Introduction
Pin-site infections are a common complication of external fixation, with reported incidence rates ranging from 0% to 100%.[1] A lack of consistency in the definition of a pin-site infection is one of the reasons blamed for the wide variation in rates from published studies.[2] Consequently, this makes it difficult to objectively compare infection prevention strategies at pin sites.[3] Nevertheless, pin-site infections represent a significant complication with the potential to adversely affect outcomes following bone lengthening and deformity correction procedures as well as treatment of fractures.
Multiple different protocols for the prevention of pin-site infection have been used with varying levels of success.[456789101112] These strategies range from modifications of the surgical technique to management of the pin–skin interface and promotion of pin/wire integration at the bone–pin interface. Despite the varying options available, pin-site infections continue to be a significant source of morbidity following application of external fixators and transcutaneous pins/wires.
The burden of pin-site infection provides a strong drive for research in this area. The search for the most universally efficacious protocol continues. New strategies aimed at reducing the risk of pin-site infection have been developed. They are aimed at improving osseointegration at the bone–pin interface, enhancing the rate of healing at the pin–skin interface, and prevention of bacterial colonization of the pin or wire.[13141516] With the promise of improved outcomes following treatment with external fixators, research in this area continues to grow.
The goal of this scoping review was to identify, evaluate, and summarize published literature on unique techniques for the prevention of pin-site infection that are being investigated for future use. The primary focus was on experimental procedures aimed at preventing pin-site infection including studies involving surface morphology of pins and wires, nanotube technology, covalent bonding, and coating.
Methods
Following completion of title and abstract screening, we discovered a very broad variation in the study design and type of data generated among studies that met the inclusion criteria. This meant that a critical appraisal of the literature was not practical. We concluded that a scoping review to identify and map the conduct of research in this area was a more pragmatic methodology. We thus revised our protocol to reflect this new approach. We report our findings utilizing the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews statement.[17] The original protocol for this study was registered with the Open Science Framework Registries, OSF https://doi.org/10.17605/OSF.IO/ZWU8A.
Eligibility criteria
Eligible studies were selected using the Participants, Intervention, Comparators, and Outcomes criteria.
Participants
The review included studies involving human and animal subjects treated with external fixators or studies looking at implant coating to prevent infection. There was no age restriction for the eligible human studies. The studies included experimental as well as standard of care treatments with prevention of pin-site infection as the study outcome.
Interventions
Intervention included surgical procedures of external fixation, pin–skin interface interventions, bone–pin interface interventions, and hardware surface morphology interventions. Details gathered included pin-site management protocols, modifications to hardware as well as any other management strategy aimed at reducing the incidence of pin-site infection.
Comparators
In this review, studies that compared intervention to no intervention were considered. We also considered studies that compared intervention with alternative interventions or other control groups.
Outcomes
This review evaluated the investigator/observer-reported outcomes of infection prevention. Primary outcome measures were prevention of infection. Secondary outcome measures were incidence of complications to specific intervention protocols. Infection was defined and reported as within each study.
Types of studies
This review considered studies involving human subjects as well as animal studies. It considered experimental, randomized controlled trials and nonrandomized controlled trials. Other studies that were considered included case–control studies, and descriptive observational studies including case series. Only studies published in English were included and the publication date was limited to 1980–present.
Information sources
A structured search of the following electronic databases was the primary source of literature for this review: MEDLINE (PubMed), EMBASE, Cumulative Index to Nursing and Allied Health Literature (EBSCO platform), Scopus, Web of Science, and the Cochrane Library.
Search strategy
A qualified medical librarian (AG) designed and conducted the literature searches (February 7, 2021–September 7, 2021). The search was conducted using a range of keywords related to pin-site infection. The reference list of all included studies was considered in addition. Only full-text articles published in English were included in the review.
Study records
Data management
All references were imported into a single EndNote library version X9 (Clarivate Analytics, PA, USA), following which all duplicates were removed. The revised reference list was then exported from EndNote into the Covidence software tool,[18] which was used to facilitate and support the screening process.[19]
Selection process
Two reviewers using the eligibility criteria screened study titles and abstracts independently using the Covidence screening tool. Following determination of eligibility, full texts were retrieved and independently assessed for study characteristics by three reviewers. Reasons for all exclusions were collated and tabulated. Disagreements were resolved by consensus.
Data extraction
Study details (author, title, year, and study location), study methods (aims, setting, and design), and results were extracted and collated in tabular form [Tables 1 and 2].
