Skip to main content

Advertisement

SpringerLink
Log in

Development of clindamycin-loaded alginate/pectin/hyaluronic acid composite hydrogel film for the treatment of MRSA-infected wounds

  • Original Article
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

Abstract

Purpose

Methicillin-resistant Staphylococcus aureus (MRSA) infection on wounds possesses a high risk in increased cases of morbidity and mortality worldwide. Antibiotic-loaded composite biopolymer film wound dressings are one approach to cover the chronic wound area, promote the healing process, and create suitable healing environments. In this study, we developed clindamycin (Cly)-loaded composite biopolymer films using hydrogel-forming biopolymers, such as sodium alginate (SA), pectin (P), and hyaluronic acid (HA) for the treatment of MRSA-infected wounds.

Methods

Composite films were prepared using a solvent casting method. Cly-loaded composites hydrogel films were evaluated for their physical properties (e.g., film thickness, surface morphology, pH, water vapor transmission, expansion profile, and fluid uptake), in vitro drug release, in vitro bactericidal effects, and in vivo wound healing activity in an ICR mouse model of MRSA-infected wounds.

Results

Thin, transparent, and highly absorbent Cly-loaded SA-P (Cly/SA-P) and Cly-loaded SA-P-HA (Cly/SA-P-HA) film dressings were successfully prepared with good physical properties. The Cly/SA-P and Cly/SA-P-HA films exhibited drug release over 12 h under immersed conditions and potent antibacterial activity against MRSA (> 5 log reduction in bacterial viability). Furthermore, compared with the other groups, the Cly/SA-P-HA-treated group significantly accelerated the healing and re-epithelialization of wounds in a mouse model of MRSA-infected wounds. All prepared film dressings were not toxic to healthy fibroblast cells.

Conclusion

Thus, the Cly-loaded composite hydrogel film prepared in this study could be a promising wound dressing for the treatment of infected cutaneous wounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Abou-Okeil A, Fahmy HM, El-Bisi MK, Ahmed-Farid OA (2018) Hyaluronic acid/Na-alginate films as topical bioactive wound dressings. Eur Polym J 109:101–109

    Article  CAS  Google Scholar 

  • Bae SH, Bae YC, Nam SB, Choi SJ (2012) A skin fixation method for decreasing the influence of wound contraction on wound healing in a rat model. Arch Plast Surg 39:457

    Article  PubMed  PubMed Central  Google Scholar 

  • Banna H, Hasan N, Lee J, Kim J, Cao J, Lee EH, Moon HR, Chung HY, Yoo J-W (2018) In vitro and in vivo evaluation of MHY908-loaded nanostructured lipid carriers for the topical treatment of hyperpigmentation. J Drug Deliv Sci Technol 48:457–465

    Article  CAS  Google Scholar 

  • Cao J, Su M, Hasan N, Lee J, Kwak D, Kim DY, Kim K, Lee EH, Jung JH, Yoo J-WJP (2020) Nitric oxide-releasing thermoresponsive pluronic F127/alginate hydrogel for enhanced antibacterial activity and accelerated healing of infected wounds. Pharmaceutics 12:926

    Article  CAS  PubMed Central  Google Scholar 

  • Cho H-J (2020) Recent progresses in the development of hyaluronic acid-based nanosystems for tumor-targeted drug delivery and cancer imaging. J Pharm Investig 50:115–129

    Article  CAS  Google Scholar 

  • Choi M, Hasan N, Cao J, Lee J, Hlaing SP, Yoo J-W (2020) Chitosan-based nitric oxide-releasing dressing for anti-biofilm and in vivo healing activities in MRSA biofilm-infected wounds. Int J Biol Macromol 142:680–692

    Article  CAS  PubMed  Google Scholar 

  • Coleman DL, Gregonis DE, Andrade JD (1982) Blood–materials interactions: the minimum interfacial free energy and the optimum polar/apolar ratio hypotheses. J Biomed Mater Res 16:381–398

    Article  CAS  PubMed  Google Scholar 

  • Dou J-L, Jiang Y-W, Xie J-Q, Zhang X-G (2016) New is old, and old is new: recent advances in antibiotic-based, antibiotic-free and ethnomedical treatments against methicillin-resistant Staphylococcus aureus wound infections. Int J Mol Sci 17:617

