Study on chitosan/gelatin hydrogels containing ceria nanoparticles for promoting the healing of diabetic wound
Yonghui Wu
School of Materials Science and Engineering, Zhengzhou University, Zhengzhou, China
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorQianqian Wu
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorXialian Fan
Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Search for more papers by this authorLu Yang
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorLing Zou
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorQingshan Liu
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorGuangyou Shi
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorCorresponding Author
Xiaochao Yang
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Correspondence
Keyong Tang, School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450004, China.
Email: [email protected]
Xiaochao Yang, School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing 400038, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Keyong Tang
School of Materials Science and Engineering, Zhengzhou University, Zhengzhou, China
Correspondence
Keyong Tang, School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450004, China.
Email: [email protected]
Xiaochao Yang, School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing 400038, China.
Email: [email protected]
Search for more papers by this authorYonghui Wu
School of Materials Science and Engineering, Zhengzhou University, Zhengzhou, China
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorQianqian Wu
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorXialian Fan
Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Search for more papers by this authorLu Yang
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorLing Zou
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorQingshan Liu
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorGuangyou Shi
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Search for more papers by this authorCorresponding Author
Xiaochao Yang
School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing, China
Correspondence
Keyong Tang, School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450004, China.
Email: [email protected]
Xiaochao Yang, School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing 400038, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Keyong Tang
School of Materials Science and Engineering, Zhengzhou University, Zhengzhou, China
Correspondence
Keyong Tang, School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450004, China.
Email: [email protected]
Xiaochao Yang, School of Biomedical Engineering and Medical Imaging, Army Medical University, Chongqing 400038, China.
Email: [email protected]
Search for more papers by this authorYonghui Wu and Qianqian Wu contributed equally to this study.
Abstract
Chronic inflammation at diabetic wound sites results in the uncontrolled accumulation of pro-inflammatory factors and reactive oxygen species (ROS), which impedes cell proliferation and delays wound healing. To promote the healing of diabetic wounds, chitosan/gelatin hydrogels containing ceria nanoparticles (CNPs) of various sizes were created in the current study. CNPs' efficacy in removing , •OH, and H2O2 was demonstrated, and the scavenging ability of CNPs of varying sizes was compared. The in vitro experiments demonstrated that hydrogels containing CNPs could effectively protect cells from ROS-induced damage and facilitate mouse fibroblast migration. Furthermore, during the treatment of diabetic wounds in vivo, hydrogels containing CNPs exhibited anti-inflammatory activity and could reduce the expression of the pro-inflammatory factors TNF-α (above 30%), IL-6 (above 90%), and IL-1β (above 80%), and effectively promote wound closure (above 80%) by inducing re-epithelialization, collagen deposition, and angiogenesis. In addition, the biological properties and therapeutic effects of hydrogels containing CNPs of various sizes were compared and discussed. The finding revealed that hydrogels with 4 nm CNPs exhibited more significant biological properties and had implications for diabetic wound treatment.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| jbma37701-sup-0001-Supinfo.docxWord 2007 document , 1.7 MB | Data S1: Supporting Information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Matoori S, Veves A, Mooney D. Advanced bandages for diabetic wound healing. Sci Transl Med. 2021; 13(585):eabe4839.
- 2Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017; 376(24): 2367-2375.
- 3Okur M, Bülbül E, Mutlu G, et al. An updated review for the diabetic wound healing systems. Curr Drug Targets. 2022; 23(4): 393-419.
- 4Bonham PA, Brunette G, Crestodina L, et al. 2021 Guideline for management of patients with lower-extremity wounds due to diabetes mellitus and/or neuropathic disease: an executive summary. J Wound Ostomy Cont. 2022; 49(3): 267-285.
- 5Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science. 2017; 356(6342): 1026-1030.
- 6Cheng F, Wang S, Zheng H, et al. Ceria nanoenzyme-based hydrogel with antiglycative and antioxidative performance for infected diabetic wound healing. Small Methods. 2022; 6(11):e2200949.
- 7Deng L, Du C, Song P, et al. The role of oxidative stress and antioxidants in diabetic wound healing. Oxid Med Cell Longev. 2021; 2021:8852759.
- 8Catrina SB, Zheng X. Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers. Diabetes/Metab Res Rev. 2016; 32(S1): 179-185.
- 9Desmet CM, Preat V, Gallez B. Nanomedicines and gene therapy for the delivery of growth factors to improve perfusion and oxygenation in wound healing. Adv Drug Del Rev. 2018; 129: 262-284.
- 10Bai Q, Han K, Dong K, et al. Potential applications of nanomaterials and technology for diabetic wound healing. Int J Nanomed. 2020; 15: 9717-9743.
