Visible light cross-linking and bioactive peptides loaded integrated hydrogel with sequential release to accelerate wound healing complicated by bacterial infection
), Yuguang Wang3()Graphical Abstract
Abstract
The effective management of bacterial infections that are resistant to multiple drugs remains a substantial clinical challenge. The eradication of drug-resistant bacteria and subsequent promotion of angiogenesis are imperative for the regeneration of the infected wounds. Here, a novel and facile peptide containing injectable hydrogel with sustained antibacterial and angiogenic capabilities is developed. The antibacterial peptide that consists of 11 residues (CM11, WKLFKKILKVL) is loaded onto acrylate-modified gelatin through charge interactions. A vascular endothelial growth factor mimetic peptide KLT (KLTWQELYQLKYKGI) with a GCG (Gly-Cys-Gly) modification at the N-terminal is covalently coupled through a visible light-induced thiol-ene reaction. In this reaction, the acrylate gelatin undergoes cross-linkage within seconds. Based on the physical/chemical double crosslinking strategy, the bioactive peptides achieve sustained and sequential release. The results show that the hydrogel significantly inhibits methicillin-resistant Staphylococcus aureus (MRSA) growth through the rapid release of CM11 peptides at early stage; it forms obvious growth inhibition zones against pathogenic bacterial strains. Moreover, cell counting kit-8 assay and scratch test confirm that the CM11/KLT-functionalized hydrogels promote cell proliferation and migration through the later release of KLT peptides. In a mouse skin wound infected with self-luminous MRSA, the CM11/KLT-functionalized hydrogels enhance wound healing, with rapidly bacterial infection reduction, lower expression of inflammatory factors, and neovascularization promotion. These results suggest that the rationally designed, sustained and sequential release CM11/KLT-functionalized hydrogels have huge potential in promoting the healing of multi-drug resistant bacterial infected wounds.
Keywords
Electronic Supplementary Material
References
Zhang, Y.; Wu, H. X.; Li, P. P.; Liu, W. X.; Zhang, Y. L.; Dong, A. Dual-light-triggered in situ structure and function regulation of injectable hydrogels for high-efficient anti-infective wound therapy. Adv. Healthcare Mater. 2022, 11, 2101722.
Yi, S. X.; Zhou, Y.; Zhang, J. M.; Wang, M.; Zheng, S. H.; Yang, X.; Duan, L.; Reis, R. L.; Dai, F. Y.; Kundu, S. C. et al. Flat silk cocoon-based dressing: Daylight-driven rechargeable antibacterial membranes accelerate infected wound healing. Adv. Healthcare Mater. 2022, 11, 2201397.
Guan, T.; Li, J. Y.; Chen, C. Y.; Liu, Y. Self-assembling peptide-based hydrogels for wound tissue repair. Adv. Sci. (Weinh. ) 2022, 9, 2104165.
Jia, W.; Wu, Y. F.; Chen, Y. F.; He, D. S.; Li, J. P.; Wang, Y.; Wang, Z.; Zhu, W.; Chen, C.; Peng, Q. et al. Interface-induced formation of onion-like alloy nanocrystals by defects engineering. Nano Res. 2016, 9, 584–592.
Jiang, Y. X.; Rong, H. T.; Wang, Y. F.; Liu, S. G.; Xu, P.; Luo, Z.; Guo, L. M.; Zhu, T.; Rong, H. P.; Wang, D. S. et al. Single-atom cobalt nanozymes promote spinal cord injury recovery by anti-oxidation and neuroprotection. Nano Res 2023, in press, DOI: 10.1007/s12274-023-5588-z.
Xu, T. M.; Tian, Y. C.; Zhang, R.; Yu, B.; Cong, H. L.; Shen, Y. Q. Hydrogel vectors based on peptide and peptide-like substances: For treating bacterial infections and promoting wound healing. Appl. Mater. Today 2021, 25, 101224.
Kern, W. V.; Rieg, S. Burden of bacterial bloodstream infection-a brief update on epidemiology and significance of multidrug-resistant pathogens. Clin. Microbiol. Infect. 2020, 26, 151–157.
Luo, Y.; Song, Y. Z. Mechanism of antimicrobial peptides: Antimicrobial, anti-inflammatory and antibiofilm activities. Int. J. Mol. Sci. 2021, 22, 11401.