    Article  PubMed Central  CAS  Google Scholar 

  • Etxabide A, Vairo C, Santos-Vizcaino E, Guerrero P, Pedraz JL, Igartua M, De La Caba K, Hernandez RM (2017) Ultra thin hydro-films based on lactose-crosslinked fish gelatin for wound healing applications. Int J Pharm 530:455–467

    Article  CAS  PubMed  Google Scholar 

  • Hasan N, Cao J, Lee J, Hlaing SP, Oshi MA, Naeem M, Ki M-H, Lee BL, Jung Y, Yoo J-W (2019a) Bacteria-targeted clindamycin loaded polymeric nanoparticles: effect of surface charge on nanoparticle adhesion to MRSA, antibacterial activity, and wound healing. Pharmaceutics 11:236

    Article  CAS  PubMed Central  Google Scholar 

  • Hasan N, Cao J, Lee J, Naeem M, Hlaing SP, Kim J, Jung Y, Lee B-L, Yoo J-W (2019b) PEI/NONOates-doped PLGA nanoparticles for eradicating methicillin-resistant Staphylococcus aureus biofilm in diabetic wounds via binding to the biofilm matrix. Mater Sci Eng C 103:109741

    Article  CAS  Google Scholar 

  • Hasan N, Lee J, Kwak D, Kim H, Saparbayeva A, Ahn H-J, Yoon I-S, Kim M-S, Jung Y, Yoo J-W (2021) Diethylenetriamine/NONOate-doped alginate hydrogel with sustained nitric oxide release and minimal toxicity to accelerate healing of MRSA-infected wounds. Carbohydr Polym 270:118387

    Article  CAS  PubMed  Google Scholar 

  • Hlaing SP, Kim J, Lee J, Hasan N, Cao J, Naeem M, Lee EH, Shin JH, Jung Y, Lee B-L (2018) S-Nitrosoglutathione loaded poly (lactic-co-glycolic acid) microparticles for prolonged nitric oxide release and enhanced healing of methicillin-resistant Staphylococcus aureus-infected wounds. Eur J Pharm Biopharm 132:94–102

    Article  CAS  PubMed  Google Scholar 

  • Huanbutta K, Sittikijyothin W, Sangnim T (2020) Development of topical natural based film forming system loaded propolis from stingless bees for wound healing application. J Pharm Investig 50:625–634

    Article  CAS  Google Scholar 

  • Kim JO, Noh J-K, Thapa RK, Hasan N, Choi M, Kim JH, Lee J-H, Ku SK, Yoo J-W (2015) Nitric oxide-releasing chitosan film for enhanced antibacterial and in vivo wound-healing efficacy. Int J Biol Macromol 79:217–225

    Article  CAS  PubMed  Google Scholar 

  • Kokabi M, Sirousazar M, Hassan ZMJEPJ (2007) PVA–clay nanocomposite hydrogels for wound dressing. Eur Polym J 43:773–781

    Article  CAS  Google Scholar 

  • Lamke LO, Nilsson GEA, Reithner HL (1977) The evaporative water loss from burns and the water-vapour permeability of grafts and artificial membranes used in the treatment of burns. Burns 3:159–165

    Article  Google Scholar 

  • Leaper DJ, Van Goor H, Reilly J, Petrosillo N, Geiss HK, Torres AJ, Berger A (2004) Surgical site infection–a European perspective of incidence and economic burden. Int Wound J 1:247–273

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee KY, Mooney DJ (2012) Alginate: properties and biomedical applications. Prog Polym Sci 37:106–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J, Hlaing SP, Cao J, Hasan N, Ahn H-J, Song K-W, Yoo J-W (2019) In situ hydrogel-forming/nitric oxide-releasing wound dressing for enhanced antibacterial activity and healing in mice with infected wounds. Pharmaceutics 11:496

    Article  CAS  PubMed Central  Google Scholar 

  • Lee J, Hlaing SP, Cao J, Hasan N, Yoo J-W (2020a) In vitro and in vivo evaluation of a novel nitric oxide-releasing ointment for the treatment of methicillin-resistant Staphylococcus aureus-infected wounds. J Pharm Investig 50(5):505–512

