TY - JOUR
AU - PhD, Paul Ducheyne,
AB - ABSTRACT Orthopedic injuries constitute the majority of wounds sustained by U.S. soldiers in recent conflicts. The risk of infection is considerable with fracture fixation devices. In this pilot study, we examined the use of unique bactericidal micron-thin sol–gel films on fracture fixation devices and their ability to prevent and eradicate infections. External fixation was studied with micron-thin sol–gel coated percutaneous pins releasing triclosan and inserted medially into rabbit tibiae. A total of 11 rabbits received percutaneous pins that were either uncoated or sol–gel/triclosan coated. Internal fracture fixation was also studied using sol–gel coated intramedullary (IM) nails releasing vancomycin in the intramedullary tibiae. Six sheep received IM nails that were coated with a sol–gel film that either contained vancomycin or did not contain vancomycin. All animals were challenged with Staphylococcus aureus around the implant. Animals were euthanized at 1 month postoperative. Rabbits receiving triclosan/sol–gel coated percutaneous pins did not show signs of infection. Uncoated percutaneous pins had a significantly higher infection rate. In the sheep study, there were no radiographic signs of osteomyelitis with vancomycin/sol–gel coated IM nails, in contrast to the observations in the control cohort. Hence, the nanostructured sol–gel controlled release technology offers the promise of a reliable and continuous delivery system of bactericidals from orthopedic devices to prevent and treat infection. INTRODUCTION During combat operations in Iraq and Afghanistan in support of Operation Iraqi Freedom and Operation Enduring Freedom, extremity injuries have accounted for the majority of wounds (65%).1 One of the lessons learned during these wars was that infections associated with combat-related injuries can have a significant impact on morbidity and mortality. Among the extremity injuries in U.S. casualties, orthopedic injuries constituted the majority of wounds.2,3 Typically, these included a large percentage of fractures, the majority of which were open, complex injuries prone to infection and other complications. Approximately 5% to 15% of these injuries developed osteomyelitis.4 Depending on the nature, condition and location of the fracture, surgeons may choose internal or external fixation devices to provide stability during the healing process. These orthopedic implants are most commonly made from stainless steel or titanium and its alloys. A vexing issue is that in the presence of bacteria, a biofilm is prone to form on these metallic implant surfaces. Once such a biofilm forms, treatment with systemic antimicrobials rarely eradicates infection because bacteria are protected within this extracellular matrix. As a result, the adherent bacteria can then cause a chronic infection that has been reported to persist for months, years, or even a lifetime.5 Biofilm infections are very difficult to treat. Once formed, high doses of very potent antibiotics are needed, which exacerbates the risk of fostering bacterial resistance. The use of these systemically administered antibiotics also creates the risk of irreversible damage to organs. Furthermore, the failure of systemic antibiotic treatment to eradicate biofilm-associated infection typically necessitates additional surgeries. Fracture fixation devices, which include both internal and external devices, incur a postoperative infection rate of 5% overall.6 In the specific case where external fixation of bone fragments is the treatment of choice for achieving bone stability, the incidence of deep infection is high, namely 16.2% overall, with 4.2% of the cases developing chronic osteomyelitis. A rate of infection, up to 32.2%, has been reported for the external fixation of femoral fractures.7 As the care of combat casualties continues to improve, thereby achieving enhanced survival after initial injury, infectious complications will remain a major cause of short- and long-term morbidity. A major hurdle to overcome in the treatment of orthopedic-related infections is that bacterial adhesion and biofilm formation on the orthopedic implant may result in decreased antibiotic sensitivity. One emerging method attracting attention is the coating or impregnating antimicrobial agents onto the surface of these implants to inhibit biofilm formation. Our laboratory has developed room-temperature-processed, biocompatible, nanostructured