Mahdavi Abhari, F.; Pirestani, M.; Dalimi, A. Anti-amoebic activity of a cecropin-melittin hybrid peptide (CM11) against trophozoites of Entamoeba histolytica. Wien. Klin. Wochenschr. 2019, 131, 427–434.
Moosazadeh Moghaddam, M.; Eftekhary, M.; Erfanimanesh, S.; Hashemi, A.; Fallah Omrani, V.; Farhadihosseinabadi, B.; Lasjerdi, Z.; Mossahebi-Mohammadi, M.; Pal Singh Chauhan, N.; Seifalian, A. M. et al. Comparison of the antibacterial effects of a short cationic peptide and 1% silver bioactive glass against extensively drug-resistant bacteria, Pseudomonas aeruginosa and Acinetobacter baumannii, isolated from burn patients. Amino Acids 2018, 50, 1617–1628.
Moghaddam, M. M.; Barjini, K. A.; Ramandi, M. F.; Amani, J. Investigation of the antibacterial activity of a short cationic peptide against multidrug-resistant Klebsiella pneumoniae and Salmonella typhimurium strains and its cytotoxicity on eukaryotic cells. World J. Microbiol. Biotechnol. 2014, 30, 1533–1540.
Khalili, S.; Ebrahimzade, E.; Mohebali, M.; Shayan, P.; Mohammadi-Yeganeh, S.; Moosazadeh Moghaddam, M.; Elikaee, S.; Akhoundi, B.; Sharifi-Yazdi, M. K. Investigation of the antimicrobial activity of a short cationic peptide against promastigote and amastigote forms of Leishmania major (MHRO/IR/75/ER): An in vitro study. Exp. Parasitol. 2019, 196, 48–54.
Thapa, R. K.; Diep, D. B.; Tønnesen, H. H. Topical antimicrobial peptide formulations for wound healing: Current developments and future prospects. Acta Biomater. 2020, 103, 52–67.
Wang, C.; Hong, T. T.; Cui, P. F.; Wang, J. H.; Xia, J. Antimicrobial peptides towards clinical application: Delivery and formulation. Adv. Drug Deliv. Rev. 2021, 175, 113818.
Yang, X.; Guo, J. L.; Han, J.; Si, R. J.; Liu, P. P.; Zhang, Z. R.; Wang, A. M.; Zhang, J. Chitosan hydrogel encapsulated with LL-37 peptide promotes deep tissue injury healing in a mouse model. Mil. Med. Res. 2020, 7, 20.
Maleki, A.; He, J. H.; Bochani, S.; Nosrati, V.; Shahbazi, M. A.; Guo, B. L. Multifunctional photoactive hydrogels for wound healing acceleration. ACS Nano 2021, 15, 18895–18930.
Suo, H. N.; Hussain, M.; Wang, H.; Zhou, N. Y.; Tao, J.; Jiang, H.; Zhu, J. T. Injectable and pH-sensitive hyaluronic acid-based hydrogels with on-demand release of antimicrobial peptides for infected wound healing. Biomacromolecules 2021, 22, 3049–3059.
Tang, W.; Yu, Y. M.; Wang, J.; Liu, H.; Pan, H. B.; Wang, G. C.; Liu, C. S. Enhancement and orchestration of osteogenesis and angiogenesis by a dual-modular design of growth factors delivery scaffolds and 26SCS decoration. Biomaterials 2020, 232, 119645.
D'Andrea, L. D.; Iaccarino, G.; Fattorusso, R.; Sorriento, D.; Carannante, C.; Capasso, D.; Trimarco, B.; Pedone, C. Targeting angiogenesis: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide. Proc. Natl. Acad. Sci. USA 2005, 102, 14215–14220.
Wang, G. Y.; Yuan, N.; Li, N. Y.; Wei, Q. J.; Qian, Y. P.; Zhang, J.; Qin, M.; Wang, Y. G.; Dong, S. W. Vascular endothelial growth factor mimetic peptide and parathyroid hormone (1-34) delivered via a blue-light-curable hydrogel synergistically accelerate bone regeneration. ACS Appl. Mater. Interfaces 2022, 14, 35319–35332.