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Table 1: Characteristics of studies looking at implant surface coating/morphology
Table 2: Studies looking at pin-skin interface
Results
A total of 4622 articles were identified using the search strategy. Seventy-six studies had full-text review done, with 43 being excluded. Thirty-three studies were found eligible for inclusion in this review. The flow diagram for the study search and selection is illustrated in [Figure 1].
Figure 1: PRISMA flowchart, PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses
Characteristics of included studies
Studies were grouped based on infection prevention strategy. There were thirty studies that evaluated the integration of the pin or wire at the bone–hardware interface [Table 1] and three studies that evaluated modifications to management of the pin–skin interface [Table 2].
Implant surface coating and the bone–pin interface
Of the 30 studies that evaluated implant surface coating, 12 (40%) were in vivo studies, 8 (26.6%) were in vitro studies, 5 (16.7%) combined in vitro and in vivo techniques, while 5 (16.7) were human and/or cadaver studies. The 12 in vivo studies included 6 studies involving rabbits, 3 studies involving the use of rats, and 3 large animal model studies (2 sheep studies and 1 goat study). The human studies included 2 prospective cohort studies, 2 prospective case–control studies, and 1 prospective randomized study. The 5 combined in vitro and in vivo studies included 4 studies involving rabbits and 1 study involving a mouse model [Table 3].
Table 3: A summary of the results
Seven studies involved silver-based coatings either in isolation (1 study) or in combination with other compounds (6 studies; 3 with hydroxyapatite and 1 each with SiOxCy plasma polymer, zirconium, and titanium dioxide). Four studies evaluated the efficacy of antibiotic-impregnated coatings. This included 2 studies that utilized tobramycin and 1 study each that utilized vancomycin alone and a vancomycin/chitosan combination. Eight studies examined modifications to surface morphology that either encouraged better osseointegration of hardware at the implant/bone interphase or discouraged bacterial adhesion/growth on the hardware. These studies evaluated the use of polymers such as poly D, L-lactide, and poly (ethylene glycol)-poly (propylene sulfide). It also included studies involving the use of fibroblast growth factor (FGF) combined with hydroxyapatite and studies involving the use of ceramic/titanium, calcium titanate, and titanium dioxide coating. One of these studies evaluated the nature of biofilm formed on 3 different surfaces (titanium, stainless steel, and hydroxyapatite). There were 4 studies that examined physical methods of treatment of implanted hardware. These included the use of photoactive titanium dioxide, alkali treatment to hydroxyapatite coating, electrical stimulation of implants, and the use of anodized titanium pins. There were 2 studies that evaluated the effects of iodine coating and 1 that evaluated copper coating. Four studies evaluated the antibacterial effects of monolaurin (1), triclosan (2), and carboxymethyl chitosan (1) [Figure 2].
Figure 2: Methodological approach for studies evaluating improvements to the bone–pin interphase
Most studies used more than 1 criterion for the diagnosis of infection [Figure 3]. Microbiological evaluation was used in 18 studies (60%), radiological parameters were measured in 10 studies (33.3%), histological evaluation was carried out in 13 studies (43.3%), while clinical evaluation was used in 14 studies (46.7%).
Figure 3: Outcome assessment for studies evaluating strategies to modify the bone–pin interphase
Eight studies carried out toxicity studies. These included 6 studies involving serum assays (4 serum assays for exogenous coatings materials and 2 hormone assays) and 2 in vitro studies. Two studies carried out biocompatibility testing using cell culture, seeding, and viability assessment.
Pin–skin interphase studies
Three studies evaluated pin–skin interphase dressing materials/treatment protocols [Table 2]. These consisted of 1 human (a randomized control trial) and 2 animal studies (an in vivo rabbit study and a combined in vitro/in vivo rabbit study). Two of these studies compared antibiotic-impregnated dressing materials to dressings without antibiotics while another compared treatment outcome with 4 different disinfectant solutions.
All 3 studies in this section of the review utilized clinical evaluation as an outcome assessment tool. Two of these 3 studies utilized the Checketts–Otterburn classification,[53] while the 3rd study utilized unspecified observations of redness and irritation around the pin sites. Microbiological and histological (hematoxylin and eosin staining for inflammatory cells) evaluation was carried out in both animal studies in this group. In addition, one animal study carried out hematological (C-reactive protein and white blood cell counts) evaluation [Table 3].