    Article  CAS  Google Scholar 

  • Lee J, Kwak D, Kim H, Kim J, Hlaing SP, Hasan N, Cao J, Yoo J-W (2020b) Nitric oxide-releasing s-nitrosoglutathione-conjugated poly (Lactic-Co-Glycolic Acid) nanoparticles for the treatment of MRSA-infected cutaneous wounds. Pharmaceutics 12:618

    Article  CAS  PubMed Central  Google Scholar 

  • Li Y, Tian Y, Zheng W, Feng Y, Huang R, Shao J, Tang R, Wang P, Jia Y, Zhang J (2017) Composites of bacterial cellulose and small molecule-decorated gold nanoparticles for treating gram-negative bacteria-infected wounds. Small 13:1700130

    Article  CAS  Google Scholar 

  • Martínez-Aguilar G, Hammerman WA, Mason EO Jr, Kaplan SL (2003) Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus in children. Pediatr Infect Dis J 22:593–599

    PubMed  Google Scholar 

  • Matthews KH, Stevens HNE, Auffret AD, Humphrey MJ, Eccleston GM (2005) Lyophilised wafers as a drug delivery system for wound healing containing methylcellulose as a viscosity modifier. Int J Pharm 289:51–62

    Article  CAS  PubMed  Google Scholar 

  • Mohamad N, Amin MCIM, Pandey M, Ahmad N, Rajab NF (2014) Bacterial cellulose/acrylic acid hydrogel synthesized via electron beam irradiation: accelerated burn wound healing in an animal model. Carbohydr Polym 114:312–320

    Article  CAS  PubMed  Google Scholar 

  • Mohebali A, Abdouss M (2020) Layered biocompatible pH-responsive antibacterial composite film based on HNT/PLGA/chitosan for controlled release of minocycline as burn wound dressing. Int J Biol Macromol 164:4193–4204

    Article  CAS  PubMed  Google Scholar 

  • Moura LI, Dias AM, Carvalho E, De Sousa HC (2013) Recent advances on the development of wound dressings for diabetic foot ulcer treatment—A review. Acta Biomater 9:7093–7114

    Article  CAS  PubMed  Google Scholar 

  • Munarin F, Tanzi MC, Petrini P (2012) Advances in biomedical applications of pectin gels. Int J Biol Macromol 51:681–689

    Article  CAS  PubMed  Google Scholar 

  • Neuman MG, Nanau RM, Oruña-Sanchez L, Coto G (2015) Hyaluronic acid and wound healing. J Pharm Pharm Sci 18:53–60

    Article  CAS  PubMed  Google Scholar 

  • Nurhasni H, Cao J, Choi M, Kim I, Lee BL, Jung Y, Yoo J-W (2015) Nitric oxide-releasing poly (lactic-co-glycolic acid)-polyethylenimine nanoparticles for prolonged nitric oxide release, antibacterial efficacy, and in vivo wound healing activity. Int J Nanomedicine 10:3065

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oshi MA, Naeem M, Bae J, Kim J, Lee J, Hasan N, Kim W, Im E, Jung Y, Yoo J-WJCP (2018) Colon-targeted dexamethasone microcrystals with pH-sensitive chitosan/alginate/Eudragit S multilayers for the treatment of inflammatory bowel disease. Carbohydr Polym 198:434–442

    Article  CAS  PubMed  Google Scholar 

  • Parris N, Coffin DR (1997) Composition factors affecting the water vapor permeability and tensile properties of hydrophilic zein films. J Agric Food Chem 45:1596–1599

    Article  CAS  Google Scholar 

  • Paul W, Sharma CP (2004) Chitosan and alginate wound dressings: a short review. Trends Biomater Artif Organs 18:18–23

    Google Scholar 

  • Rezvanian M, Amin MCIM, Ng S-F (2016) Development and physicochemical characterization of alginate composite film loaded with simvastatin as a potential wound dressing. Carbohydr Polym 137:295–304

    Article  CAS  PubMed  Google Scholar 

  • Round AN, Rigby NM, Macdougall AJ, Morris VJ (2010) A new view of pectin structure revealed by acid hydrolysis and atomic force microscopy. Carbohydr Res 345:487–497

