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LL37 Microspheres Loaded on Activated Carbon-chitosan Hydrogel: Anti-bacterial and Anti-toxin Wound Dressing for Chronic Wound Infections

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Abstract

Antimicrobial peptide LL37 is a promising antibacterial candidate due to its potent antimicrobial activity with no known bacterial resistance. However, intrinsically LL37 is susceptible to degradation in wound fluids limits its effectiveness. Bacterial toxins which are released after cell lysis are found to hinder wound healing. To address these challenges, encapsulating LL37 in microspheres (MS) and loading the MS onto activated carbon (AC)-chitosan (CS) hydrogel. This advanced wound dressing not only protects LL37 from degradation but also targets bacterial toxins, aiding in the healing of chronic wound infections. First, LL37 MS and LL37-AC-CS hydrogel were prepared and characterised in terms of physicochemical properties, drug release, and peptide-polymer compatibility. Antibacterial and antibiofilm activity, bacterial toxin elimination, cell migration, and cell cytotoxicity activities were investigated. LL37-AC-CS hydrogel was effective against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. LL37-AC-CS hydrogel bound more endotoxin than AC with CS hydrogel alone. The hydrogel also induced cell migration after 72 h and showed no cytotoxicity towards NHDF after 72 h of treatment. In conclusion, the LL37-AC-CS hydrogel was shown to be a stable, non-toxic advanced wound dressing method with enhanced antimicrobial and antitoxin activity, and it can potentially be applied to chronic wound infections to accelerate wound healing.

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Data Availability

The raw data presented in this study are available on request from the corresponding author.

References

  1. Sen CK. Human wound and its burden: Updated 2020 compendium of estimates. Adv Wound Care (New Rochelle). 2021;10:281. https://doi.org/10.1089/WOUND.2021.0026.

    Article  PubMed  Google Scholar 

  2. Sanya DRA, Onésime D, Vizzarro G, Jacquier N. Recent advances in therapeutic targets identification and development of treatment strategies towards Pseudomonas aeruginosa infections. BMC Microbiol. 2023;23:86. https://doi.org/10.1186/s12866-023-02832-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Paleczny J, Junka A, Brożyna M, Dydak K, Oleksy-Wawrzyniak M, Ciecholewska-Juśko D, Dziedzic E, Bartoszewicz M. The high impact of staphylococcus aureus biofilm culture medium on in vitro outcomes of antimicrobial activity of wound antiseptics and antibiotic. Pathogens. 2021;10:1387. https://doi.org/10.3390/PATHOGENS10111385/S1.

    Article  Google Scholar 

  4. Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle). 2015;4:560. https://doi.org/10.1089/WOUND.2015.0635.

    Article  PubMed  Google Scholar 

  5. Omar A, Wright JB, Schultz G, Burrell R, Nadworny P. Microbial biofilms and chronic wounds. Microorganisms. 2017;5:9. https://doi.org/10.3390/MICROORGANISMS5010009.

    Article  PubMed  PubMed Central  Google Scholar 

  6. James GA, Swogger E, Wolcott R, Pulcini ED, Secor P, Sestrich J, Costerton JW, Stewart PS. Biofilms in chronic wounds. Wound Repair and Regeneration. 2008;16:37–44. https://doi.org/10.1111/J.1524-475X.2007.00321.X.

    Article  PubMed  Google Scholar 

  7. Shumba P, Shambat SM, Siemens N. The role of streptococcal and staphylococcal exotoxins and proteases in human necrotizing soft tissue infections. Toxins. 2019;11:332. https://doi.org/10.3390/TOXINS11060332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Browne K, Chakraborty S, Chen R, Willcox MDP, Black DS, Walsh WR, Kumar N. (2020) A new era of antibiotics: The clinical potential of antimicrobial peptides. Int J Mol Sci. 2020;21(7047):21. https://doi.org/10.3390/IJMS21197047.

    Article  Google Scholar 

  9. Lopes BS, Hanafiah A, Nachimuthu R, Muthupandian S, MdNesran ZN, Patil S. The role of antimicrobial peptides as antimicrobial and antibiofilm agents in tackling the silent pandemic of antimicrobial resistance. Molecules. 2022;27:2995. https://doi.org/10.3390/molecules27092995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Silva JP, Appelberg R, Gama FM. Antimicrobial peptides as novel anti-tuberculosis therapeutics. Biotechnol Adv. 2016;34:924–40. https://doi.org/10.1016/j.biotechadv.2016.05.007.

