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A novel hydrogel with glucose-responsive hyperglycemia regulation and antioxidant activity for enhanced diabetic wound repair

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Abstract

Enhanced diabetic wound repair remained a global challenge. Herein, we reported a novel hydrogel with glucose-responsive hyperglycemia regulation and antioxidant activity for enhanced diabetic wound repair. In this study, gallic acid (GA) with strong antioxidant activity was grafted onto chitosan (CS) chains by one-step synthesis, and then incorporated into poly (ethylene glycol) diacrylate (PEG-DA) hydrogel matrix to obtain a novel antioxidant hybrid hydrogel (PEG-DA/CS-GA). Meanwhile, polyethyleneimine (PEI) was modified with a unique glucose-sensitive phenylboronic acid (PBA) molecule to load insulin (PEI-PBA/insulin nano-particles, PEI-PBA/insulin NPs), which could be immobilized in the PEG-DA/CS-GA hybrid hydrogel by the formation of dynamic borate bond between the phenylboronic acid groups on the PEI-PBA and the polyphenol groups on the CS-GA. The results indicated that the PEG-DA/PEI-PBA/insulin/CS-GA (PPIC) hydrogel platform not only had remarkable biocompatibility, but also displayed extraordinary antioxidant properties (DPPH scavenging rate > 95.0%), and effectively protected cells from oxidative damage (decreased MDA levels, increased Superoxide dismutase (SOD) levels and stable GSH/GSSG levels). Meanwhile, the PPIC hydrogel also exhibited unique glucose-responsive insulin release characteristics, and effectively regulated the blood glucose level. The in vitro and in vivo results demonstrated that our PPIC hydrogel could promoted angiogenesis (increased VEGF and CD 31 expression), reshaped the inflammatory microenvironment (decreased IL-6 and increased IL-10 level), and achieved wound closure within 20 days. All these results strongly indicated that the PPIC hydrogel represented a tough and efficient platform for diabetic wound treatment.

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References

  1. Veith, A. P.; Henderson, K.; Spencer, A.; Sligar, A. D.; Baker, A. B. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv. Drug Deliv. Rev. 2019, 146, 97–125.

    Article  CAS  Google Scholar 

  2. Qiao, Y.; Ping, Y.; Zhang, H. B.; Zhou, B.; Liu, F. Y.; Yu, Y. H.; Xie, T. T.; Li, W. L.; Zhong, D. N.; Zhang, Y. Z. et al. Laser-activatable CuS nanodots to treat multidrug-resistant bacteria and release copper ion to accelerate healing of infected chronic nonhealing wounds. ACS Appl. Mater. Interfaces 2019, 11, 3809–3822.

    Article  CAS  Google Scholar 

  3. Santarella, F.; Sridharan, R.; Marinkovic, M.; Do Amaral, R. J. F. C.; Cavanagh, B.; Smith, A.; Kashpur, O.; Gerami-Naini, B.; Garlick, J. A.; O’Brien, F. J. et al. Scaffolds functionalized with matrix from induced pluripotent stem cell fibroblasts for diabetic wound healing. Adv. Healthc. Mater. 2020, 9, 2000307.

    Article  CAS  Google Scholar 

  4. Kim, H. S.; Sun, X. Y.; Lee, J. H.; Kim, H. W.; Fu, X. B.; Leong, K. W. Advanced drug delivery systems and artificial skin grafts for skin wound healing. Adv. Drug Deliv. Rev. 2019, 146, 209–239.

    Article  CAS  Google Scholar 

  5. Chen, Y. S.; Li, Y.; Yang, X. X.; Cao, Z. J.; Nie, H. L.; Bian, Y. G.; Yang, G. Glucose-triggered in situ forming keratin hydrogel for the treatment of diabetic wounds. Acta Biomater. 2021, 125, 208–218.

    Article  CAS  Google Scholar 

  6. Zhang, S. H.; Hou, J. Y.; Yuan, Q. J.; Xin, P. K.; Cheng, H. T.; Gu, Z. P.; Wu, J. Arginine derivatives assist dopamine-hyaluronic acid hybrid hydrogels to have enhanced antioxidant activity for wound healing. Chem. Eng. J. 2020, 392, 123775.

    Article  CAS  Google Scholar 

  7. Zhang, X. X.; Chen, G. P.; Liu, Y. X.; Sun, L. Y.; Sun, L. Y.; Zhao, Y. J. Black phosphorus-loaded separable microneedles as responsive oxygen delivery carriers for wound healing. ACS Nano 2020, 14, 5901–5908.