Discussion
Even though Ilizarov's circular external fixator and his principles of distraction osteogenesis were introduced to the Western world approximately 40 years ago, pin-site infections continue to be a consistent problem. Various pin-site protocols using different methods of dressings, different cleaning regimens, and different frequencies of care have been investigated. However, no clear, universally successful strategy has emerged. Therefore, research looking for novel and effective approaches to reducing pin-site infections is crucial and should be encouraged. We identified 33 publications presenting unique methods of modulating the pin-site environment to reduce infections. While most of the data remain experimental, these ideas represent the potential future of pin-site management.
The publications describing future pin-site ideas could be loosely grouped into two types: those proposing modulation of the pin–bone interface and those proposing modulation of the pin–skin interface. Within the studies that investigated the pin–bone interface, three subcategories were identified: (1) studies examining the application of a coating to the pin, (2) studies analyzing the effects of modifying the surface morphology of the pin, and (3) studies investigating physical methods of treatment to the implanted hardware. Only 6 of the 33 total studies had any human data to report which reflects the still largely experimental nature of this research track.
For the 18 pin–bone interface publications looking at novel coatings, they were separated into studies involving coatings with silver (7), antibiotics (4), antibacterial compounds (4), iodine (2), and copper (1). The following five studies were the only ones that presented clinical outcomes in humans. Two studies from Japan documented the positive effects of iodine-supported titanium half pins and wires.[3653] In a prospective cohort of 36 patients, Tsuchiya et al. had excellent outcomes in infection prevention (no infections) using their innovative antimicrobial coating of titanium implants with iodine. Similarly, Shirai et al. reported only a 3.6% overall pin-site infection rate in a prospective cohort of 38 patients using iodine-supported titanium pins. Despite a previously published in vivo rabbit study that showed lower infection rates, a prospective, open-label controlled feasibility study involving 15 Japanese distal radius fracture patients using external fixator pins coated with a FGF 2–apatite composite layer did not show any significant difference in infection rates between coated and uncoated pins.[2346] Similarly, a prospective, randomized study from Italy comparing silver-coated and uncoated stainless steel pins in 24 patients did not find any statistically significant difference in infection rates.[20] However, a study from Germany evaluating a new calcium titanate coating on Schanz screws in cadavers and in clinical patients demonstrated better fixation compared to uncoated pins or pins with hydroxyapatite.[47] Since the clinical sample only involved 4 patients, further research using a larger sample size will need to be performed to determine if this coating is truly more effective.
In the nonhuman studies, three pin-coating studies investigated the effects of combining silver's antimicrobial potential with hydroxyapatite with favorable results.[314149] A fourth study created a silver plasma polymer coating that demonstrated a >99.9% reduction in the growth of colony-forming units in vitro.[26] Perhaps, most intriguing is the concept of using silver at the nanosized level as a method of delivering antimicrobial protection. Wickens et al. found an increased antimicrobial activity using a nanocomposite zirconium nitride/silver coating on fixator pins in vitro.[28] In a rabbit study, Zhang et al. found that superhydrophobic silver titanium nanotubes had the lowest bacterial counts.[41] While this technology is still developing and not currently feasible for clinical use, the potential to design half pins with nanotubules carrying single or multiple antimicrobial materials is exciting.
Five studies were identified that investigated the antibacterial effects of alternative materials. Qu et al. performed two studies in rabbits and sheep with external fixator pins coated in triclosan sol-gel.[3739] They found no infections in the animals using the experimental triclosan pins compared to 100% and 80% infection rates in the uncoated pin control animals, respectively. An in vitro study using monolaurin-coated wires demonstrated increased efficiency against Staphylococcus strains versus uncoated wires.[44] Using a rabbit model, a carboxymethyl chitosan-zinc coating placed on stainless steel pins developed no infections compared to the control group using uncoated pins which had a 100% infection rate.[45] Prinz et al. found a reduction in the attachment of bacteria to the implant surface in copper-coated implants compared to noncoated implants in rabbits.[43] These promising results indicate that continued exploration of alternative coating materials is warranted.
Coating the half pins with antibiotics, such as vancomycin or tobramycin, has been attempted. Rahimnia et al. found that pins coated with hydroxyapatite and vancomycin performed better than uncoated pins in a rabbit study.[29] Yang et al. created a vancomycin–chitosan composite coating that demonstrated significant antibacterial activity compared to uncoated pins in both in vitro and in vivo studies (rabbit model).[30] Stavrakis et al. have tested a “smart” antimicrobial implant coating consisting of a poly (ethylene glycol)-poly (propylene sulfide) polymer-coating titanium wires that are impregnated with vancomycin or tigecycline. The antibiotic-coated wires showed statistically significantly increased antibacterial properties compared to the polymer-coated wires alone.[40] Two separate studies confirmed a sustained release rate of tobramycin for 8 and 12 days, respectively, using tobramycin-loaded hydroxyapatite-coated fixation pins.[3334] Further study on the use of these antibiotic coatings is required before it will be ready for human trials.
