Alexandra I Stavrakis1, Suwei Zhu2, Vishal Hegde1, Amanda H Loftin1, Alyssa G Ashbaugh3, Jared A Niska1, Lloyd S Miller3, Tatiana Segura2, Nicholas M Bernthal4. 1. Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California. 2. Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California. 3. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 4. Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California nbernthal@mednet.ucla.edu.
Abstract
BACKGROUND: Postoperative infection is a devastating complication following arthroplasty. The goals of this study were to introduce a "smart" implant coating that combines passive elution of antibiotic with an active-release mechanism that "targets" bacteria, and to use an established in vivo mouse model of post-arthroplasty infection to longitudinally evaluate the efficacy of this polymer implant coating in decreasing bacterial burden. METHODS: A novel, biodegradable coating using branched poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) polymer was designed to deliver antibiotics both passively and actively. In vitro-release kinetics were studied using high-performance liquid chromatography (HPLC) quantification in conditions representing both the physiologic environment and the more oxidative, hyperinflammatory environment of periprosthetic infection. The in vivo efficacy of the PEG-PPS coating delivering vancomycin and tigecycline was tested using an established mouse model of post-arthroplasty infection. Noninvasive bioluminescence imaging was used to quantify the bacterial burden; radiography, to assess osseointegration and bone resorption; and implant sonication, for colony counts. RESULTS: In vitro-release kinetics confirmed passive elution above the minimum inhibitory concentration (MIC). A rapid release of antibiotic was noted when challenged with an oxidative environment (p < 0.05), confirming a "smart" active-release mechanism. The PEG-PPS coating with tigecycline significantly lowered the infection burden on all days, whereas PEG-PPS-vancomycin decreased infection on postoperative day (POD) 1, 3, 5, and 7 (p < 0.05). A mean of 0, 9, and 2.6 × 10(2) colony-forming units (CFUs) grew on culture from the implants treated with tigecycline, vancomycin, and PEG-PPS alone, respectively, and a mean of 1.2 × 10(2), 4.3 × 10(3), and 5.9 × 10(4) CFUs, respectively, on culture of the surrounding tissue (p < 0.05). CONCLUSIONS: The PEG-PPS coating provides a promising approach to preventing periprosthetic infection. This polymer is novel in that it combines both passive and active antibiotic-release mechanisms. The tigecycline-based coating outperformed the vancomycin-based coating in this study. CLINICAL RELEVANCE: PEG-PPS polymer provides a controlled, "smart" local delivery of antibiotics that could be used to prevent postoperative implant-related infections.
BACKGROUND:Postoperative infection is a devastating complication following arthroplasty. The goals of this study were to introduce a "smart" implant coating that combines passive elution of antibiotic with an active-release mechanism that "targets" bacteria, and to use an established in vivo mouse model of post-arthroplasty infection to longitudinally evaluate the efficacy of this polymer implant coating in decreasing bacterial burden. METHODS: A novel, biodegradable coating using branchedpoly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) polymer was designed to deliver antibiotics both passively and actively. In vitro-release kinetics were studied using high-performance liquid chromatography (HPLC) quantification in conditions representing both the physiologic environment and the more oxidative, hyperinflammatory environment of periprosthetic infection. The in vivo efficacy of the PEG-PPS coating delivering vancomycin and tigecycline was tested using an established mouse model of post-arthroplasty infection. Noninvasive bioluminescence imaging was used to quantify the bacterial burden; radiography, to assess osseointegration and bone resorption; and implant sonication, for colony counts. RESULTS: In vitro-release kinetics confirmed passive elution above the minimum inhibitory concentration (MIC). A rapid release of antibiotic was noted when challenged with an oxidative environment (p < 0.05), confirming a "smart" active-release mechanism. The PEG-PPS coating with tigecycline significantly lowered the infection burden on all days, whereas PEG-PPS-vancomycindecreased infection on postoperative day (POD) 1, 3, 5, and 7 (p < 0.05). A mean of 0, 9, and 2.6 × 10(2) colony-forming units (CFUs) grew on culture from the implants treated with tigecycline, vancomycin, and PEG-PPS alone, respectively, and a mean of 1.2 × 10(2), 4.3 × 10(3), and 5.9 × 10(4) CFUs, respectively, on culture of the surrounding tissue (p < 0.05). CONCLUSIONS: The PEG-PPS coating provides a promising approach to preventing periprosthetic infection. This polymer is novel in that it combines both passive and active antibiotic-release mechanisms. The tigecycline-based coating outperformed the vancomycin-based coating in this study. CLINICAL RELEVANCE: PEG-PPSpolymer provides a controlled, "smart" local delivery of antibiotics that could be used to prevent postoperative implant-related infections.
Authors: Jonathan R Pribaz; Nicholas M Bernthal; Fabrizio Billi; John S Cho; Romela Irene Ramos; Yi Guo; Ambrose L Cheung; Kevin P Francis; Lloyd S Miller Journal: J Orthop Res Date: 2011-08-11 Impact factor: 3.494
Authors: Paul Stoodley; Laura Nistico; Sandra Johnson; Leslie-Ann Lasko; Mark Baratz; Vikram Gahlot; Garth D Ehrlich; Sandeep Kathju Journal: J Bone Joint Surg Am Date: 2008-08 Impact factor: 5.284
Authors: Nicholas M Bernthal; Brad N Taylor; Jeffrey A Meganck; Yu Wang; Jonathan H Shahbazian; Jared A Niska; Kevin P Francis; Lloyd S Miller Journal: J Vis Exp Date: 2014-10-16 Impact factor: 1.355
Authors: Kenneth David Illingworth; William M Mihalko; Javad Parvizi; Thomas Sculco; Benjamin McArthur; Youssef el Bitar; Khaled J Saleh Journal: J Bone Joint Surg Am Date: 2013-04-17 Impact factor: 5.284
Authors: John M Thompson; Robert J Miller; Alyssa G Ashbaugh; Carly A Dillen; Julie E Pickett; Yu Wang; Roger V Ortines; Robert S Sterling; Kevin P Francis; Nicholas M Bernthal; Taylor S Cohen; Christine Tkaczyk; Li Yu; C Kendall Stover; Antonio DiGiandomenico; Bret R Sellman; Daniel Lj Thorek; Lloyd S Miller Journal: JCI Insight Date: 2018-09-06
Authors: Nathan K Archer; Yu Wang; Roger V Ortines; Haiyun Liu; Sabrina J Nolan; Qi Liu; Martin P Alphonse; Dustin A Dikeman; Momina Mazhar; Robert J Miller; Leif S Anderson; Kevin P Francis; Scott I Simon; Lloyd S Miller Journal: Methods Mol Biol Date: 2020
Authors: Richard J Jackson; P Stephen Patrick; Kristopher Page; Michael J Powell; Mark F Lythgoe; Mark A Miodownik; Ivan P Parkin; Claire J Carmalt; Tammy L Kalber; Joseph C Bear Journal: ACS Omega Date: 2018-04-19
Authors: A I Stavrakis; S Zhu; A H Loftin; X Weixian; J Niska; V Hegde; T Segura; N M Bernthal Journal: Biomed Res Int Date: 2019-12-12 Impact factor: 3.411
Authors: Robert J Miller; John M Thompson; Jesse Zheng; Mark C Marchitto; Nathan K Archer; Bret L Pinsker; Roger V Ortines; Xuesong Jiang; Russell A Martin; Isabelle D Brown; Yu Wang; Robert S Sterling; Hai-Quan Mao; Lloyd S Miller Journal: J Bone Joint Surg Am Date: 2019-02-20 Impact factor: 5.284