- 11Ezhilarasu H, Vishalli D, Dheen ST, Bay BH, Srinivasan DK. Nanoparticle-based therapeutic approach for diabetic wound healing. Nanomaterials. 2020; 10(6): 1234.
- 12Wu H, Li F, Shao W, Gao J, Ling D. Promoting angiogenesis in oxidative diabetic wound microenvironment using a nanozyme-reinforced self-protecting hydrogel. ACS Cent Sci. 2019; 5(3): 477-485.
- 13Kim HS, Sun X, Lee JH, Kim HW, Fu X, Leong KW. Advanced drug delivery systems and artificial skin grafts for skin wound healing. Adv Drug Deliv Rev. 2019; 146: 209-239.
- 14Farahani M, Shafiee A. Wound healing: from passive to smart dressings. Adv Healthc Mater. 2021; 10(16):2100477.
- 15Martins Green M, Saeed S. Role of oxidants and antioxidants in diabetic wound healing. In: D Bagchi, A Das, S Roy, eds. Wound Healing, Tissue Repair, and Regeneration in Diabetes. California; 2020: 13-38.
10.1016/B978-0-12-816413-6.00002-2 Google Scholar
- 16Liu J, Chen Z, Wang J, et al. Encapsulation of curcumin nanoparticles with MMP9-responsive and thermos-sensitive hydrogel improves diabetic wound healing. ACS Appl Mater Interfaces. 2018; 10(19): 16315-16326.
- 17Wang Y, Chen L, Ren DY, et al. Mussel-inspired collagen-hyaluronic acid composite scaffold with excellent antioxidant properties and sustained release of a growth factor for enhancing diabetic wound healing. Mater Today Bio. 2022; 15:100320.
- 18Xu Z, Liu G, Huang J, Wu J. Novel glucose-responsive antioxidant hybrid hydrogel for enhanced diabetic wound repair. ACS Appl Mater Interfaces. 2022; 14(6): 7680-7689.
- 19Xu Z, Liu G, Liu P, et al. Hyaluronic acid-based glucose-responsive antioxidant hydrogel platform for enhanced diabetic wound repair. Acta Biomater. 2022; 147: 147-157.
- 20Wang T, Li Y, Cornel EJ, Li C, du J. Combined antioxidant-antibiotic treatment for effectively healing infected diabetic wounds based on polymer vesicles. ACS Nano. 2021; 15(5): 9027-9038.
- 21Vijayakumar V, Samal SK, Mohanty S, Nayak SK. Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int J Biol Macromol. 2019; 122: 137-148.
- 22Ma T, Zhai X, Huang Y, et al. A smart nanoplatform with photothermal antibacterial capability and antioxidant activity for chronic wound healing. Adv Healthc Mater. 2021; 10(13):2100033.
- 23Lee Y, Hong Y, Wu T. Novel silver and nanoparticle-encapsulated growth factor co-loaded chitosan composite hydrogel with sustained antimicrobility and promoted biological properties for diabetic wound healing. Mater Sci Eng C. 2021; 118:111385.
- 24Yin M, Wu J, Deng M, et al. Multifunctional magnesium organic framework-based microneedle patch for accelerating diabetic wound healing. ACS Nano. 2021; 15(11): 17842-17853.
- 25Li Y, Fu R, Duan Z, Zhu C, Fan D. Artificial nonenzymatic antioxidant MXene nanosheet-anchored injectable hydrogel as a mild photothermal-controlled oxygen release platform for diabetic wound healing. ACS Nano. 2022; 16(5): 7486-7502.
- 26Yanlan L, Jinjun S. Antioxidative nanomaterials and biomedical applications. Nano Today. 2019; 27: 146-177.
- 27Wu Y, Ta HT. Different approaches to synthesising cerium oxide nanoparticles and their corresponding physical characteristics, and ROS scavenging and anti-inflammatory capabilities. J Mater Chem B. 2021; 9(36): 7291-7301.
- 28Kwon HJ, Cha MY, Kim D, et al. Mitochondria-targeting ceria nanoparticles as antioxidants for Alzheimer's disease. ACS Nano. 2016; 10(2): 2860-2870.
- 29Yan R, Sun S, Yang J, et al. Nanozyme-based bandage with single-atom catalysis for brain trauma. ACS Nano. 2019; 13(10): 11552-11560.
- 30Kang DW, Kim CK, Jeong HG, et al. Biocompatible custom ceria nanoparticles against reactive oxygen species resolve acute inflammatory reaction after intracerebral hemorrhage. Nano Res. 2017; 10(8): 2743-2760.