    Article  CAS  PubMed  Google Scholar 

  11. Geitani R, AyoubMoubareck C, Touqui L, KaramSarkis D. Cationic antimicrobial peptides: alternatives and/or adjuvants to antibiotics active against methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa. BMC Microbiol. 2019;19:54. https://doi.org/10.1186/s12866-019-1416-8.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lin Z, Wu T, Wang W, Li B, Wang M, Chen L, Xia H, Zhang T. Biofunctions of antimicrobial peptide-conjugated alginate/hyaluronic acid/collagen wound dressings promote wound healing of a mixed-bacteria-infected wound. Int J Biol Macromol. 2019;140:330–42. https://doi.org/10.1016/j.ijbiomac.2019.08.087.

    Article  CAS  PubMed  Google Scholar 

  13. Dürr UHN, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides, Biochimica et Biophysica Acta (BBA). Biomembranes. 2006;1758:1408–25. https://doi.org/10.1016/j.bbamem.2006.03.030.

    Article  CAS  Google Scholar 

  14. Yang B, Good D, Mosaiab T, Liu W, Ni G, Kaur J, Liu X, Jessop C, Yang L, Fadhil R, Yi Z, Wei MQ. Significance of LL-37 on immunomodulation and disease outcome. Biomed Res Int. 2020;2020:8349712. https://doi.org/10.1155/2020/8349712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rippon MG, Westgate S, Rogers AA. Implications of endotoxins in wound healing: a narrative review. J Wound Care. 2022;31:380–92. https://doi.org/10.12968/jowc.2022.31.5.380.

    Article  PubMed  Google Scholar 

  16. Osmokrovic A, Jancic I, Vunduk J, Petrovic P, Milenkovic M, Obradovic B. Achieving high antimicrobial activity: Composite alginate hydrogel beads releasing activated charcoal with an immobilized active agent. Carbohydr Polym. 2018;196:279–88. https://doi.org/10.1016/j.carbpol.2018.05.045.

    Article  CAS  PubMed  Google Scholar 

  17. Chereddy KK, Her C-H, Comune M, Moia C, Lopes A, Porporato PE, Vanacker J, Lam MC, Steinstraesser L, Sonveaux P, Zhu H, Ferreira LS, Vandermeulen G, Préat V. PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing. J Contr Release. 2014;194:138–47. https://doi.org/10.1016/j.jconrel.2014.08.016.

    Article  CAS  Google Scholar 

  18. Thoniyot P, Tan MJ, Karim AA, Young DJ, Loh XJ. Nanoparticle-hydrogel composites: concept, design, and applications of these promising, multi-functional materials. Adv Sci (Weinh). 2015;2(1–2):1400010. https://doi.org/10.1002/advs.201400010.

  19. Puvirajesinghe TM, Zhi ZL, Craster RV, Guenneau S. Tailoring drug release rates in hydrogel-based therapeutic delivery applications using graphene oxide. J R Soc Interface. 2018;15:20170949. https://doi.org/10.1098/rsif.2017.0949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen XY, Butt AM, Mohd Amin MCI. Enhanced paracellular delivery of vaccine by hydrogel microparticles-mediated reversible tight junction opening for effective oral immunization. J Contr Release. 2019;311–312:50–64. https://doi.org/10.1016/j.jconrel.2019.08.031.

    Article  CAS  Google Scholar 

  21. Bhatnagar P, Law JX, Ng SF. Chitosan reinforced with kenaf nanocrystalline cellulose as an effective carrier for the delivery of platelet lysate in the acceleration of wound healing. Polymers. 2021;4392(13):4392. https://doi.org/10.3390/POLYM13244392.

    Article  Google Scholar 

  22. Jacob B, Park I-S, Bang J-K, Shin SY. Short KR-12 analogs designed from human cathelicidin LL-37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity. J Peptide Sci. 2013;19:700–7. https://doi.org/10.1002/psc.2552.

    Article  CAS  Google Scholar 

  23. Liang C-C, Park AY, Guan J-L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2:329–33. https://doi.org/10.1038/nprot.2007.30.

