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Research Article

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

Zejun Xu1,§, Guiting Liu3,§, Qing Li4, Jun Wu1,2( )
School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518107, China
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital Sun Yat-sen University, Guangzhou 510120, China
The State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu 610065, China
School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan 250012, China

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

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Graphical Abstract

A novel hydrogel with glucose-responsive hyperglycemia regulation and antioxidant activity has been developed forenhanced diabetic wound repair.

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.

Keywords

diabetic woundglucose responsiveantioxidationhyperglycemia regulationinsulin

Electronic Supplementary Material

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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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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 inflammasome-neutrophil extracellular traps" axis. Cell Death Discov. 2020, 6, 84.
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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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 angiogenesis-promoting 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
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.
Crossref 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.
Crossref 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.
Crossref 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 virus-like hollow mesoporous CuO adhesive hydrogel spray through glucose-activated cascade reaction to efficiently promote diabetic wound healing. Chem. Eng. J. 2021, 415, 128901.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref Google Scholar
Nano Research
Volume 15 Issue 6,
June 2022
Pages 5305-5315
DOI: 10.1007/s12274-022-4192-y
Cite this article:
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 Research, 2022, 15(6): 5305-5315. https://doi.org/10.1007/s12274-022-4192-y
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Received: 13 December 2021
Revised: 20 January 2022
Accepted: 25 January 2022
Published: 29 March 2022
© Tsinghua University Press 2022
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