Abstract
Calcium alginate (CA) wafer dressings were prepared by lyophilization of hydrogels to deliver ciprofloxacin (CIP) directly to the wound site of infected diabetic foot ulcers (DFUs). The dressings were physically characterized by scanning electron microscopy (SEM), texture analysis (for mechanical and in vitro adhesion properties), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Further, functional properties essential for wound healing, i.e., porosity, in vitro swelling index, water absorption (Aw), equilibrium water content (EWC), water vapor transmission rate (WVTR), evaporative water loss (EWL), moisture content, in vitro drug release and kinetics, antimicrobial activity, and cell viability (MTT assay) were investigated. The wafers were soft, of uniform texture and thickness, and pliable in nature. Wafers showed ideal wound dressing characteristics in terms of fluid handling properties due to high porosity (SEM). XRD confirmed crystalline nature of the dressings and FTIR showed hydrogen bond formation between CA and CIP. The dressings showed initial fast release followed by sustained drug release which can inhibit and prevent re-infection caused by both Gram-positive and Gram-negative bacteria. The dressings also showed biocompatibility (> 85% cell viability over 72 h) with human adult keratinocytes. Therefore, it will be a potential medicated dressing for patients with DFUs infected with drug-resistant bacteria.
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References
Boateng J, Catanzano O. Advanced therapeutic dressings for effective wound healing - a review. J Pharm Sci. 2015;104(11):3653–80. https://doi.org/10.1002/jps.24610.
Sarheed O, Ahmed A, Shouqair D, Boateng JS. Antimicrobial dressings for improving wound healing. In: Alexandrescu V, editor. Wound healing—new insights into ancient challenges. InTech (online); 2016. pp. 377–402. https://www.intechopen.com/books/wound-healing-new-insights-into-ancient-challenges/antimicrobial-dressings-for-improving-wound-healing. Accessed 4 Dec 2016, DOI: https://doi.org/10.5772/63961.
Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010;89(3):219–29. https://doi.org/10.1177/0022034509359125.
Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293(2):217–28. https://doi.org/10.1001/jama.293.2.217.
Ravichandran P, Chitti SP. Antimicrobial dressing for diabetic foot ulcer colonized with MRSA. Online J Biol Sci. 2015;15:282–91.
Kerr M. Diabetic Foot Care in England: an economic study. Insight Heal Econ. 2017;(January):1–52. https://www.diabetes.org.uk/Upload/Shared practice/Diabetic footcare in England, An economic case study (January 2017).pdf. Accessed 5 Oct, 2017.
Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, et al. Diabetic foot ulcers: Part I Pathophysiology and prevention. J Am Acad Dermatol. 2014;70(1):1.e1–1.e18. https://doi.org/10.1016/j.jaad.2013.06.055.
Edmonds M. The treatment of diabetic foot infections: focus on ertapenem. Vasc Health Risk Manag. 2009;5:949–63.
Chiță T, Muntean D, Badițoiu L, Timar B, Moldovan R, Timar R, et al. Staphylococcus aureus strains isolated from diabetic foot ulcers. Identification of the antibiotic resistant phenotypes. Rom J Diabetes Nutr Metab Dis. 2013;20:389–93.
Zubair M, Malik A, Ahmad J. Clinico-microbiological study and antimicrobial drug resistance profile of diabetic foot infections in North India. Foot (Edinb). 2011;21(1):6–14. https://doi.org/10.1016/j.foot.2010.10.003.
O’Loughlin A, McIntosh C, Dinneen SF, O’Brien T. Review paper: basic concepts to novel therapies: a review of the diabetic foot. Int J Low Extrem Wounds. 2010;9(2):90–102. https://doi.org/10.1177/1534734610371600.
Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG. Wound dressings in diabetic foot disease. Clin Infect Dis. 2004;39(Suppl 2):100–3.
Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015;6:37–53.