    Article  CAS  PubMed  Google Scholar 

  24. Machado HA, Abercrombie JJ, You T, DeLuca PP, Leung KP. Release of a wound-healing agent from PLGA microspheres in a thermosensitive gel. Biomed Res Int. 2013;2013:387863. https://doi.org/10.1155/2013/387863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ali NH, Amin MCIM, Ng S-F. Sodium carboxymethyl cellulose hydrogels containing reduced graphene oxide (rGO) as a functional antibiofilm wound dressing. J Biomater Sci Polym Ed. 2019;30:629–45. https://doi.org/10.1080/09205063.2019.1595892.

    Article  CAS  PubMed  Google Scholar 

  26. Chereddy KK, Lopes A, Koussoroplis S, Payen V, Moia C, Zhu H, Sonveaux P, Carmeliet P, Rieux A, Vandermeulen G, Préat V. Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. Nanomedicine. 2015;11:1975–84. https://doi.org/10.1016/j.nano.2015.07.006.

    Article  CAS  PubMed  Google Scholar 

  27. McClements DJ. Encapsulation, protection, and delivery of bioactive proteins and peptides using nanoparticle and microparticle systems: A review. Adv Colloid Interface Sci. 2018;253:1–22. https://doi.org/10.1016/j.cis.2018.02.002.

    Article  CAS  PubMed  Google Scholar 

  28. Feczkó T, Tóth J, Dósa GY, Gyenis J. Optimization of protein encapsulation in PLGA nanoparticles. Chem Eng Process Process Intens. 2011;50:757–65. https://doi.org/10.1016/j.cep.2011.06.008.

    Article  CAS  Google Scholar 

  29. Lozeau LD, Grosha J, Smith IM, Stewart EJ, Camesano TA, Rolle MW. Alginate affects bioactivity of chimeric collagen binding LL37 antimicrobial peptides adsorbed to collagen-alginate wound dressings. ACS Biomater Sci Eng. 2020;6(6):3398–410. https://doi.org/10.1021/acsbiomaterials.0c00227.

  30. Toppazzini M, Coslovi A, Boschelle M, Marsich E, Benincasa M, Gennaro R, et al. Can the interaction between the antimicrobial peptide LL-37 and alginate be exploited for the formulation of new biomaterials with antimicrobial properties? Carbohydr Polym. 2011;83(2):578–85. https://doi.org/10.1016/j.carbpol.2010.08.020.

  31. Zarzycki R, Modrzejewska Z, Nawrotek K. Drug release from hydrogel matrices. Ecol Chem Eng S. 2010;17(2):117–36.

    CAS  Google Scholar 

  32. Nicolle L, Journot CMA, Gerber-Lemaire S. Chitosan functionalization: Covalent and non-covalent interactions and their characterization. Polymers (Basel). 2021;13(23):4118. https://doi.org/10.3390/polym13234118.

  33. Dong L, Henderson A, Field C. Antimicrobial activity of single-walled carbon nanotubes suspended in different surfactants. J Nanotechnol. 2012;2012:928924. https://doi.org/10.1155/2012/928924.

    Article  CAS  Google Scholar 

  34. Szymańska E, Winnicka K. Stability of chitosan—a challenge for pharmaceutical and biomedical applications. Mar Drugs. 2015;13:1819–46. https://doi.org/10.3390/md13041819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Quesada HB, de Araújo TP, Vareschini DT, de Barros MASD, Gomes RG, Bergamasco R. Chitosan, alginate and other macromolecules as activated carbon immobilizing agents: A review on composite adsorbents for the removal of water contaminants. Int J Biol Macromol. 2020;164:2535–49. https://doi.org/10.1016/j.ijbiomac.2020.08.118.

    Article  CAS  PubMed  Google Scholar 

  36. Sidik AM, Othaman R, Anuar FH. The effect of molecular weight on the surface and permeation of poly(L-lactic acid)-poly(ethylene glycol) membrane with activated carbon filler. Sains Malays. 2018;47:1181–7.

    Article  CAS  Google Scholar 

  37. Xu K, An N, Zhang H, Zhang Q, Zhang K, Hu X, Wu Y, Wu F, Xiao J, Zhang H, Peng R, Li H, Jia C. Sustained-release of PDGF from PLGA microsphere embedded thermo-sensitive hydrogel promoting wound healing by inhibiting autophagy. J Drug Deliv Sci Technol. 2020;55:101405. https://doi.org/10.1016/j.jddst.2019.101405.

    Article  CAS  Google Scholar 

  38. Bernal-Chávez SA, Alcalá-Alcalá S, Cerecedo D, Ganem-Rondero A. Platelet lysate-loaded PLGA nanoparticles in a thermo-responsive hydrogel intended for the treatment of wounds. Eur J Pharm Sci. 2020;146:105231. https://doi.org/10.1016/j.ejps.2020.105231.