    Article  CAS  Google Scholar 

  8. Huang, W.; Jiao, J. Y.; Liu, J.; Huang, M.; Hu, Y. Y.; Ran, W. Z.; Yan, L.; Xiong, Y.; Li, M.; Quan, Z. Y. et al. MFG-E8 accelerates wound healing in diabetes by regulating “NLRP3 inflammasomeneutrophil extracellular traps” axis. Cell Death Discov. 2020, 6, 84.

    Article  CAS  Google Scholar 

  9. Liu, T. F.; Xiao, B. W.; Xiang, F.; Tan, J. L.; Chen, Z.; Zhang, X. R.; Wu, C. Z.; Mao, Z. W.; Luo, G. X.; Chen, X. Y. et al. Ultrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases. Nat. Commun. 2020, 11, 2788.

    Article  CAS  Google Scholar 

  10. Vijayakumar, V.; Samal, S. K.; Mohanty, S.; Nayak, S. K. Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int. J. Biol. Macromol. 2019, 122, 137–148.

    Article  CAS  Google Scholar 

  11. Wang, M.; Wang, C. G.; Chen, M.; Xi, Y. W.; Cheng, W.; Mao, C.; Xu, T. Z.; Zhang, X. X.; Lin, C.; Gao, W. Y. et al. Efficient angiogenesis-based diabetic wound healing/skin reconstruction through bioactive antibacterial adhesive ultraviolet shielding nanodressing with exosome release. ACS Nano 2019, 13, 10279–10293.

    Article  CAS  Google Scholar 

  12. Wang, S. Q.; Zheng, H.; Zhou, L.; Cheng, F.; Liu, Z.; Zhang, H. P.; Wang, L. L.; Zhang, Q. Y. Nanoenzyme-reinforced injectable hydrogel for healing diabetic wounds infected with multidrug resistant bacteria. Nano Lett. 2020, 20, 5149–5158.

    Article  CAS  Google Scholar 

  13. Lin, S. Y.; Zhang, Q.; Li, S. H.; Zhang, T.; Wang, L.; Qin, X.; Zhang, M.; Shi, S. R.; Cai, X. X. Antioxidative and angiogenesispromoting effects of tetrahedral framework nucleic acids in diabetic wound healing with activation of the Akt/Nrf2/HO-1 pathway. ACS Appl. Mater. Interfaces 2020, 12, 11397–11408.

    Article  CAS  Google Scholar 

  14. Moura, J.; Madureira, P.; Leal, E. C.; Fonseca, A. C.; Carvalho, E. Immune aging in diabetes and its implications in wound healing. Clin. Immunol. 2019, 200, 43–54.

    Article  CAS  Google Scholar 

  15. Xu, Z. J.; Han, S. Y.; Gu, Z. P.; Wu, J. Advances and impact of antioxidant hydrogel in chronic wound healing. Adv. Healthc. Mater. 2020, 9, 1901502.

    Article  CAS  Google Scholar 

  16. He, M. Y.; Sun, L. Y.; Fu, X. L.; McDonough, S. P.; Chu, C. C. Biodegradable amino acid-based poly(ester amine) with tunable immunomodulating properties and their in vitro and in vivo wound healing studies in diabetic rats’ wounds. Acta Biomater. 2019, 84, 114–132.

    Article  CAS  Google Scholar 

  17. Rendra, E.; Riabov, V.; Mossel, D. M.; Sevastyanova, T.; Harmsen, M. C.; Kzhyshkowska, J. Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology 2019, 224, 242–253.

    Article  CAS  Google Scholar 

  18. Liu, S.; Zhang, Q. F.; Yu, J.; Shao, N. N.; Lu, H. T.; Guo, J. S.; Qiu, X. P.; Zhou, D. F.; Huang, Y. B. Absorbable thioether grafted hyaluronic acid nanofibrous hydrogel for synergistic modulation of inflammation microenvironment to accelerate chronic diabetic wound healing. Adv. Healthc. Mater. 2020, 9, 2000198.

    Article  CAS  Google Scholar 

  19. Zhao, Y.; Li, Z. H.; Song, S. L.; Yang, K. R.; Liu, H.; Yang, Z.; Wang, J. C.; Yang, B.; Lin, Q. Skin-inspired antibacterial conductive hydrogels for epidermal sensors and diabetic foot wound dressings. Adv. Funct. Mater. 2019, 29, 1901474.

