Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective

Derek Overstreet, Alex McLaren, Francis Calara, Brent Vernon, Ryan McLemore

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)337-347
Number of pages11
JournalClinical Orthopaedics and Related Research
Volume473
Issue number1
DOIs
StatePublished - 2014

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Hydrogels
Gentamicins
Hydrogel
Infection
Bone Wires
Blood Urea Nitrogen
Rabbits
Orthopedics
Creatinine
Kidney
Bone Cements
Acrylamide
Biofilms
Treatment Failure
Sprague Dawley Rats
Staphylococcus aureus
Histology
Polymers
Stem Cells

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Medicine(all)

Cite this

Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective. / Overstreet, Derek; McLaren, Alex; Calara, Francis; Vernon, Brent; McLemore, Ryan.

In: Clinical Orthopaedics and Related Research, Vol. 473, No. 1, 2014, p. 337-347.

Research output: Contribution to journalArticle

Overstreet, Derek ; McLaren, Alex ; Calara, Francis ; Vernon, Brent ; McLemore, Ryan. / Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective. In: Clinical Orthopaedics and Related Research. 2014 ; Vol. 473, No. 1. pp. 337-347.
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title = "Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective",
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{\circledR} 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, d{\'e}bridement 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 postd{\'e}bridement. (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 postd{\'e}bridement, 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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N2 - 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.

AB - 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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