silica sol–gels that can release bactericidals in a controlled fashion for weeks and months.8,–10 These include a wide variety of molecules ranging in size from 500 to 70,000 Daltons.8,–10 The release properties can be varied extensively by modifying the nanostructure of the sol–gels as a result of understanding the property relationships as they relate to the sol–gel processing variables.8,–10 In the studies reported here, micron-thin sol–gel films were applied onto 2 types of orthopedic implants: percutaneous pin of external fixators and intramedullary (IM) nails. A broad-spectrum antimicrobial agent, triclosan (2,4,4′-trichloro-2′-hydroxydiphenylether), was incorporated into the sol–gel film on percutaneous stainless steel pins. The broad-spectrum antibiotic drug, vancomycin, was incorporated into the sol–gel films on IM nails made of titanium alloy (Ti6Al4V). The current studies were formulated to verify the hypothesis that, using a rabbit tibia model, the infection arising from bacterial ingress along the percutaneous pin surfaces can be prevented by the triclosan/sol–gel films and, using a sheep osteomyelitis tibia model, osteomyelitis can be treated and biofilm formation on the surface of IM nails can be prevented by vancomycin/sol–gel films. MATERIALS AND METHODS Synthesis of Sol–Gel Coatings Sol–gel coatings containing 20 wt% triclosan were used for the study with percutaneous pins. Triclosan solutions in ethanol were used for incorporation of triclosan during the sol synthesis. TEOS (tetraethoxysilane, Sigma-Aldrich, St. Louis, Missouri), ethanol, deionized water, and 1N HCl were mixed to form an acid-catalyzed silica sol. The H2O/TEOS molar ratio and the ethanol/TEOS volume ratio were equal to 5 and 1.8, respectively. The coatings were applied on percutaneous pins (AISI 316L stainless steel, diameter of 2 mm and length of 14 mm) by dipping at a withdrawal speed of 100 mm/min. The number of applied sol–gel layers was 8 to arrive at films with a total thickness of about 2 μm. Sols with nominal vancomycin concentrations of 5 wt% or 20 wt% were used for the sol–gel coatings on IM nails (Ti6Al4V titanium alloy, length of 140 mm and diameter of 6 mm). The sol–gel coatings comprised 15 layers (5 layers of 5% vancomycin and 10 layers of 20% vancomycin). All applied sol–gel compositions resulted in the formation of uniform films. Surgeries and Outcome Measures The 2 animal study protocols were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania. Rabbit Tibia Percutaneous Pin Study Eleven adult male New Zealand White rabbits (Charles River Laboratories) between 4 and 18 months of age and weighing between 3.0 and 4.5 kg at the time of surgery were used for the experiments. The implants, with or without sol–gel coating, were placed from the medial side into the tibia, engaged and then screwed tightly into the lateral side of the cortex; the pins protruded approximately 5 to 6 mm from the skin. An aliquot of 0.1 mL of S. aureus solution (1.5 × 107 cfu/mL, ATCC™ 25923) was inoculated around the implant using a sharp injection needle. Six of the 11 rabbits received triclosan containing sol–gel coated pins and the remaining 5 received uncoated percutaneous pins. The rabbits were sacrificed 4 weeks after surgery. A scoring system was used to quantify pin tract infection as follows (grading from least to most severe): 0, no sign of infection; 1, marginal inflammation without drainage; 2, serous-type discharge; 3, purulent discharge; or 4, seropurulent drainage with redness and/or osteolysis.11 Sheep Tibia IM Nail Study Skeletally mature (2.5–3.5 years) Dorset-cross ewes were used for the experiment. Sol–gel coated IM nails, with and without vancomycin, were implanted into the IM tibial canal of sheep via the tibial plateau. Using a percutaneous stab incision to gain access to the proximal tibial diaphysis, 3 mL of bacterial inoculum (108 cfu/mL, S. aureus) was slowly injected into the medullary space via a drill hole that was sealed afterward. Six sheep were operated on with 3 receiving vancomycin-containing sol–gel coated IM nails and 3 receiving nails coated with a control sol–gel film, this is, a film without the antibiotic. After surgery, radiographs were taken to monitor the status of the indwelling implants and to record any evidence of infection and osteolytic changes. One month after surgery and implantation, the animals were sacrificed and the tibiae were dissected using an autopsy