    Article  CAS  PubMed  Google Scholar 

  • Šiširak M, Zvizdić A, Hukić M (2010) Methicillin-resistant Staphylococcus aureus (MRSA) as a cause of nosocomial wound infections. Bosn J Basic Med Sci 10:32

    Article  PubMed  PubMed Central  Google Scholar 

  • Spížek J, Řezanka T (2004) Lincomycin, clindamycin and their applications. Appl Microbiol Biotechnol 64:455–464

    Article  PubMed  CAS  Google Scholar 

  • Spížek J, Řezanka T (2017) Lincosamides: Chemical structure, biosynthesis, mechanism of action, resistance, and applications. Biochem Pharmacol 133:20–28

    Article  PubMed  CAS  Google Scholar 

  • Stein M, Komerska J, Prizade M, Sheinberg B, Tasher D, Somekh E (2016) Clindamycin resistance among Staphylococcus aureus strains in Israel: implications for empirical treatment of skin and soft tissue infections. Int J Infect Dis 46:18–21

    Article  CAS  PubMed  Google Scholar 

  • Thu H-E, Zulfakar MH, Ng S-F (2012) Alginate based bilayer hydrocolloid films as potential slow-release modern wound dressing. Int J Pharm 434:375–383

    Article  CAS  PubMed  Google Scholar 

  • Toole BP (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4:528–539

    Article  CAS  PubMed  Google Scholar 

  • Tsukada K (1992) The pH changes of pressure ulcers related headling process of wound. Wounds 4:16–20

    Google Scholar 

  • Vivekanandan L, Sheik H, Singaravel S, Thangavel S (2020) Assessment of efficacy and safety of clindamycin against methicillin-resistant staphylococcus aureus (MRSA) infected subcutaneous abscess model. Antinfect Agents 18:144–151

    CAS  Google Scholar 

  • Vowden K, Vowden P (2017) Wound Dressings: Principles and Practice Surgery (oxford) 35:489–494

    Google Scholar 

  • Wang L, MaE A, Kerry JP (2010) Physical assessment of composite biodegradable films manufactured using whey protein isolate, gelatin and sodium alginate. J Food Eng 96:199–207

    Article  CAS  Google Scholar 

  • Wong T, Mcgrath JA, Navsaria H (2007) The role of fibroblasts in tissue engineering and regeneration. Br J Dermatol 156:1149–1155

    Article  CAS  PubMed  Google Scholar 

  • Wynne R, Botti M, Stedman H, Holsworth L, Harinos M, Flavell O, Manterfield C (2004) Effect of three wound dressings on infection, healing comfort, and cost in patients with sternotomy wounds: a randomized trial. Chest 125:43–49

    Article  PubMed  Google Scholar 

  • Yang D, Jones KS (2009) Effect of alginate on innate immune activation of macrophages. J Biomed Mater Res a 90:411–418

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was financially supported by the 2021 Post-Doc. Development Program of Pusan National University and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2019R1I1A3A01057849).

Author information

Authors and Affiliations

  1. College of Pharmacy, Pusan National University, Busan, 609-735, South Korea

    Nurhasni Hasan, Juho Lee, Hyunwoo Kim & Jin-Wook Yoo

  2. Faculty of Pharmacy, Hasanuddin University, Jl. Perintis Kemerdekaan Km 10, Makassar, 90245, Republic of Indonesia

    Nurhasni Hasan

  3. State Key Laboratory for Function and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550-014, China

    Jiafu Cao

Authors
  1. Nurhasni Hasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiafu Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyunwoo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jin-Wook Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin-Wook Yoo.

Ethics declarations

Conflict of interest

All authors (N. Hasan, J. Cao, J. Lee, H. Kim, and J.-W. Yoo) declare that they have no conflict of interest.

Research involved in Human and Animal Rights

All animal experiments were reviewed and approved by the Pusan National University Institutional Animal Care and Use Committee (PNU-IACUC) in 2020 (PNU-2020–2839).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hasan, N., Cao, J., Lee, J. et al. Development of clindamycin-loaded alginate/pectin/hyaluronic acid composite hydrogel film for the treatment of MRSA-infected wounds. J. Pharm. Investig. 51, 597–610 (2021). https://doi.org/10.1007/s40005-021-00541-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-021-00541-z

Keywords

Search

Navigation