    Article  CAS  PubMed  Google Scholar 

  39. Yoo J, Won Y-Y. Phenomenology of the initial burst release of drugs from PLGA microparticles. ACS Biomater Sci Eng. 2020;6:6053–62. https://doi.org/10.1021/acsbiomaterials.0c01228.

    Article  CAS  PubMed  Google Scholar 

  40. Kaur T, Thirugnanam A. Effect of porous activated charcoal reinforcement on mechanical and in-vitro biological properties of polyvinyl alcohol composite scaffolds. J Mater Sci Technol. 2017;33:734–43. https://doi.org/10.1016/j.jmst.2016.06.020.

    Article  CAS  Google Scholar 

  41. Nagant C, Pitts B, Nazmi K, Vandenbranden M, Bolscher JG, Stewart PS, Dehaye J-P. Identification of peptides derived from the human antimicrobial peptide LL-37 active against biofilms formed by pseudomonas aeruginosa using a library of truncated fragments. Antimicrob Agents Chemother. 2012;56:5698–708. https://doi.org/10.1128/aac.00918-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Morgera F, Vaccari L, Antcheva N, Scaini D, Pacor S, Tossi A. Primate cathelicidin orthologues display different structures and membrane interactions. Biochemical Journal. 2009;417:727–35. https://doi.org/10.1042/BJ20081726.

    Article  CAS  PubMed  Google Scholar 

  43. El Maguana Y, Elhadiri N, Bouchdoug M, Benchanaa M, Jaouad A. Activated carbon from prickly pear seed cake: Optimization of preparation conditions using experimental design and its application in dye removal. Int J Chem Eng. 2019;2019:8621951. https://doi.org/10.1155/2019/8621951.

    Article  CAS  Google Scholar 

  44. Rosenfeld Y, Papo N, Shai Y. Endotoxin (Lipopolysaccharide) neutralization by innate immunity host-defense peptides: Peptide properties and plausible modes of action. J Biol Chem. 2006;281:1636–43. https://doi.org/10.1074/jbc.M504327200.

    Article  CAS  PubMed  Google Scholar 

  45. Cirioni O, Giacometti A, Ghiselli R, Bergnach C, Orlando F, Silvestri C, Mocchegiani F, Licci A, Skerlavaj B, Rocchi M, Saba V, Zanetti M, Scalise G. LL-37 protects rats against lethal sepsis caused by gram-negative bacteria. Antimicrob Agents Chemother. 2006; 50(5):1672–9. https://doi.org/10.1128/aac.50.5.1672-1679.2006.

  46. Illsley MJ, Akhmetova A, Bowyer C, Nurgozhin T, Mikhalovsky SV, Farrer J, Dubruel P, Allan IU. Activated carbon-plasticised agarose composite films for the adsorption of thiol as a model of wound malodour. J Mater Sci Mater Med. 2017;28:154. https://doi.org/10.1007/s10856-017-5964-x.

    Article  CAS  PubMed  Google Scholar 

  47. Müller G, Winkler Y, Kramer A. Antibacterial activity and endotoxin-binding capacity of actisorb® silver 220. J Hospital Infect. 2003;53:211–4. https://doi.org/10.1053/jhin.2002.1369.

    Article  Google Scholar 

  48. Tomasinsig L, Pizzirani C, Skerlavaj B, Pellegatti P, Gulinelli S, Tossi A, Di Virgilio F, Zanetti M. The human cathelicidin LL-37 modulates the activities of the P2X7 receptor in a structure-dependent manner. J Biol Chem. 2008;283:30471–81. https://doi.org/10.1074/jbc.M802185200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Oudhoff MJ, Blaauboer ME, Nazmi K, Scheres N, Bolscher JGM, Veerman ECI. The role of salivary histatin and the human cathelicidin LL-37 in wound healing and innate immunity. Biol Chem. 2010;391:541–8. https://doi.org/10.1515/bc.2010.057.

    Article  CAS  PubMed  Google Scholar 

  50. Howling GI, Dettmar PW, Goddard PA, Hampson FC, Dornish M, Wood EJ. The effect of chitin and chitosan on the proliferation of human skin fibroblasts and keratinocytes in vitro. Biomaterials. 2001;22:2959–66. https://doi.org/10.1016/S0142-9612(01)00042-4.

