@article{acbb4b99e36a4d88a9d7563276b31191,
title = "Injectable hydrogel as a carrier of vancomycin and a cathelicidin-derived peptide for osteomyelitis treatment",
abstract = "A local drug delivery system that attempts to find a suitable balance between antimicrobial and regenerative actions was developed for osteomyelitis treatment (OM). This system combines the angiogenic and immunomodulatory peptide LLKKK18 (LL18) and vancomycin hydrochloride (VH), loaded into an injectable oxidized dextrin (ODEX)-based hydrogel (HG). In vitro cytotoxicity was analyzed in MC3T3-E1 pre-osteoblasts and erythrocytes. The kinetics of LL18 release was studied. Antimicrobial activity was assessed in vitro against a clinical Methicillin-Resistant Staphylococcus aureus (MRSA) strain. A rat model of acute OM was developed by direct inoculation into a tibia defect, concomitantly with the implantation of the drug-loaded HG. The local bioburden was quantified and damage in surrounding tissues was examined histologically. In vitro, ODEX-based HG displayed a safe hemolytic profile. Half of LL18 (53%) is released during the swelling phase at physiological pH, then being gradually released until complete HG degradation. LL18-loaded HG at 300 μM was the most effective peptide formulation in decreasing in vivo infection among concentrations ranging from 86 to 429 μM. The histopathological scores observed in vivo varied with the LL18 concentration in a dose-dependent manner. VH at 28 mM completely eradicated bacteria, although with substantial tissue injury. We have found that sub-millimolar doses of VH combined with LL18 at 300 μM may suffice to eradicate the infection, with reduced tissue damage. We propose an easy-to-handle, shape-fitting HG formulation with the potential to treat MRSA-infected bone with low VH doses associated with LL18.",
keywords = "cathelicidin, dextrin, hydrogel, osteomyelitis, Staphylococcus aureus, vancomycin",
author = "Alexandra Machado and Isabel Pereira and Vanessa Silva and Isabel Pires and Justina Prada and Patr{\'i}cia Poeta and Lu{\'i}s Costa and Pereira, {Jos{\'e} Eduardo} and Miguel Gama",
note = "Funding Information: European Regional Development Fund under the scope of Norte 2020; BioTecNorte Operation, Grant/Award Number: NORTE‐01‐0145‐FEDER‐000004; COMPETE 2020, Grant/Award Number: POCI‐01‐0145‐FEDER‐006684; Portuguese Foundation for Science and Technology (FCT), Grant/Award Numbers: LA/P/0059/2020, UIDB/CVT/00772/2020, SFRH/BD/137947/2018, SFRH/BD/132000/2017, UID/BIO/04469; iBONE therapies: advanced solutions for bone regeneration, Grant/Award Number: 003262 Funding information dil 50 Staphylococcus aureus 50 SD Funding Information: The authors acknowledge the funding from FEDER and NORTE 2020 through the project n° 003262 titled “iBONE therapies: advanced solutions for bone regeneration”. This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469 unit and COMPETE 2020 (POCI‐01‐0145‐FEDER‐006684) and BioTecNorte Operation (NORTE‐01‐0145‐FEDER‐000004) funded by the European Regional Development Fund under the scope of Norte 2020 ‐ Programa Operacional Regional do Norte. Alexandra Machado and Vanessa Silva o gratefully acknowledge FCT for the granted scholarships (SFRH/BD/132000/2017 and SFRH/BD/137947/2018). The work was also funded by the project UIDB/CVT/00772/2020 supported by FCT. The participation of Isabel Pires, Justina Prada, Patr{\'i}cia Poeta, Lu{\'i}s Costa e Jos{\'e} Eduardo Pereira was funded by the projects UIDB/CVT/00772/2020 and LA/P/0059/2020 supported by FCT. Publisher Copyright: {\textcopyright} 2022 Wiley Periodicals LLC.",
year = "2022",
month = nov,
doi = "10.1002/jbm.a.37432",
language = "English",
volume = "110",
pages = "1786--1800",
journal = "Journal of Biomedical Materials Research - Part A",
issn = "1549-3296",
publisher = "Heterocorporation",
number = "11",
}