Lu, J. J.; Guan, F. Y.; Cui, F. Z.; Sun, X. D.; Zhao, L. Y.; Wang, Y.; Wang, X. M. Enhanced angiogenesis by the hyaluronic acid hydrogels immobilized with a VEGF mimetic peptide in a traumatic brain injury model in rats. Regen. Biomater. 2019, 6, 325–334.
Jang, M. J.; Bae, S. K.; Jung, Y. S.; Kim, J. C.; Kim, J. S.; Park, S. K.; Suh, J. S.; Yi, S. J.; Ahn, S. H.; Lim, J. O. Enhanced wound healing using a 3D printed VEGF-mimicking peptide incorporated hydrogel patch in a pig model. Biomed. Mater. 2021, 16, 045013.
Liang, Y. P.; He, J. H.; Guo, B. L. Functional hydrogels as wound dressing to enhance wound healing. ACS Nano 2021, 15, 12687–12722.
Wang, L.; Zhang, X. H.; Yang, K.; Fu, Y. V.; Xu, T. S.; Li, S. L.; Zhang, D. W.; Wang, L. N.; Lee, C. S. A novel double-crosslinking-double-network design for injectable hydrogels with enhanced tissue adhesion and antibacterial capability for wound treatment. Adv. Funct. Mater. 2020, 30, 1904156.
Hoyle, C. E.; Bowman, C. N. Thiol-Ene click chemistry. Angew. Chem., Int. Ed. 2010, 49, 1540–1573.
Rydholm, A. E.; Bowman, C. N.; Anseth, K. S. Degradable thiol-acrylate photopolymers: Polymerization and degradation behavior of an in situ forming biomaterial. Biomaterials 2005, 26, 4495–4506.
Tyson, E. L.; Niemeyer, Z. L.; Yoon, T. P. Redox mediators in visible light photocatalysis: Photocatalytic radical thiol-Ene additions. J. Org. Chem. 2014, 79, 1427–1436.
Xu, Z. J.; Han, S. Y.; Gu, Z. P.; Wu, J. Advances and impact of antioxidant hydrogel in chronic wound healing. Adv. Healthcare Mater. 2020, 9, 1901502.
Li, L. L.; Lu, C. L.; Wang, L.; Chen, M.; White, J.; Hao, X. J.; McLean, K. M.; Chen, H.; Hughes, T. C. Gelatin-based photocurable hydrogels for corneal wound repair. ACS Appl. Mater. Interfaces 2018, 10, 13283–13292.
Sani, E. S.; Lara, R. P.; Aldawood, Z.; Bassir, S. H.; Nguyen, D.; Kantarci, A.; Intini, G.; Annabi, N. An antimicrobial dental light curable Bioadhesive hydrogel for treatment of Peri-implant diseases. Matter 2019, 1, 926–944.
Pensa, N. W.; Curry, A. S.; Reddy, M. S.; Bellis, S. L. Sustained delivery of the angiogenic QK peptide through the use of polyglutamate domains to control peptide release from bone graft materials. J. Biomed. Mater. Res. A 2019, 107, 2764–2773.
Xiao, P.; Zhu, X.; Sun, J. P.; Zhang, Y. H.; Qiu, W. J.; Li, J. Q.; Wu, X. J. Cartilage tissue miR-214-3p regulates the TrkB/ShcB pathway paracrine VEGF to promote endothelial cell migration and angiogenesis. Bone 2021, 151, 116034.
Pensa, N. W.; Curry, A. S.; Reddy, M. S.; Bellis, S. L. The addition of a polyglutamate domain to the angiogenic QK peptide improves peptide coupling to bone graft materials leading to enhanced endothelial cell activation. PLoS One 2019, 14, e0213592.
Huang, Y.; Mu, L.; Zhao, X.; Han, Y.; Guo, B. L. Bacterial growth-induced tobramycin smart release self-healing hydrogel for Pseudomonas aeruginosa-infected burn wound healing. ACS Nano 2022, 16, 13022–13036.
Liang, Y. P.; Li, M.; Yang, Y. T.; Qiao, L. P.; Xu, H. R.; Guo, B. L. pH/Glucose dual responsive metformin release hydrogel dressings with adhesion and self-healing via dual-dynamic bonding for athletic diabetic foot wound healing. ACS Nano 2022, 16, 3194–3207.
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