Stimulated phase-shift acoustic nanodroplets enhance vancomycin efficacy against methicillin-resistant Staphylococcus aureus biofilms

International Journal of Nanomedicine Dovepress open access to scientific and medical research O r i g in a l R e s e a r c h International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 5.135.254.153 on 13-Jul-2018 For personal use only. Open Access Full Text Article Stimulated phase-shift acoustic nanodroplets enhance vancomycin efficacy against methicillinresistant Staphylococcus aureus biofilms This article was published in the following Dove Press journal: International Journal of Nanomedicine 30 June 2017 Number of times this article has been viewed Hao Guo 1 Ziming Wang 1 Quanyin Du 1 Pan Li 2 Zhigang Wang 2 Aimin Wang 1 Department of Orthopedics, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China; 2Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China 1 Correspondence: Aimin Wang Department of Orthopedics, Institute of Surgery Research, Daping Hospital, Third Military Medical University, No 10, Daping Changjiang Branch Road, Yuzhong District, Chongqing 400042, China Tel +86 23 6875 7936 Email Pan Li Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, Second Affiliated Hospital of Chongqing Medical University, No 76, Linjiang Road, Yuzhong District, Chongqing 400010, China Tel +86 136 3798 0781 Email Introduction Periprosthetic joint infection (PJI) following arthroplasty presents notably morbid consequences to the health of patients, although PJI occurs only in 2.0% and 2.4% of total hip arthroplasties (THA) and total knee arthroplasties (TKA), respectively.1 As total joint arthroplasties are widely used, the number of PJI is constantly increasing. These infections may render patients extremely agonizing and often require orthopedic surgeons to surgically remove the compromised implant, replace it, and fight the infection with long-term antibiotics, which is costly, demanding but may be unproductive.2,3 Due to increasing evidence of past decades, bacterial biofilms formed on the surface 4679 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2017:12 4679–4690 Dovepress © 2017 Guo et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/IJN.S134525 Powered by TCPDF (www.tcpdf.org) Purpose: Bacterial biofilms on the surface of prostheses are becoming a rising concern in managing prosthetic joint infections. The inherent resistant features of biofilms render traditional antimicrobial therapy unproductive and revision surgery outcomes uncertain. This situation has prompted the exploration of novel antimicrobial strategies. The synergy of ultrasound microbubbles and vancomycin has been proposed as an efficient alternative for biofilm eradication. The purpose of this study was to evaluate the anti-biofilm effect of stimulated phase-shift acoustic nanodroplets (NDs) combined with vancomycin. Materials and methods: We fabricated lipid phase-shift NDs with a core of liquid perfluoropentane. A new phase change mode for NDs incorporating an initial unfocused low-intensity pulsed ultrasound for 5 minutes and a subsequent incubation at 37°C into a 24-hour duration was developed. Methicillin-resistant Staphylococcus aureus (MRSA) biofilms were incubated with vancomycin and NDs under the hybrid stimulation. Biofilm morphology following treatment was determined using confocal laser scanning microscopy and scanning electron microscopy. Resazurin assay was used to quantify bactericidal efficacy against MRSA biofilm bacteria. Results: NDs treated sequentially with ultrasound and heating at 37°C achieved gradual and substantial ND vaporization and cavitation in a successive process. NDs after stimulation were capable of generating stronger destruction on biofilm structure which was best characterized by residual circular arc margins and more dead bacteria. Furthermore, NDs combined with vancomycin contributed to significantly decreasing the metabolic activity of bacteria in MRSA biofilms (P,0.05). Conclusion: Phase-shift acoustic NDs could exert a significant bactericidal effect against MRSA biofilms through a new stimulation mode. Acoustic NDs present advantages over microbubbles for biofilm damage. This anti-biofilm strategy could be used either alone or as an enhancer of traditional antibiotics in the control of prosthetic joint infections. Keywords: nanodroplets, MRSA, biofilm matrix, ultrasound, phase change, cavitation Dovepress International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 5.135.254.153 on 13-Jul-2018 For personal use only. Guo et al of implants appear to be a major player in PJI pathogenesis, which has been taken into consideration for the next iteration of PJI guidelines.4,5 Microorganisms sequestered in biofilms are characterized by enhanced resistance against common antimicrobial agents and reduced susceptibility to host immune defenses.6 Because of the inherent resistant properties, biofilms are extremely difficult to eradicate. Of all the factors related to the recalcitrance of biofilm-associated infection, the key may be attributed to the highly complex and variable structure of biofilm matrix, predominantly produced by organisms themselves, which result in markedly decreased penetration of antibiotics and reduced metabolic activity of biofilm-encased bacteria.7,8 Therefore, there have been growing research efforts on potential candidate strategies targeting disruption of biofilm structure, especially nonoperative, for the sake of improving the efficacy of antimicrobial chemotherapy. Acoustic cavitation effects, often triggered by either ultrasound (US) alone or US plus microbubbles (MBs), suggest a promising noninvasive method for biofilm eradication when combining with antimicrobial substances. It has been widely accepted that the collapse of MBs leads to transient cavitation that can create pores in cell membranes or holes in blood vessels.9 Recent studies have found that the cavitation-induced bactericidal effects against biofilms are based upon the cavitationally enhanced antibiotic activity within biofilms and the restored susceptibility of biofilmencapsulated cells to antibiotic action.10–13 These effects are of high relevance to the mechanical destruction of (...truncated)