- 31Zgheib C, Hilton SA, Dewberry LC, et al. Use of cerium oxide nanoparticles conjugated with microRNA-146a to correct the diabetic wound healing impairment. J Am Coll Surg. 2019; 228(1): 107-115.
- 32Augustine R, Hasan A, Patan NK, et al. Cerium oxide nanoparticle incorporated electrospun poly(3-hydroxybutyrate-co-3-hydroxyvalerate) membranes for diabetic wound healing applications. ACS Biomater Sci Eng. 2020; 6(1): 58-70.
- 33Zhang DY, Liu H, Li C, et al. Ceria nanozymes with preferential renal uptake for acute kidney injury alleviation. ACS Appl Mater Interfaces. 2020; 12(51): 56830-56838.
- 34Wu H, Li F, Wang S, et al. Ceria nanocrystals decorated mesoporous silica nanoparticle based ROS-scavenging tissue adhesive for highly efficient regenerative wound healing. Biomaterials. 2018; 151: 66-77.
- 35Ma X, Cheng Y, Jian H, et al. Hollow, rough, and nitric oxide-releasing cerium oxide nanoparticles for promoting multiple stages of wound healing. Adv Healthc Mater. 2019; 8(16):1900256.
- 36Yu X, Fu X, Yang J, et al. Glucose/ROS cascade-responsive ceria nanozymes for diabetic wound healing. Mater Today Bio. 2022; 15:100308.
- 37Huang X, He D, Pan Z, Luo G, Deng J. Reactive oxygen species scavenging nanomaterials for resolving inflammation. Mater Today Bio. 2021; 11:100124.
- 38Khurana A, Tekula S, Godugu C. Nanoceria suppresses multiple low doses of streptozotocin-induced Type 1 diabetes by inhibition of Nrf2/NF-κB pathway and reduction of apoptosis. Nanomedicine. 2018; 13(15): 1905-1922.
- 39Das S, Singh S, Dowding JM, et al. The induction of angiogenesis by cerium oxide nanoparticles through the modulation of oxygen in intracellular environments. Biomaterials. 2012; 33(31): 7746-7755.
- 40Chigurupati S, Mughal MR, Okun E, et al. Effects of cerium oxide nanoparticles on the growth of keratinocytes, fibroblasts and vascular endothelial cells in cutaneous wound healing. Biomaterials. 2013; 34(9): 2194-2201.
- 41Augustine R, Zahid AA, Hasan A, Dalvi YB, Jacob J. Cerium oxide nanoparticle-loaded gelatin methacryloyl hydrogel wound-healing patch with free radical scavenging activity. ACS Biomater Sci Eng. 2021; 7(1): 279-290.
- 42Singh R, Shitiz K, Singh A. Chitin and chitosan: biopolymers for wound management. Int Wound J. 2017; 14(6): 1276-1289.
- 43Park JU, Song EH, Jeong SH, et al. Chitosan-based dressing materials for problematic wound management. In: HJ Chun, K Park, C-H Kim, G Khang, eds. Novel Biomaterials for Regenerative Medicine. Springer; 2018: 527-537.
10.1007/978-981-13-0947-2_28 Google Scholar
- 44Matica MA, Aachmann FL, Tondervik A, et al. Chitosan as a wound dressing starting material: antimicrobial properties and mode of action. Int J Mol Sci. 2019; 20(23): 5889.
- 45Yoon D, Lee Y, Ryu H, et al. Cell recruiting chemokine-loaded sprayable gelatin hydrogel dressings for diabetic wound healing. Acta Biomater. 2016; 38: 59-68.
- 46Li F, Zou L, He J, et al. On the correlation between structure and catalytic activity of mesoporous ceria nanoparticles. J Catal. 2021; 402: 300-309.
- 47Li F, Yang L, Zou L, et al. Decreasing crystallinity is beneficial to the superoxide dismutase-like activity of ceria nanoparticles. ChemNanoMat. 2022; 8(3):e202100466.
- 48Ahmed EM, Aggor FS. Swelling kinetic study and characterization of crosslinked hydrogels containing silver nanoparticles. J Appl Polym Sci. 2010; 117: 2168-2174.
- 49Pezeshki Modaress M, Zandi M, Rajabi S. Tailoring the gelatin/chitosan electrospun scaffold for application in skin tissue engineering: an in vitro study. Prog Biomater. 2018; 7(3): 207-218.
- 50Mesgar AS, Mohammadi Z, Setareh K. Improvement of mechanical properties and in vitro bioactivity of freeze dried gelatin chitosan scaffolds by functionalized carbon nanotubes. Int J Polym Mater Polym Biomater. 2018; 67(5): 267-276.
