A new strategy for the treatment of middle ear infection using ciprofloxacin/amoxicillin-loaded ethyl cellulose/polyhydroxybutyrate nanofibers

Hatice Karabulut; Dingli Xu; Yuxi Ma; Tufan Arslan Tut; Songul Ulag; Orkun Pinar; Dilek Kazan; Mehmet Mucahit Guncu; Ali Sahin; Hua Wei; Jing Chen; Oguzhan Gunduz

doi:10.1016/j.ijbiomac.2024.131794

A new strategy for the treatment of middle ear infection using ciprofloxacin/amoxicillin-loaded ethyl cellulose/polyhydroxybutyrate nanofibers

Int J Biol Macromol. 2024 Apr 30;269(Pt 1):131794. doi: 10.1016/j.ijbiomac.2024.131794. Online ahead of print.

Authors

Hatice Karabulut¹, Dingli Xu², Yuxi Ma³, Tufan Arslan Tut⁴, Songul Ulag⁴, Orkun Pinar⁵, Dilek Kazan⁶, Mehmet Mucahit Guncu⁷, Ali Sahin⁸, Hua Wei⁹, Jing Chen¹⁰, Oguzhan Gunduz¹¹

Affiliations

¹ Department of Systems Science and Industrial Engineering, State University of New York at Binghamton, New York, USA; Center for Nanotechnology & Biomaterials Research, Marmara University, Istanbul, Turkey.
² Health Science Center, Ningbo University, Zhejiang, China.
³ Ningbo Institute of Materials Technology & Engineering, Chinese Academy of Sciences, Ningbo, China; University of Chinese Academy of Sciences, Beijing, China.
⁴ Center for Nanotechnology & Biomaterials Research, Marmara University, Istanbul, Turkey; Department of Metallurgy and Materials Engineering, Faculty of Technology, Marmara University, Istanbul, Turkey.
⁵ Department of Separation Science, LUT School of Engineering Science, LUT University, Sammonkatu 12, 50130, Mikkeli, Finland.
⁶ Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey; Bacpolyzyme Bioengineering LLC., Marmara University Technopark., Istanbul, Turkey.
⁷ Institute of Health Sciences, Department of Microbiology, Marmara University, Istanbul, Turkey.
⁸ Department of Biochemistry, School of Medicine/ Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey.
⁹ Key Laboratory of Colloid and Interface Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. Electronic address: weihua@mail.sdu.edu.cn.
¹⁰ Institute of Medical Sciences, The Second Hospital & Shandong University Centre for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.. Electronic address: jc@email.sdu.edu.cn.
¹¹ Center for Nanotechnology & Biomaterials Research, Marmara University, Istanbul, Turkey; Department of Metallurgy and Materials Engineering, Faculty of Technology, Marmara University, Istanbul, Turkey. Electronic address: ucemogu@ucl.ac.uk.

PMID: 38697434
DOI: 10.1016/j.ijbiomac.2024.131794

Abstract

A middle ear infection occurs due to the presence of several microorganisms behind the eardrum (tympanic membrane) and is very challenging to treat due to its unique location and requires a well-designed treatment. If not treated properly, the infection can result in severe symptoms and unavoidable side effects. In this study, excellent biocompatible ethyl cellulose (EC) and biodegradable polyhydroxybutyrate (PHB) biopolymer were used to fabricate drug-loaded nanofiber scaffolds using an electrospinning technique to overcome antibiotic overdose and insufficient efficacy of drug release during treatment. PHB polymer was produced from Halomonas sp., and the purity of PHB was found to around be 90 %. Additionally, ciprofloxacin (CIP) and amoxicillin (AMX) are highly preferable since both drugs are highly effective against gram-negative and gram-positive bacteria to treat several infections. Obtained smooth nanofibers were between 116.24 and 171.82 nm in diameter and the addition of PHB polymer and antibiotics improved the morphology of the nanofiber scaffolds. Thermal properties of the nanofiber scaffolds were tested and the highest T_g temperature resulted at 229 °C. The mechanical properties of the scaffolds were tested, and the highest tensile strength resulted in 4.65 ± 6.33 MPa. Also, drug-loaded scaffolds were treated against the most common microorganisms that cause the infection, such as S.aureus, E.coli, and P.aeruginosa, and resulted in inhibition zones between 10 and 21 mm. MTT assay was performed by culturing human adipose-derived mesenchymal stem cells (hAD MSCs) on the scaffolds. The morphology of the hAD MSCs' attachment was tested with SEM analysis and hAD MSCs were able to attach, spread, and live on each scaffold even on the day of 7. The cumulative drug release kinetics of CIP and AMX from drug-loaded scaffolds were analysed in phosphate-buffered saline (pH: 7.4) within different time intervals of up to 14 days using a UV spectrophotometer. Furthermore, the drug release showed that the First-Order and Korsmeyer-Peppas models were the most suitable kinetic models. Animal testing was performed on SD rats, matrix and collagen deposition occurred on days 5 and 10, which were observed using Hematoxylin-eosin and Masson's trichrome staining. At the highest drug concentration, a better repair effect was observed. Results were promising and showed potential for novel treatment.

Keywords: Amoxicillin; Ciprofloxacin; Electrospinning; Ethyl cellulose; Middle ear infection; Polyhydroxybutyrate.