saw. To determine bacterial presence, swabs were taken around the cortex screw, the IM nail head, and in the medullary cavity, and analyzed. RESULTS Rabbit Tibia Percutaneous Pin Study Results showed that the 5 rabbits implanted with percutaneous pins without a triclosan/sol–gel coating had a significantly higher infection rate as determined clinically 4 weeks post implantation. Four of the 5 rabbits showed the signs of infection with 3 demonstrating a serous-type discharge and 1 showing a purulent discharge around the percutaneous pins. By way of contrast, none of the 6 rabbits receiving triclosan/sol–gel coated percutaneous pin showed any signs of infection at 4 weeks (Table I). The difference between rabbits receiving a coated versus uncoated pin was statistically significant (p < 0.001, Fisher's test). Clinical photos of the implants taken 4 weeks after implantation are shown in Figure 1. No signs of infection were around the triclosan/sol–gel coated implant (Fig. 1A). However, strong signs of infection (purulent discharge) were visible around the control implant (Fig. 1B). TABLE I Infection Rates of Rabbits Receiving Different Percutaneous Pins Percutaneous Pin  Animals for Evaluation  Animals With Clinical Signs of Infectiona  Stainless Steel  5  4  Triclosan/Sol–Gel  6  0  Percutaneous Pin  Animals for Evaluation  Animals With Clinical Signs of Infectiona  Stainless Steel  5  4  Triclosan/Sol–Gel  6  0  The difference between animals receiving triclosan/sol–gel coated and uncoated pins was statistically significant (p < 0.001, Fisher's test). a An animal showing discharge, cellulitis, and/or deep infection at the time of sacrifice was checked as infected. View Large TABLE I Infection Rates of Rabbits Receiving Different Percutaneous Pins Percutaneous Pin  Animals for Evaluation  Animals With Clinical Signs of Infectiona  Stainless Steel  5  4  Triclosan/Sol–Gel  6  0  Percutaneous Pin  Animals for Evaluation  Animals With Clinical Signs of Infectiona  Stainless Steel  5  4  Triclosan/Sol–Gel  6  0  The difference between animals receiving triclosan/sol–gel coated and uncoated pins was statistically significant (p < 0.001, Fisher's test). a An animal showing discharge, cellulitis, and/or deep infection at the time of sacrifice was checked as infected. View Large FIGURE 1 View largeDownload slide Clinical observation of (A) sol–gel coated and (B) control percutaneous pin 4 weeks after implantation. Note the strong signs of infection (purulent discharge) around the control implant, but not around the triclosan/sol–gel coated pin. FIGURE 1 View largeDownload slide Clinical observation of (A) sol–gel coated and (B) control percutaneous pin 4 weeks after implantation. Note the strong signs of infection (purulent discharge) around the control implant, but not around the triclosan/sol–gel coated pin. Sheep Tibia IM Nail Study No radiographic signs of infection were observed in animals that received vancomycin/sol–gel IM nails (Fig. 2A). All 3 animals that received IM nails coated with sol–gel films without vancomycin showed radiographic signs of osteomyelitis (endosteal lysis). In addition, 1 sheep showed both periosteal reaction and endosteal lysis (Fig. 2B). The periosteal proliferation was this animal's reaction to the infection in its tibia. Generally, a periosteal proliferation is considered a positive marker for osteomyelitis.12 The radiographic results differ significantly between treatment and control groups (p < 0.05, Fisher's test). Bacterial culture was used to detect the presence of bacteria on 2 implant sites (the cortex screw head and the IM nail head) and within the medullary cavity 4 weeks after implantation. All animals that received a control IM nail had positive culture results, whereas the animals that received a treatment IM nail had negative culture results. Table II summarizes these postsacrifice results. FIGURE 2 View largeDownload slide Radiographic images showing progressive signs of periosteal proliferation (arrow with a solid line) and intramedullary bone matrix response (arrow with a dotted line) in control sheep at 4 weeks post implantation (B); such responses are not seen in the sheep treated with vancomycin/sol–gel coated IM nails (A). FIGURE 2 View largeDownload slide Radiographic images showing progressive signs of periosteal proliferation (arrow with a solid line) and intramedullary bone matrix response (arrow with a dotted line) in control sheep at 4 weeks post