Boateng JS, Matthews KH, Stevens HNE, Eccleston GM. Wound healing dressings and drug delivery systems: a review. J Pharm Sci. 2008;9:2892–923.
Chang KW, Alsagoff S, Ong KT, Sim PH. Pressure ulcers—randomised controlled trial comparing hydrocolloid and saline gauze dressings. Med J Malaysia. 1998;53(4):428–31.
File TM, Tan JS. Amdinocillin plus cefoxitin versus cefoxitin alone in therapy of mixed soft tissue infections (including diabetic foot infections). Am J Med. 1983;75(2):100–5. https://doi.org/10.1016/0002-9343(83)90103-1.
Fierer J, Daniel D. The fetid foot: lower-extremity infections in patients with diabetes mellitus. Rev Infect Dis. 1979;1(1):210–7. https://doi.org/10.1093/clinids/1.1.210.
Lipsky BA, Pecoraro RE, Larson SA, Hanley ME, Ahroni JH. Outpatient management of uncomplicated lower-extremity infections in diabetic patients. Arch Intern Med. 1990;150(4):790–7. https://doi.org/10.1001/archinte.1990.00390160058013.
Lipsky BA, Baker PD, Landon GC, Fernau R. Antibiotic therapy for diabetic foot infections: comparison of two parenteral-to-oral regimens. Clin Infect Dis. 1997;24(4):643–8. https://doi.org/10.1093/clind/24.4.643.
Lipsky BA, Stoutenburgh U. Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother. 2005;55(2):240–5. https://doi.org/10.1093/jac/dkh531.
Boateng J, Burgos-Amador R, Okeke O, Pawar H. Composite alginate and gelatin based bio-polymeric wafers containing silver sulfadiazine for wound healing. Int J Biol Macromol. 2015;79:63–71. https://doi.org/10.1016/j.ijbiomac.2015.04.048.
Labovitiadi O, Lamb AJ, Matthews KH. vitro efficacy of antimicrobial wafers against methicillin-resistant Staphylococcus aureus. Ther Deliv. 2012;3(4):443–55. https://doi.org/10.4155/tde.12.27.
Pawar HV, Boateng JS, Ayensu I, Tetteh J. Multifunctional medicated lyophilised wafer dressing for effective chronic wound healing. J Pharm Sci. 2014;103(6):1720–33. https://doi.org/10.1002/jps.23968.
Boateng JS, Pawar HV, Tetteh J. Evaluation of in vitro wound adhesion characteristics of composite film and wafer based dressings using texture analysis and FTIR spectroscopy: a chemometrics factor analysis approach. RSC Adv. 2015;5(129):107064–75. https://doi.org/10.1039/C5RA20787H.
Boateng JS, Auffret AD, Matthews KH, Humphrey MJ, Stevens HNE, Eccleston GM. Characterisation of freeze-dried wafers and solvent evaporated films as potential drug delivery systems to mucosal surfaces. Int J Pharm. 2010;389(1-2):24–31. https://doi.org/10.1016/j.ijpharm.2010.01.008.
Catanzano O, Docking R, Schofield P, Boateng J. Advanced multi-targeted composite biomaterial dressing for pain and infection control in chronic leg ulcers. Carbohydr Polym. 2017;172:40–8. https://doi.org/10.1016/j.carbpol.2017.05.040.
Rezvanian M, Tan CK, Ng SF. Simvastatin-loaded lyophilized wafers as a potential dressing for chronic wounds. Drug Dev Ind Pharm. 2016;42(12):2055–62. https://doi.org/10.1080/03639045.2016.1195400.
Sarheed O, Abdul Rasool BK, Abu-Gharbieh E, Aziz US. An investigation and characterization on alginate hydogel dressing loaded with metronidazole prepared by combined inotropic gelation and freeze-thawing cycles for controlled release. AAPS PharmSciTech. 2015;16(3):601–9. https://doi.org/10.1208/s12249-014-0237-1.