    Article  CAS  PubMed  Google Scholar 

  51. Barańska-Rybak W, Sonesson A, Nowicki R, Schmidtchen A. Glycosaminoglycans inhibit the antibacterial activity of LL-37 in biological fluids. J Antimicrob Chemother. 2006;57:260–5. https://doi.org/10.1093/jac/dki460.

    Article  CAS  PubMed  Google Scholar 

  52. Ridyard KE, Overhage J. The potential of human peptide LL-37 as an antimicrobial and anti-biofilm agent. Antibiotics. 2021;10:650. https://doi.org/10.3390/antibiotics10060650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ke C-L, Deng F-S, Chuang C-Y, Lin C-H. Antimicrobial actions and applications of chitosan. Polymers (Basel). 2021;13:905. https://doi.org/10.3390/polym13060904.

    Article  CAS  Google Scholar 

  54. Voljč T, Semenič D. Contribution of topical agents to wound healing. In: S. Aghaei (Ed.), Recent Advances in Wound Healing, IntechOpen, Rijeka, 2021: p Ch. 10. https://doi.org/10.5772/intechopen.97170.

  55. Luo Y, McLean DTF, Linden GJ, McAuley DF, McMullan R, Lundy FT. The naturally occurring host defense peptide, LL-37, and its truncated mimetics KE-18 and KR-12 have selected biocidal and antibiofilm activities against candida albicans, staphylococcus aureus, and escherichia coli in vitro. Front Microbiol. 2017;8:544. https://doi.org/10.3389/fmicb.2017.00544.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Dean S, Bishop B, Van Hoek M. Susceptibility of pseudomonas aeruginosa biofilm to alpha-helical peptides: D-enantiomer of LL-37. Front Microbiol. 2011;2:128. https://doi.org/10.3389/fmicb.2011.00128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kang J, Dietz MJ, Li B. Antimicrobial peptide LL-37 is bactericidal against Staphylococcus aureus biofilms. PLoS ONE. 2019;14:e0216676. https://doi.org/10.1371/JOURNAL.PONE.0216676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Overhage J, Campisano A, Bains M, Torfs EC, Rehm BH, Hancock RE. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun. 2008;76(9):4176–82. https://doi.org/10.1128/iai.00318-08.

  59. Kai-Larsen Y, Lüthje P, Chromek M, Peters V, Wang X, Holm Å, Kádas L, Hedlund KO, Johansson J, Chapman MR, Jacobson SH, Römling U, Agerberth B, Brauner A. Uropathogenic escherichia coli modulates immune responses and its curli fimbriae interact with the antimicrobial peptide LL-37. PLoS Pathog. 2010;6:e1001010. https://doi.org/10.1371/JOURNAL.PPAT.1001010.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Begun J, Gaiani JM, Rohde H, Mack D, Calderwood SB, Ausubel FM, Sifri CD. Staphylococcal biofilm exopolysaccharide protects against caenorhabditis elegans immune defenses. PLoS Pathog. 2007;3:e57. https://doi.org/10.1371/journal.ppat.0030057.

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Acknowledgements

Authors would like to thank the Faculty of Pharmacy, UKM for the research facilities support and special thanks to UKM Medical Molecular Biology Institute (UMBI) for supporting the C. elegans work.

Funding

This research is financially supported by the research grant no. GUP-2019–003, Universiti Kebangsaan Malaysia (UKM).

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  1. National Pharmaceutical Regulatory Agency, 36, Jalan Profesor Diraja Ungku Aziz, PJS 13, Petaling Jaya, Selangor, 46200, Malaysia

    Bee-Yee Lim

  2. Centre for Drug Delivery Technology and Vaccine, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia

    Bee-Yee Lim, Fazren Azmi & Shiow-Fern Ng

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Conceptualization and methodology, S.-F. Ng., writing—original draft preparation, B.-Y. Lim., and S.-F. Ng.; review and editing, F.Azmi. and S.-F.Ng. funding acquisition, S.-F. Ng. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Shiow-Fern Ng.

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Lim, BY., Azmi, F. & Ng, SF. LL37 Microspheres Loaded on Activated Carbon-chitosan Hydrogel: Anti-bacterial and Anti-toxin Wound Dressing for Chronic Wound Infections. AAPS PharmSciTech 25, 110 (2024). https://doi.org/10.1208/s12249-024-02826-6

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