    Article  CAS  Google Scholar 

  20. Zhang, P. J.; Li, Y.; Tang, Y. H.; Shen, H.; Li, J. K.; Yi, Z. F.; Ke, Q. F.; Xu, H. Copper-based metal-organic framework as a controllable nitric oxide-releasing vehicle for enhanced diabetic wound healing. ACS Appl. Mater. Interfaces 2020, 12, 18319–18331.

    Article  CAS  Google Scholar 

  21. Zhang, X. Q.; Li, Z.; Yang, P.; Duan, G. G.; Liu, X. H.; Gu, Z. P.; Li, Y. W. Polyphenol scaffolds in tissue engineering. Mater. Horiz. 2021, 8, 145–167.

    Article  CAS  Google Scholar 

  22. Zhang, S. H.; Ou, Q. M.; Xin, P. K.; Yuan, Q. J.; Wang, Y.; Wu, J. Polydopamine/puerarin nanoparticle-incorporated hybrid hydrogels for enhanced wound healing. Biomater. Sci. 2019, 7, 4230–4236.

    Article  CAS  Google Scholar 

  23. Liang, Y. P.; Zhao, X.; Hu, T. L.; Han, Y.; Guo, B. L. Mussel-inspired, antibacterial, conductive, antioxidant, injectable composite hydrogel wound dressing to promote the regeneration of infected skin. J. Colloid Interface Sci. 2019, 556, 514–528.

    Article  CAS  Google Scholar 

  24. Liu, J.; Chen, Z. Q.; Wang, J.; Li, R. H.; Li, T. T.; Chang, M. Y.; Yan, F.; Wang, Y. F. Encapsulation of curcumin nanoparticles with MMP9-responsive and thermos-sensitive hydrogel improves diabetic wound healing. ACS Appl. Mater. Interfaces 2018, 10, 16315–16326.

    Article  CAS  Google Scholar 

  25. Yu, J. C.; Zhang, Y. Q.; Wang, J. Q.; Wen, D.; Kahkoska, A. R.; Buse, J. B.; Gu, Z. Glucose-responsive oral insulin delivery for postprandial glycemic regulation. Nano Res. 2019, 12, 1539–1545.

    Article  CAS  Google Scholar 

  26. Zhu, Y. N.; Zhang, J. M.; Song, J. Y.; Yang, J.; Du, Z.; Zhao, W. Q.; Guo, H. S.; Wen, C. Y.; Li, Q. S.; Sui, X. J. et al. A multifunctional pro-healing zwitterionic hydrogel for simultaneous optical monitoring of pH and glucose in diabetic wound treatment. Adv. Funct. Mater. 2019, 30, 1905493.

    Article  CAS  Google Scholar 

  27. Huynh, C. T.; Liu, F. Z.; Cheng, Y. X.; Coughlin, K. A.; Alsberg, E. Thiol-epoxy “click” chemistry to engineer cytocompatible PEG-based hydrogel for siRNA-mediated osteogenesis of hMSCs. ACS Appl. Mater. Interfaces 2018, 10, 25936–25942.

    Article  CAS  Google Scholar 

  28. Xu, Z. J.; Liu, G. T.; Huang, J.; Wu, J. Novel glucose-responsive antioxidant hybrid hydrogel for enhanced diabetic wound repair. ACS Appl. Mater. Interfaces 2022, 14, 7680–7689.

    Article  CAS  Google Scholar 

  29. Kim, A. R.; Lee, S. L.; Park, S. N. Properties and in vitro drug release of pH- and temperature-sensitive double cross-linked interpenetrating polymer network hydrogels based on hyaluronic acid/poly (N-isopropylacrylamide) for transdermal delivery of luteolin. Int. J. Biol. Macromol. 2018, 118, 731–740.

    Article  CAS  Google Scholar 

  30. Qian, C.; Zhang, T. B.; Gravesande, J.; Baysah, C.; Song, X. Y.; Xing, J. F. Injectable and self-healing polysaccharide-based hydrogel for pH-responsive drug release. Int. J. Biol. Macromol. 2019, 123, 140–148.

    Article  CAS  Google Scholar 

  31. Huang, J.; Chen, L.; Gu, Z. P.; Wu, J. Red jujube-incorporated gelatin methacryloyl (GelMA) hydrogels with anti-oxidation and immunoregulation activity for wound healing. J. Biomed. Nanotechnol. 2019, 15, 1357–1370.

