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Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective

  • Basic Research
  • Published:
Clinical Orthopaedics and Related Research®

A CORR Insights to this article was published on 10 October 2014

Abstract

Background

Local delivery can achieve the high antimicrobial concentrations necessary to kill biofilm-related microbes. Degradation times for resorbable carriers are too long. Hydrogels (gels of hydrophilic polymer in water) can degrade faster but release antimicrobials too quickly. We previously developed hydrogels based on the copolymer poly(N-isopropylacrylamide-co-dimethyl-γ-butyrolactone acrylate-co-Jeffamine® M-1000 acrylamide) (PNDJ) with delivery times of several days with complete degradation in less than 6 weeks.

Questions/purposes

We asked: (1) What is the elution profile of gentamicin from PNDJ hydrogels? (2) Is gentamicin released from gentamicin-loaded PNDJ (G-PNDJ) hydrogel effective for treatment of orthopaedic infection? (3) Does local gentamicin delivery from G-PNDJ hydrogel cause renal dysfunction?

Methods

(1) Two formulations of G-PNDJ, lower dose (1.61 wt%) and higher dose (3.14 wt%), five samples each, were eluted in buffered saline under infinite sink conditions. (2) Infections were induced in 16 New Zealand White rabbits by inserting a Kirschner wire in a devascularized radius segment and inoculating with 7.5 × 106 colony-forming units Staphylococcus aureus. At 3 weeks, débridement was performed and a new Kirschner wire was placed in the dead space. Treatment was randomized to higher-dose G-PNDJ or no hydrogel. No systemic antimicrobials were used. Positive culture and acute inflammation on histology were used to determine the presence of infection 4 weeks postdébridement. (3) 3.14 wt% G-PNDJ, 0.75, 1.5, or 3.0 mL, was injected subcutaneously in nine Sprague-Dawley rats, three of each dose. Serum gentamicin, blood urea nitrogen, and creatinine were measured on Days 1, 3, 7, 14, and 28.

Results

(1) Gentamicin release was sustained over 7 days with the higher-dose formulation release profile similar to release from high-dose antimicrobial-loaded bone cement. (2) Four weeks postdébridement, infection was present in eight of eight no-hydrogel rabbits but zero of eight rabbits treated with G-PNDJ hydrogel (p < 0.001). (3) Blood urea nitrogen and creatinine were transiently elevated (p < 0.05) only for the two of three rats receiving the 3.0-mL dose on Days 3 and 7.

Conclusions

Gentamicin is delivered from PNDJ hydrogel with low systemic exposure and decreased treatment failure for orthopaedic infection. Transient renal dysfunction occurs at high doses. Biodistribution and toxicity testing are needed for G-PNDJ to be clinically usable.

Clinical Relevance

Resorbable viscous hydrogels for local antimicrobial delivery may improve outcomes for one-stage management of implant infections when uncemented reconstructions are performed.

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Acknowledgments

We acknowledge Dr Allan Dovigi for histopathological interpretation and the Arizona State University Department of Animal Care and Technologies for their assistance with this work.

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Authors and Affiliations

  1. Sonoran Biosciences, Chandler, AZ, USA

    Derek Overstreet PhD

  2. Orthopaedic Residency, Banner Good Samaritan Medical Center, 1320 N 10th Street, Suite A, Phoenix, AZ, 85006, USA

    Alex McLaren MD, Francis Calara BSE & Ryan McLemore PhD

  3. Center for Interventional Biomaterials, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA

    Brent Vernon PhD

Authors
  1. Derek Overstreet PhD
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  2. Alex McLaren MD
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  3. Francis Calara BSE
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  4. Brent Vernon PhD
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  5. Ryan McLemore PhD
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Corresponding author

Correspondence to Ryan McLemore PhD.

Additional information

Research reported in this manuscript was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R41AR064080. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. One or more of the authors (DO, AM, BV, RM) have ownership in Sonoran Biosciences.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request.

Clinical Orthopaedics and Related Research ® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA-approval status, of any drug or device prior to clinical use.

Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at Arizona State University, Tempe, AZ, USA.

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Overstreet, D., McLaren, A., Calara, F. et al. Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective. Clin Orthop Relat Res 473, 337–347 (2015). https://doi.org/10.1007/s11999-014-3935-9

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