Nagesh G, Santosh J, Audumbar M, Manojkumar P. A review on recent trends in oral drug delivery—lyophilized wafer technology. Int J Res Pharm and Pharm Sci. 2016;1:5–9.
Puoci F, Piangiolino C, Givigliano F, Parisi OI, Cassano R, Trombino S, et al. Ciprofloxacin-collagen conjugate in the wound healing treatment. J Funct Biomater. 2012;3(4):361–71. https://doi.org/10.3390/jfb3020361.
Jannesari M, Varshosaz J, Morshed M, Zamani M. Composite poly(vinyl alcohol)/poly(vinyl acetate) electrospun nanofibrous mats as a novel wound dressing matrix for controlled release of drugs. Int J Nanomedicine. 2011;6:993–1003. https://doi.org/10.2147/IJN.S17595.
Kataria K, Gupta A, Rath G, Mathur RB, Dhakate SR. In vivo wound healing performance of drug loaded electrospun composite nanofibers transdermal patch. Int J Pharm. 2014;469(1):102–10. https://doi.org/10.1016/j.ijpharm.2014.04.047.
Öztürk E, Agalar C, Keçeci K, Denkbaş EB. Preparation and characterization of ciprofloxacin-loaded alginate/chitosan sponge as a wound dressing material. J Appl Polym Sci. 2006;101(3):1602–9. https://doi.org/10.1002/app.23563.
Roy DC, Tomblyn S, Burmeister DM, Wrice NL, Becerra SC, Burnett LR, et al. Ciprofloxacin-loaded keratin hydrogels prevent Pseudomonas aeruginosa infection and support healing in a porcine full-thickness excisional wound. Adv Wound Care. 2015;4(8):457–68. https://doi.org/10.1089/wound.2014.0576.
HB TVL, Vidyavathi M, Kavitha K, Sastry T, Suresh kumar RV, Hima BT, et al. Preparation and evaluation of ciprofloxacin loaded chitosan-gelatin composite films for wound healing activity. Int J Drug Deliv. 2010;2:173–82.
Shi Y, Truong VX, Kulkarni K, Qu Y, Simon GP, Boyd RL, et al. Light-triggered release of ciprofloxacin from an in situ forming click hydrogel for antibacterial wound dressings. J Mater Chem B R Soc Chem. 2015;3:3–6.
Unnithan AR, Barakat NAM, Tirupathi Pichiah PB, Gnanasekaran G, Nirmala R, Cha YS, et al. Wound-dressing materials with antibacterial activity from electrospun polyurethane-dextran nanofiber mats containing ciprofloxacin HCl. Carbohydr Polym. 2012;90(4):1786–93. https://doi.org/10.1016/j.carbpol.2012.07.071.
Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis. 2008;47(12):1537–45. https://doi.org/10.1086/593185.
Beberok A, Buszman E, Wrześniok D, Otrȩba M, Trzcionka J. Interaction between ciprofloxacin and melanin: the effect on proliferation and melanization in melanocytes. Eur J Pharmacol. 2011;669(1-3):32–7. https://doi.org/10.1016/j.ejphar.2011.08.003.
Malafaya PB, Silva GA, Reis RL. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv Drug Deliv Rev. 2007;59(4-5):207–33. https://doi.org/10.1016/j.addr.2007.03.012.
Daemi H, Barikani M. Synthesis and characterization of calcium alginate nanoparticles, sodium homopolymannuronate salt and its calcium nanoparticles. Sci Iran. 2012;19(6):2023–8. https://doi.org/10.1016/j.scient.2012.10.005.
Taskin AK, Yasar M, Ozaydin I, Kaya B, Bat O, Ankarali S, et al. The hemostatic effect of calcium alginate in experimental splenic injury model. Ulus Travma Acil Cerrahi Derg. 2013;19(3):195–9. https://doi.org/10.5505/tjtes.2013.30676.