- 51Huang J, Fu J, Liu B, Wang R, You T. A synthetic curcuminoid analog, (2E,6E)-2,6-bis (2-(trifluoromethyl) benzylidene) cyclohexanone, ameliorates impaired wound healing in streptozotocin-induced diabetic mice by increasing miR-146a. Molecules. 2020; 25(4): 920.
- 52Vinothkumar G, Arunkumar P, Mahesh A, Dhayalan A, Suresh Babu K. Size- and defect-controlled anti-oxidant enzyme mimetic and radical scavenging properties of cerium oxide nanoparticles. New J Chem. 2018; 42(23): 18810-18823.
- 53Baldim V, Bedioui F, Mignet N, Margaill I, Berret JF. The enzyme-like catalytic activity of cerium oxide nanoparticles and its dependency on Ce3+ surface area concentration. Nanoscale. 2018; 10(15): 6971-6980.
- 54Herget K, Hubach P, Pusch S, et al. Haloperoxidase mimicry by CeO2-x nanorods combats biofouling. Adv Mater. 2017; 29(4):1603823.
- 55Wu Y, Yang L, Wu Q, et al. Regulation of the oxidase mimetic activity of ceria nanoparticles by buffer composition. Chem A Eur J. 2023; 29:202204071.
- 56Yu Y, Xu S, Li S, Pan H. Genipin-cross-linked hydrogels based on biomaterials for drug delivery: a review. Biomater Sci. 2021; 9(5): 1583-1597.
- 57Alavarse AC, Frachini ECG, Da Silva R, et al. Crosslinkers for polysaccharides and proteins: synthesis conditions, mechanisms, and crosslinking efficiency, a review. Int J Biol Macromol. 2022; 202: 558-596.
- 58Yan LP, Wang YJ, Ren L, et al. Genipin-cross-linked collagen/chitosan biomimetic scaffolds for articular cartilage tissue engineering applications. J Biomed Mater Res A. 2010; 95(2): 465-475.
- 59Cui L, Jia J, Guo Y. Preparation and characterization of IPN hydrogels composed of chitosan and gelatin cross-linked by genipin. Carbohydr Polym. 2014; 99(2): 31-38.
- 60Simoni RC, Lemes GF, Fialho S, et al. Effect of drying method on mechanical, thermal and water absorption properties of enzymatically crosslinked gelatin hydrogels. An Acad Bras Cienc. 2017; 89: 745-755.
- 61Felinto MCFC, Parra DF, Da Silva CC, et al. The swelling behavior of chitosan hydrogels membranes obtained by UV- and γ-radiation. Nucl Instrum Meth B. 2007; 265(1): 418-424.
- 62Zhao SP, Li LY, Cao MJ, Xu WL. pH- and thermo-sensitive semi-IPN hydrogels composed of chitosan, N-isopropylacrylamide, and poly(ethylene glycol)-co-poly(ε-caprolactone) macromer for drug delivery. Polym Bull. 2010; 66(8): 1075-1087.
10.1007/s00289-010-0390-y Google Scholar
- 63Sarem M, Moztarzadeh F, Mozafari M, Shastri VP. Optimization strategies on the structural modeling of gelatin/chitosan scaffolds to mimic human meniscus tissue. Mat Sci Eng C-Mater. 2013; 33(8): 4777-4785.
- 64Huang X, Li LD, Lyu GM, et al. Chitosan-coated cerium oxide nanocubes accelerate cutaneous wound healing by curtailing persistent inflammation. Inorg Chem Front. 2018; 5(2): 386-393.
- 65Wang Y, Li C, Wan Y, et al. Quercetin-loaded ceria nanocomposite potentiate dual-directional immunoregulation via macrophage polarization against periodontal inflammation. Small. 2021; 17(41):e2101505.
- 66Shao Z, Yin T, Jiang J, He Y, Xiang T, Zhou S. Wound microenvironment self-adaptive hydrogel with efficient angiogenesis for promoting diabetic wound healing. Bioact Mater. 2023; 20: 561-573.
- 67Saifi MA, Seal S, Godugu C. Nanoceria, the versatile nanoparticles: promising biomedical applications. J Control Release. 2021; 338: 164-189.
- 68Huang Y, Ren J, Qu X. Nanozymes: classification, catalytic mechanisms, activity regulation, and applications. Chem Rev. 2019; 119(6): 4357-4412.
- 69Soo LS, Wensi S, Minjung C, et al. Antioxidant properties of cerium oxide nanocrystals as a function of nanocrystal diameter and surface coating. ACS Nano. 2013; 7(11): 9693-9703.
Citing Literature