Some of the most innovative work investigates modifications to the surface morphology of the half pins themselves. These modifications are designed to either encourage better osseointegration of the pin at the implant/bone interface or discourage bacterial adhesion/growth on the surface. McEvoy et al. confirmed that titanium Kirschner wires resist bacterial biofilms better than stainless steel or hydroxyapatite wires in an in vitro study.[48] In a sheep study, Partale et al. found better osseointegration and decreased colonization with Staphylococcus aureus using poly (D, L-lactide)-coated pins versus uncoated pins.[21] Titanium dioxide-coated pins were studied by Koseki et al. and demonstrated less infection risk than uncoated stainless steel pins in a rat model.[31] Finally, Dong et al. tested the antibacterial properties of titanium external fixation pins through surface ceramic conversion.[42] They reported a 50% decrease in bacterial isolates after a 20-h incubation in ceramic conversion-treated pins versus untreated pins. The ability to change the surface morphology of titanium to make it more resistant to infection remains an intriguing potential opportunity for helping to reduce pin-site infections.
The final category of research at the pin–bone interface involves studies investigating physical methods of treatment to the implanted hardware. Lakstein et al. found enhanced osseointegration in rabbits using grit-blasted, NaOH-treated, and electrochemically hydroxyapatite-coated Ti–6Al–4V implants compared to rods without that combination of modifications.[25] Van der Borden attempted to use an electric current as a means of reducing pin-site infections.[24] They found an 11% infection rate in stainless steel pins treated with 100 μA electric current versus an 89% infection rate in pins receiving no electric treatment in their goat model. Using ultraviolet irradiation, Villatte et al. tested photoactive titanium dioxide-coated pins.[38] In their in vitro model using stainless steel discs, the photoactive titanium dioxide coating displayed a delayed cumulative bactericidal effect compared to the uncoated discs. Finally, Neuhoff et al. used anodized plasma chemical calcium-phosphate (APC-CaP) surface treated Schanz screws in a sheep model.[22] The APC-CaP-coated pins had reduced infection, increased extraction torque, and decreased loosening compared to standard anodized titanium screws. These studies demonstrate that outside-the-box methods of thinking are valuable and may ultimately provide new and improved methods of managing pin sites.
There were three studies that investigated whether treatment to the pin–skin interface could potentially improve pin-site care. Pema et al. performed a randomized control trial in a cohort of patients who had external fixation for deformity correction.[51] They evaluated the use of a novel microbicidal liquid polymer dressing versus standard pin-site care and found a decreased infection rate in the group receiving the liquid polymer dressing. Mutsuzaki et al. also evaluated a novel sponge pad in rabbits.[50] The cefazolin-containing poly(ε-caprolactone) sponge pad decreased the infection rate compared to the poly(ε-caprolactone) sponge alone. The final study in this group compared the effects of four different disinfectants on pin-site infection in rabbits.[52] The chlorhexidine gluconate alcohol was found to be superior to Maokang iodine, 75% alcohol, or physiologic saline.
Studies included in this review employed an assortment of methodologies. Similarly, the interpretation of results and outcomes varied widely. This, in itself, creates a challenge in identifying the most “promising direction” for research in this area. Furthermore, the disparate nature of the various studies and the relatively small volume of publications within the scope of this review in the last 5 years were a limitation of this study. To make for a more robust assessment, we extended our search parameters to include studies carried out in the last 25 years. This gave us a semblance of the direction of research in this area which seems to indicate that improving the stability of the bone–pin interface utilizing techniques that promote osteointegration of the pins or wires is the current focus of research. Another limitation of this review was that only 6 of the 33 studies reviewed reported on human data and these had relatively small sample sizes ranging from just 4–38. None of these six studies were epidemiologic in nature and so prevalence data were not available for review.
Conclusions
There is still no universally proven method to prevent pin-site infections. Eliminating, or at least minimizing, pin-site infections would be a huge benefit to patients undergoing external fixation. This article summarizes the published pertinent research investigating novel approaches to pin-site infection prevention. While most of the data are still experimental, there are a number of potential solutions that involve modulating the pin–bone or pin–skin interface. Perhaps, a combination of several of these proposals will prove to be the optimal answer. Regardless, further research into this topic is necessary and should be encouraged.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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