Shilpa A, Agrawal SS, Ray AR. Controlled delivery of drugs from alginate matrix. J Macromol Sci Part C Polym Rev. 2003;43:187–221.
Lloyd LL, Kennedy JF, Methacanon P, Paterson M, Knill CJ. Carbohydrate polymers as wound management aids. Carbohydr Polym. 1998;37(3):315–22. https://doi.org/10.1016/S0144-8617(98)00077-0.
Tarun K, Gobi N. Calcium alginate/PVA blended nano fibre matrix for wound dressing. Indian J Fibre Text Res. 2012;37:127–32.
Moura LIF, Dias AMA, Carvalho E, de Sousa HC. Recent advances on the development of wound dressings for diabetic foot ulcer treatment—a review. Acta Biomater. 2013;9(7):7093–114. https://doi.org/10.1016/j.actbio.2013.03.033.
Lansdown ABG, Lansdown ABG. A pharmacological and toxicological profile of silver as an antimicrobial agent in medical devices. Adv Pharmacol Sci. 2010;2010:1–16. https://doi.org/10.1155/2010/910686.
Hiro ME, Pierpont YN, Ko F, Wright TE, Robson MC, Payne WG. Comparative evaluation of silver-containing antimicrobial dressings on in vitro and in vivo processes of wound healing. Eplasty. 2012;12:409–19.
Burd A, Kwok CH, Hung SC, Chan HS, Gu H, Lam WK, et al. A comparative study of the cytotoxicity of silver-based dressings in monolayer cell, tissue explant, and animal models. Wound Repair Regen. 2007;15(1):94–104. https://doi.org/10.1111/j.1524-475X.2006.00190.x.
Bergin S, Wraight P. Silver based wound dressings and topical agents for treating diabetic foot ulcers. Cochrane Database Syst Rev. 2006; https://doi.org/10.1002/14651858.CD005082.pub2.
Han J, Zhou Z, Yin R, Yang D, Nie J. Alginate-chitosan/hydroxyapatite polyelectrolyte complex porous scaffolds: preparation and characterization. Int J Biol Macromol. 2010;46(2):199–205. https://doi.org/10.1016/j.ijbiomac.2009.11.004.
Gombotz WR, Wee S. Protein release from alginate matrixes. Adv Drug Deliv Rev. 1998;31(3):267–85. https://doi.org/10.1016/S0169-409X(97)00124-5.
Kim IY, Yoo MK, Seo JH, Park SS, Na HS, Lee HC, et al. Evaluation of semi-interpenetrating polymer networks composed of chitosan and poloxamer for wound dressing application. Int J Pharm. 2007;341(1-2):35–43. https://doi.org/10.1016/j.ijpharm.2007.03.042.
Speak K. Management of highly exuding diabetic foot ulcers. Diabet Foot Canada. 2014;2:28–33.
Nireesha G, Divya L, Sowmya C, Venkateshan N, Niranjan Babu M, Lavakumar V. Lyophilization/freeze drying—an review. Ijntps. 2013;3:87–98.
Dhandayuthapani B, Yoshida Y, Maekawa T, Kumar DS. Polymeric scaffolds in tissue engineering application: a review. Int J Polym Sci. 2011; https://doi.org/10.1155/2011/290602.
Xu R, Xia H, He W, Li Z, Zhao J, Liu B, et al. Controlled water vapor transmission rate promotes wound-healing via wound re-epithelialization and contraction enhancement. Sci Rep. Nature Publishing Group; 2016; https://doi.org/10.1038/srep24596.
Thomas S, Hay P. Fluid handling properties of hydrogel dressings. Ostomy Wound Manage. 1995;41:54–9.
Balakrishnan B, Mohanty M, Umashankar PR, Jayakrishnan A. Evaluation of an in situ forming hydrogel wound dressing based on oxidized alginate and gelatin. Biomaterials. 2005;26(32):6335–42. https://doi.org/10.1016/j.biomaterials.2005.04.012.
