Infections after orthopaedic surgery are catastrophic. Implants are easily colonized by bacteria, and eradication of infection often requires surgical removal of the implant, a luxury not available for patients in whom the implant provides essential structural support. These infections are also a major public health expense, costing more than $8 billion of additional spending per year. Current implant coating technologies exist that locally deliver antibiotics, attempting to prevent bacterial infection from taking hold. These methods have achieved limited translation because of i) the inability to achieve sustained release above necessary minimum inhibitory concentrations of the antibiotic, ii) the addition of an additional inert scaffolding that is itself a surface for bacterial adhesion and biofilm formation, and iii) limited effectiveness of current antibiotics against slow-growing bacterial cells that comprise biofilm-state bacteria. In order to address these issues, this proposal will investigate two conceptually innovative hypotheses that probe the relationship of host and bacteria with the provocation of novel antimicrobials (active-release antibiotic coatings and re-engineered antibiotics targeting slow-replicating bacteria) using novel diagnostic tools that coincidentally assess the infection and the host immune response to the infection: 1] dual RNA sequencing; and 2] non-invasive in vivo bioluminescent imaging. The proposal aims to develop a combination passive-active-release polymer coating that will deposit additional antibiotic when challenged by the acidic environment of periprosthetic infection. This implant coating will be impregnated with i) commonly used antibiotics as well as ii) a novel, re-engineered antibiotic that specifically targets the senescent bacteria that comprise biofilms. These implants will be employed in a novel in vivo mouse model of implant infection 1] to assess efficacy and 2] in sub-inhibitory and inhibitory antibiotic doses to provoke a transcriptomic response from host PMNs and bacteria. Finally, coatings developed in the proposal will be assessed for biocompatibility using techniques of osseointegration analysis. Taken together, this proposal will capitalize on existing institutional infrastructure and human capital to undertake novel, coincidental and interdependent host immune cell: bacterium imaging and deep RNA sequencing technologies to investigate host immune and infecting bacterial responses to antimicrobials. If successful, this project will i) set the stage for longitudinal studies of PMN: bacteria interaction with other strans of bacteria, ii) provide a basis for large animal pre-clinical studies of a novel coating and novel antimicrobial agent, and iii) broaden our understanding of bacterial and host response to antibiotics, laying the groundwork for future antimicrobial therapies.

Public Health Relevance

Orthopaedic implant infections are disastrous for patients, leading to multiple operations and worse outcomes, and devastating to our health system, costing more than $8 billion per year of additional spending. Here we will develop a novel implant coating that actively releases antibiotic in the presence of bacteria as well as a novel re engineered antibiotic that targets biofilms. These advances will pave the way toward new methods of prevention and treatment of implant infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR069112-04
Application #
9656963
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Washabaugh, Charles H
Project Start
2016-05-10
Project End
2020-08-31
Budget Start
2019-03-01
Budget End
2020-08-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Orthopedics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Bernthal, Nicholas M; Hegde, Vishal; Zoller, Stephen D et al. (2018) Long-term outcomes of cement in cement technique for revision endoprosthesis surgery. J Surg Oncol 117:443-450
Hegde, Vishal; Dworsky, Erik M; Stavrakis, Alexandra I et al. (2017) Single-Dose, Preoperative Vitamin-D Supplementation Decreases Infection in a Mouse Model of Periprosthetic Joint Infection. J Bone Joint Surg Am 99:1737-1744
Dworsky, Eric M; Hegde, Vishal; Loftin, Amanda H et al. (2017) Novel in vivo mouse model of implant related spine infection. J Orthop Res 35:193-199
Arshi, Armin; Sharim, Justin; Park, Don Y et al. (2017) Prognostic determinants and treatment outcomes analysis of osteosarcoma and Ewing sarcoma of the spine. Spine J 17:645-655
Wang, Yu; Thompson, John M; Ashbaugh, Alyssa G et al. (2017) Preclinical Evaluation of Photoacoustic Imaging as a Novel Noninvasive Approach to Detect an Orthopaedic Implant Infection. J Am Acad Orthop Surg 25 Suppl 1:S7-S12
Hu, Yan; Hegde, Vishal; Johansen, Daniel et al. (2017) Combinatory antibiotic therapy increases rate of bacterial kill but not final outcome in a novel mouse model of Staphylococcus aureus spinal implant infection. PLoS One 12:e0173019
Arshi, Armin; Sharim, Justin; Park, Don Y et al. (2017) Chondrosarcoma of the Osseous Spine: An Analysis of Epidemiology, Patient Outcomes, and Prognostic Factors Using the SEER Registry From 1973 to 2012. Spine (Phila Pa 1976) 42:644-652
Rendon, J S; Swinton, M; Bernthal, N et al. (2017) Barriers and facilitators experienced in collaborative prospective research in orthopaedic oncology: A qualitative study. Bone Joint Res 6:307-314
Stavrakis, Alexandra I; Zhu, Suwei; Hegde, Vishal et al. (2016) In Vivo Efficacy of a ""Smart"" Antimicrobial Implant Coating. J Bone Joint Surg Am 98:1183-9
Park, Howard Y; Yang, Sara K; Sheppard, William L et al. (2016) Current management of aneurysmal bone cysts. Curr Rev Musculoskelet Med 9:435-444