an Update Review,” Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28, no. 3 (2016): 205–209.

[42] A. M. A. Coco, T. Martins, B. R. Barrioni, and M. M. Pereira, “Effect of Incorporating Silver on the Structure and Ion Release Profile of Binary SiO₂–Ag₂O Mesoporous Bioactive Glass Submicron Spherical Particles,” Ceramics International 47, no. 18 (2021): 26100–26108.

[43] K. Venkatesan, K. Sreeramachandra Karthik, A. M. Mathew, P. V. Sreya, S. P. Mallick, and D. K. Pattanayak, “Facile Synthesis of Silver Loaded Bioactive Glass Ceramic and Reinforced Composite Scaffold Using Acrylic Polymer for Bone Tissue Engineering Applications,” Advanced Powder Technology 36, no. 6 (2025): 104892.

[44] R. Borges, J. S. S. Oliveira, A. P. Queiroz, et al., “On the Structure of Ag-Containing Sol-Gel Bioactive Glasses: A Surface Crystal Growth of Metallic Silver Removes Its Network Modifier Role in the Glass Structure,” Open Ceramics 16 (2023): 100449.

[45] S. Kothandam, V. Selvatharani, N. Vijayakumar, et al., “Zinc Doped Akermanite: A Promising Biomaterial for Orthopedic Application With Enhanced Bioactivity, Mechanical Strength, and Bacterial Study,” ACS Omega 10, no. 2 (2025): 1911–1926.

[46] A. M. Ferraria, A. P. Carapeto, and A. M. Botelho do Rego, “X-Ray Photoelectron Spectroscopy: Silver Salts Revisited,” Vacuum 86, no. 12 (2012): 1988–1991.

[47] Y. Mei, J. Yang, R. Zhang, H. Li, and Y. Guo, “Enhanced Antibacterial Activity, Dye Rejection and Anti-Fouling Performance of ZrO₂-SiO₂ Composite Ceramic Membranes Embedded by Silver Nanoparticles,” Journal of Sol-Gel Science and Technology 114, no. 2 (2025): 413–429.

[48] W. Pasanphan and S. Chirachanchai, “Conjugation of Gallic Acid Onto Chitosan: An Approach for Green and Water-Based Antioxidant,” Carbohydrate Polymers 72, no. 1 (2008): 169–177.

[49] I. F. Amaral, P. L. Granja, and M. A. Barbosa, “Chemical Modification of Chitosan by Phosphorylation: An XPS, FT-IR and SEM Study,” Journal of Biomaterials Science, Polymer Edition 16, no. 12 (2005): 1575–1593.

[50] X. Xie, L. Wu, J. Huang, J. He, and F. Liu, “Preparation of Multifunctional Chitosan Derivative Containing 10-Undecenoyl and Galloyl Groups and Its Application in Styrene-Butadiene Rubber/Silica Composites,” Carbohydrate Polymer Technologies and Applications 7 (2024): 100468.

[51] B. Jurado-López, R. S. Vieira, R. B. Rabelo, M. M. Beppu, J. Casado, and E. Rodríguez-Castellón, “Formation of Complexes Between Functionalized Chitosan Membranes and Copper: A Study by Angle Resolved XPS,” Materials Chemistry and Physics 185 (2017): 152–161.

[52] G. Lawrie, I. Keen, B. Drew, et al., “Interactions Between Alginate and Chitosan Biopolymers Characterized Using FTIR and XPS,” Biomacromolecules 8, no. 8 (2007): 2533–2541.

[53] S. Tyeb, N. Kumar, A. Kumar, and V. Verma, “Flexible Agar-Sericin Hydrogel Film Dressing for Chronic Wounds,” Carbohydrate Polymers 200 (2018): 572–582.

[54] Y. Zhang, L. Tao, S. Li, and Y. Wei, “Synthesis of Multiresponsive and Dynamic Chitosan-Based Hydrogels for Controlled Release of Bioactive Molecules,” Biomacromolecules 12, no. 8 (2011): 2894–2901.

[55] R. R. Vildanova, N. N. Sigaeva, O. S. Kukovinets, and S. V. Kolesov, “Preparation and Rheological Properties of Hydrogels Based on N-Succinyl Chitosan and Hyaluronic Acid Dialdehyde,” Polymer Testing 96 (2021): 107120.

[56] Y. Qian, Y. Zheng, J. Jin, et al., “Immunoregulation in Diabetic Wound Repair With a Photoenhanced Glycyrrhizic Acid Hydrogel Scaffold,” Advanced Materials 34, no. 29 (2022): 2200521.

[57] J. Siepmann and F. Siepmann, “Mathematical Modeling of Drug Delivery,” International Journal of Pharmaceutics 364, no. 2 (2008): 328–343.

[58] J. Siepmann and N. A. Peppas, “Modeling of Drug Release From Delivery Systems Based on Hydroxypropyl Methylcellulose (HPMC),” Advanced Drug Delivery Reviews 64 (2012): 163–174.

[59] H. Yang, Y. Chen, Y. Rong, et al., “Multifunctional Hydrogel Targeting Senescence to Accelerate Diabetic Wound Healing Through Promoting Angiogenesis,” Journal of Nanobiotechnology 23, no. 1 (2025): 177.

[60] Y. Zhang, J. Zhang, T. Jiang, and S. Wang, “Inclusion of the Poorly Water-Soluble Drug Simvastatin in Mesocellular Foam Nanoparticles: Drug Loading and Release Properties,” International Journal of Pharmaceutics 410, no. 1–2 (2011): 118–124.

[61] P. Costa and J. M. Sousa Lobo, “Modeling and Comparison of Dissolution Profiles,” European Journal of Pharmaceutical Sciences 13, no. 2 (2001): 123–133.

[62] B. Dinç, “Comprehensive Toxicity Assessment of Silver Nanoparticles on Bacteria, Human Vein Endothelial Cells, and Caenorhabditis elegans,” Results in Chemistry 14 (2025): 102092.

[63] A. Rezagholizade-shirvan, M. Soltani, S. Shokri, R. Radfar, M. Arab, and E. Shamloo, “Bioactive Compound Encapsulation: Characteristics, Applications in Food Systems, and Implications for Human Health,” Food Chemistry: X 24 (2024): 101953.

[64] Q. Li, S. Li, Z. Li, et al., “Double Network Crosslinked Antibacterial and Antioxidant Cellulose-Based Hydrogel Capable of Healing Wound for Protecting Open Abdomen,” International Journal of Biological Macromolecules 353 (2026): 151161.

[65] S. Kumari, A. Chauhan, P. Dalal, et al., “Enhancing Antibacterial, Antifungal, and Anticancer Potential of Zinc Oxide Nanorods Using Trillium govanianum Extract,” Kuwait Journal of Science 53, no. 3 (2026): 100575.

[66] S. Sharma, S. S. Kirwale, Y. T. Katakia, S. Majumder, and A. Roy, “Development and Evaluation of a Simvastatin-Loaded Biopolymeric Scaffold for Improved Angiogenesis and Healing of Diabetic Wounds,” Journal of Drug Delivery Science and Technology 87 (2023): 104832.

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