    Article  CAS  Google Scholar 

  32. Cheng, H.; Shi, Z.; Yue, K.; Huang, X. S.; Xu, Y. C.; Gao, C. H.; Yao, Z. Q.; Zhang, S. K.; Wang, J. Sprayable hydrogel dressing accelerates wound healing with combined reactive oxygen species-scavenging and antibacterial abilities. Acta Biomater. 2021, 14, 219–232.

    Article  CAS  Google Scholar 

  33. Xian, C. H.; Gu, Z. P.; Liu, G. T.; Wu, J. Whole wheat flour coating with antioxidant property accelerates tissue remodeling for enhanced wound healing. Chin. Chem. Lett. 2020, 31, 1612–1615.

    Article  CAS  Google Scholar 

  34. Yuan, Q. J.; Huang, J.; Xian, C. H.; Wu, J. Amino acid- and growth factor-based multifunctional nanocapsules for the modulation of the local microenvironment in tissue engineering. ACS Appl. Mater. Interfaces 2021, 13, 2165–2178.

    Article  CAS  Google Scholar 

  35. Hu, C.; Long, L. Y.; Cao, J.; Zhang, S. M.; Wang, Y. B. Dual-crosslinked mussel-inspired smart hydrogels with enhanced antibacterial and angiogenic properties for chronic infected diabetic wound treatment via pH-responsive quick cargo release. Chem. Eng. J. 2021, 411, 128564.

    Article  CAS  Google Scholar 

  36. Wang, P. Y.; Peng, L. L.; Lin, J. Y.; Li, Y.; Luo, Q.; Jiang, S. H.; Tian, H. N.; Zhang, Y.; Liu, X. L.; Liu, J. F. Enzyme hybrid viruslike hollow mesoporous CuO adhesive hydrogel spray through glucose-activated cascade reaction to efficiently promote diabetic wound healing. Chem. Eng. J. 2021, 415, 128901.

    Article  CAS  Google Scholar 

  37. Liu, H.; Li, Z. H.; Zhao, Y.; Feng, Y. B.; Zvyagin, A. V.; Wang, J. C.; Yang, X. Y.; Yang, B.; Lin, Q. Novel diabetic foot wound dressing based on multifunctional hydrogels with extensive temperature-tolerant, durable, adhesive, and intrinsic antibacterial properties. ACS Appl. Mater. Interfaces 2021, 13, 26770–26781.

    Article  CAS  Google Scholar 

  38. Liu, P.; Jin, K.; Wong, W.; Wang, Y. Y.; Liang, T.; He, M.; Li, H. Y.; Lu, C. F.; Tang, X.; Zong, Y. G. et al. Ionic liquid functionalized non-releasing antibacterial hydrogel dressing coupled with electrical stimulation for the promotion of diabetic wound healing. Chem. Eng. J. 2021, 415, 129025.

    Article  CAS  Google Scholar 

  39. Wang, J. Q.; Wang, Z. J.; Chen, G. J.; Wang, Y. F.; Ci, T. Y.; Li, H. J.; Liu, X. S.; Zhou, D. J.; Kahkoska, A. R.; Zhou, Z. X. et al. Injectable biodegradable polymeric complex for glucose-responsive insulin delivery. ACS Nano 2021, 15, 4294–4304.

    Article  CAS  Google Scholar 

  40. You, X. R.; Gu, Z. P.; Huang, J.; Kang, Y.; Chu, C. C.; Wu, J. Arginine-based poly(ester amide) nanoparticle platform: From structure-property relationship to nucleic acid delivery. Acta Biomater. 2018, 74, 180–191.

    Article  CAS  Google Scholar 

  41. Zhang, S. H.; Xin, P. K.; Ou, Q. M.; Hollett, G.; Gu, Z. P.; Wu, J. Poly(ester amide)-based hybrid hydrogels for efficient transdermal insulin delivery. J. Mater. Chem. B 2018, 6, 6723–6730.

    Article  CAS  Google Scholar 

  42. Jia, H. Z.; Zhang, W. Y.; Zhu, J. Y.; Yang, B.; Chen, S.; Chen, G.; Zhao, Y. F.; Feng, J.; Zhang, X. Z. Hyperbranched-hyperbranched polymeric nanoassembly to mediate controllable co-delivery of siRNA and drug for synergistic tumor therapy. J. Control. Release 2015, 216, 9–17.