implantation (B); such responses are not seen in the sheep treated with vancomycin/sol–gel coated IM nails (A). TABLE II Summary of Postsacrifice Evaluation After 4 Weeks Implantation IM Nail  Animals for Evaluation  Animals With Positive Culture of Bacteriaa  Animals With Radiographic Signs of Osteomyelitis  Treatment (Vancomycin/Sol–Gel Coated)  3  0  0  Control (Sol–Gel Coated)  3  3  3  IM Nail  Animals for Evaluation  Animals With Positive Culture of Bacteriaa  Animals With Radiographic Signs of Osteomyelitis  Treatment (Vancomycin/Sol–Gel Coated)  3  0  0  Control (Sol–Gel Coated)  3  3  3  The results in animals receiving treatment with vancomycin sol–gel coated nails differ significantly in terms of radiographic and bacterial culture outcomes (p < 0.05, Fisher's test). a Swab cultures with presence of bacteria at either the cortex screw, the IM nail head, or in the medullary cavity. View Large TABLE II Summary of Postsacrifice Evaluation After 4 Weeks Implantation IM Nail  Animals for Evaluation  Animals With Positive Culture of Bacteriaa  Animals With Radiographic Signs of Osteomyelitis  Treatment (Vancomycin/Sol–Gel Coated)  3  0  0  Control (Sol–Gel Coated)  3  3  3  IM Nail  Animals for Evaluation  Animals With Positive Culture of Bacteriaa  Animals With Radiographic Signs of Osteomyelitis  Treatment (Vancomycin/Sol–Gel Coated)  3  0  0  Control (Sol–Gel Coated)  3  3  3  The results in animals receiving treatment with vancomycin sol–gel coated nails differ significantly in terms of radiographic and bacterial culture outcomes (p < 0.05, Fisher's test). a Swab cultures with presence of bacteria at either the cortex screw, the IM nail head, or in the medullary cavity. View Large DISCUSSION The concept of endowing orthopedic devices with antimicrobial properties, such as by coating them with an antibiotic drug containing film, has been widely pursued.13,–15 Various methodologies have been tested. These include tobramycin-laden poly(methylmethacrylate) coatings,16 hydroxyapatite/chlorhexidine coatings,13 and silver coatings.17,–19 The antimicrobial properties of silver have been utilized to limit microbial colonization, and silver-coated pins have been tried in clinical applications. However, concerns have been raised related to elevated blood levels of silver in these cases.17,19 Polymer coatings have also been studied, but such coatings typically exhibit burst release profiles, followed by a relatively slow release phase.20 Both the use of silver and polymer coatings create concerns. With a slow release subsequent to the burst, minimum inhibitory concentrations for inhibiting bacterial growth or biofilm formation may not be achieved. The controlled release and local delivery of antibiotics from a room-temperature-processed sol–gel film has been studied in our laboratory.21 Using such films, it was demonstrated that antibiotic-containing sol–gel films can significantly inhibit S. aureus viability and growth in vitro and in vivo.22 In this in vivo study, we performed a pilot study to examine the feasibility of using micron-thin, adherent,23 antibiotic-containing sol–gel films for conventional trauma hardware (percutaneous pins and IM nails) to prevent bacterial infection. Inoculation with S. aureus was chosen because this bacteria is commonly identified as the pathogenic organism in infected bone and joint replacement cases.24,25 External fixation (percutaneous pin) is especially prone to infection because the percutaneous passage of the pins creates a gateway for bacterial ingress. In this study, S. aureus inoculation around the implant led to distinct outcomes. Without the treatment pins, the bacteria settled and populated tissue pockets and triggered their breakdown. As a result, 4 weeks after implantation, rabbits receiving control percutaneous fixation pin had developed infections with unambiguous clinical signs (Fig. 1A). This outcome was unlike that observed in animals implanted with the percutaneous treatment pins (triclosan/sol–gel coated pins). Here, bacterial adhesion, growth, and migration along the external fixator pins and into the tissues were prevented. IM nailing is another commonly used orthopedic technique that is associated with a high rate of infection. In the second study of this report, bacteria were injected into the intramedullary cavity after implantation. The bacterial swab culture results of the control animals suggest that bacteria continued to grow with the bacteria