Kianfar F, Antonijevic M, Chowdhry B, Boateng JS. Lyophilized wafers comprising carrageenan and pluronic acid for buccal drug delivery using model soluble and insoluble drugs. Colloids Surfaces B Biointerfaces. 2013;103:99–106. https://doi.org/10.1016/j.colsurfb.2012.10.006.
Kianfar F, Ayensu I, Boateng JS. Development and physico-mechanical characterization of carrageenan and poloxamer-based lyophilized matrix as a potential buccal drug delivery system. Drug Dev Ind Pharm. 2013;9045:1–9.
Momoh FU, Boateng JS, Richardson SCW, Chowdhry BZ, Mitchell JC. International Journal of Biological Macromolecules Development and functional characterization of alginate dressing as potential protein delivery system for wound healing. Int J Biol Macromol. 2015;81:137–50. https://doi.org/10.1016/j.ijbiomac.2015.07.037.
Kianfar F, Chowdhry BZ, Antonijevic MD, Boateng JS. Novel films for drug delivery via the buccal mucosa using model soluble and insoluble. Drugs. 2012;38:1207–20.
Thomas S. The role of dressings in the treatment of moisture-related skin damage. World Wide Wounds 2008. http://www.worldwidewounds.com/2008/march/Thomas/Maceration-and-the-role-of-dressings.html. Accessed 14 Jan 2017, 20, 3, 67, 73.
Ayensu I, Mitchell JC, Boateng JS. Development and physico-mechanical characterisation of lyophilised chitosan wafers as potential protein drug delivery systems via the buccal mucosa. Colloids Surfaces B Biointerfaces. 2012;91:258–65. https://doi.org/10.1016/j.colsurfb.2011.11.004.
Boateng JS, Matthews KH, Auffret AD, Humphrey MJ, Stevens HN, Eccleston GM. In vitro drug release studies of polymeric freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug. Int J Pharm. 2009;378(1-2):66–72. https://doi.org/10.1016/j.ijpharm.2009.05.038.
Boateng JS, Matthews KH, Auffret AD, Humphrey MJ, Eccleston GM, Stevens HN. Comparison of the in vitro release characteristics of mucosal freeze-dried wafers and solvent-cast films containing an insoluble drug. Drug Dev Ind Pharm. 2012;38(1):47–54. https://doi.org/10.3109/03639045.2011.590496.
Wiegand C, Hipler U-C. Methods for the measurement of cell and tissue compatibility including tissue regeneration processes. GMS Krankenhaushygiene Interdiszip. 2008;3:1–9.
Moritz S, Wiegand C, Wesarg F, Hessler N, Muller FA, Kralisch D, et al. Active wound dressings based on bacterial nanocellulose as drug delivery system for octenidine. Int J Pharm. 2014;471(1-2):45–55. https://doi.org/10.1016/j.ijpharm.2014.04.062.
Zhou C, Heath DE, Sharif ARM, Rayatpisheh S, BHL O, Rong X, et al. High water content hydrogel with super high refractive index. Macromol Biosci. 2013;13(11):1485–91. https://doi.org/10.1002/mabi.201300191.
Gurbay A, Garrel C, Osman M, Richard MJ, Favier A, Hincal F. Cytotoxicity in ciprofloxacin-treated human fibroblast cells and protection by vitamin E. Hum Exp Toxicol. 2002;21(12):635–41. https://doi.org/10.1191/0960327102ht305oa.
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The authors will like to thank Samantha Lewis for her help with microbial analyses, Andrew Hurt for help with XRD and SEM analyses.
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Ahmed, A., Getti, G. & Boateng, J. Ciprofloxacin-loaded calcium alginate wafers prepared by freeze-drying technique for potential healing of chronic diabetic foot ulcers. Drug Deliv. and Transl. Res. 8, 1751–1768 (2018). https://doi.org/10.1007/s13346-017-0445-9
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DOI: https://doi.org/10.1007/s13346-017-0445-9