    Article  CAS  Google Scholar 

  43. Peng, Q.; Chen, F. J.; Zhong, Z. L.; Zhuo, R. X. Enhanced gene transfection capability of polyethylenimine by incorporating boronic acidgroups. Chem. Commun. 2010, 46, 5888–5890.

    Article  CAS  Google Scholar 

  44. Zhang, X.; Liu, J.; Qian, C. L.; Kan, J.; Jin, C. H. Effect of grafting method on the physical property and antioxidant potential of chitosan film functionalized with gallic acid. Food Hydrocoll. 2019, 89, 1–10.

    Article  CAS  Google Scholar 

  45. Liu, J.; Meng, C. G.; Yan, Y. H.; Shan, Y. N.; Kan, J.; Jin, C. H. Protocatechuic acid grafted onto chitosan: Characterization and antioxidant activity. Int. J. Biol. Macromol. 2016, 89, 518–526.

    Article  CAS  Google Scholar 

  46. Li, X.; Fan, X. X.; Jiang, Z. B.; Loo, W. T.; Yao, X. J.; Leung, E. L. H.; Chow, L. W.; Liu, L. Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway. Pharmacol. Res. 2017, 115, 45–55.

    Article  CAS  Google Scholar 

  47. Hu, W.; Wang, H. B.; Liu, Z. F.; Liu, Y. L.; Wang, R.; Luo, X.; Huang, Y. F. Neuroprotective effects of lycopene in spinal cord injury in rats via antioxidative and anti-apoptotic pathway. Neurosci. Lett. 2017, 642, 107–112.

    Article  CAS  Google Scholar 

  48. Li, L.; Jiang, G. H.; Yu, W. J.; Liu, D. P.; Chen, H.; Liu, Y. K.; Huang, Q.; Tong, Z. Z.; Yao, J. M.; Kong, X. D. A composite hydrogel system containing glucose-responsive nanocarriers for oral delivery of insulin. Mater. Sci. Eng. C 2016, 69, 37–45.

    Article  CAS  Google Scholar 

  49. Zhao, L. L.; Niu, L. J.; Liang, H. Z.; Tan, H.; Liu, C. Z.; Zhu, F. Y. pH and glucose dual-responsive injectable hydrogels with insulin and fibroblasts as bioactive dressings for diabetic wound healing. ACS Appl. Mater. Interfaces 2017, 9, 37563–37574.

    Article  CAS  Google Scholar 

  50. Sun, C. Y.; Zeng, X. L.; Zheng, S. H.; Wang, Y. L.; Li, Z. Y.; Zhang, H. N.; Nie, L. L.; Zhang, Y. F.; Zhao, Y. B.; Yang, X. B. et al. Bio-adhesive catechol-modified chitosan wound healing hydrogel dressings through glow discharge plasma technique. Chem. Eng. J. 2022, 427, 130843.

    Article  CAS  Google Scholar 

  51. Xu, Z. J.; Liang, B.; Tian, J. Z.; Wu, J. Anti-inflammation biomaterial platforms for chronic wound healing. Biomater. Sci. 2021, 9, 4388–4409.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 51973243), Fundamental Research Funds for the Central Universities (No. 191gzd35), Guangdong Innovative and Entrepreneurial Research Team Program (No. 2016ZT06S029), Shenzhen Basic Research Project (No. JCYJ20190807155801657), Key international (regional) cooperative research projects of the National Natural Science Foundation of China (No. 5181001045).

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  1. Zejun Xu and Guiting Liu contributed equally to this work.

Authors and Affiliations

  1. School of Biomedical Engineering, Sun Yat-sen University, Shenzhen, 518107, China

    Zejun Xu & Jun Wu

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital Sun Yat-sen University, Guangzhou, 510120, China

    Jun Wu

  3. The State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu, 610065, China

    Guiting Liu

  4. School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China

    Qing Li

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  1. Zejun Xu
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Correspondence to Jun Wu.

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A novel hydrogel with glucose-responsive hyperglycemia regulation and antioxidant activity for enhanced diabetic wound repair

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Xu, Z., Liu, G., Li, Q. et al. A novel hydrogel with glucose-responsive hyperglycemia regulation and antioxidant activity for enhanced diabetic wound repair. Nano Res. 15, 5305–5315 (2022). https://doi.org/10.1007/s12274-022-4192-y

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