being ubiquitous within the tibia medullary cavity and on the surface of the IM nail. Such pervasive bacterial presence leads to osteomyelitis, as revealed by the radiographic results at 4 weeks after implantation of the non-vancomycin-containing IM nails (control nails). On the contrary, the vancomycin/sol–gel coated IM nail inhibited the growth of the bacteria injected into the tibial cavity with no signs of osteomyelitis being observed. Postoperative bone and joint infections are usually caused by Gram-positive organisms, especially S. aureus. Vancomycin is commonly used in the treatment of infections caused by Gram-positive bacteria. Triclosan is an antimicrobial agent, which is active against a wide range of Gram-positive and Gram-negative bacteria. In 1998, triclosan was recommended for the control of methicillin-resistant S. aureus.26 To date, resistance levels among S. aureus remain low.27 However, the extensive use in household and consumer products has resulted in elevated concentrations of triclosan in surface waters,28 leading to concerns that high environmental concentrations may trigger bacterial resistance. In an external fixation setting, the percutaneous pins containing triclosan are only intended for use up to 3 months. The few in situ studies investigating long-term triclosan exposure did not indicate changes in resistance after 6 to 12 months of exposure.29 Although no study has reported bacterial resistance to triclosan, reducing the usage of triclosan in household or consumer products is desirable by virtue of maintaining the bactericidal benefit of triclosan in important medical applications. The use of triclosan on percutaneous pins clearly falls into this category as a 30% infection rate with external fixator pins in femoral fractures and the prevention thereof is a significant clinical issue that needs a solution. CONCLUSION In this study, micron-thin sol–gel films on orthopedic devices successfully prevented bacterial adhesion, osteomyelitis, and device failure as a result of infection. This sol–gel micron-thin film technology can be used to coat surfaces of orthopedic devices made of various metallic materials (stainless steel and titanium alloy), and for various trauma devices (external fixation systems and IM nails). The sol–gel micron-thin film methodology described here opens up promising perspectives for reducing infections associated with orthopedic devices. ACKNOWLEDGMENTS This work was funded by U.S. Army contract no. W81XWH-10-2-0156 and QED Program of the University City Science Center, Philadelphia, PA. REFERENCES 1. 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Ayliffe PGAJ, Buckles MA, Casewell MW, et al.   Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infection in hospitals: report of a combined working party of the British Society for Antimicrobial Chemotherapy, the Hospital Infection Society and the Infection Control Nurses Association. J Hosp Infect  1998; 39( 4): 253– 90. Google Scholar CrossRef Search ADS PubMed  27. Wootton M, Walsh TR, Davies EM, Howe RA Evaluation of the effectiveness of common hospital hand disinfectants against methicillin-resistant Staphylococcus aureus, glycopeptide-intermediate S. aureus, and heterogeneous glycopeptide-intermediate S. aureus. Infect Control Hosp Epidemiol  2009; 30( 3): 226– 32. Google Scholar CrossRef Search ADS PubMed  28. Anger CT, Sueper C, Blumentritt DJ, McNeill K, Engstrom DR, Arnold WA Quantification of triclosan, chlorinated triclosan derivatives, and their dioxin photoproducts in lacustrine sediment cores. Environ Sci Technol  2013; 47( 4): 1833– 43. Google Scholar CrossRef Search ADS PubMed  29. Aiello AE, Marshall B, Levy SB, Della-Latta P, Larson E Relationship between triclosan and susceptibilities of bacteria isolated from hands in the community. Antimicrob Agents Chemother  2004; 48( 8): 2973– 9. Google Scholar CrossRef Search ADS PubMed  Footnotes * This article was presented as oral presentation at the 2012 Military Health System Research Symposium in Fort Lauderdale, FL, August 2012. Reprint & Copyright © Association of Military Surgeons of the U.S.
TI - Bactericidal Micron-Thin Sol–Gel Films Prevent Pin Tract and Periprosthetic Infection
JF - Military Medicine
DO - 10.7205/MILMED-D-13-00494
DA - 2014-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/bactericidal-micron-thin-sol-gel-films-prevent-pin-tract-and-IGBKfCmqyU
SP - 29
EP - 33
VL - 179
IS - suppl_8
DP - DeepDyve
ER -