Evidence-based uncertainty: do implant-related properties of titanium reduce the susceptibility to perioperative infections in clinical fracture management? A systematic review.

BACKGROUND: Implant-associated infections (IAI) remain a challenging complication in osteosynthesis. There is no consensus or clear evidence whether titanium offers a relevant clinical benefit over stainless steel. PURPOSE: In this systematic review, we sought to determine whether the implant properties of titanium reduce the susceptibility to IAI compared to stainless steel in fracture management. METHODS: A systematic literature search in German and English was performed using specific search terms and limits. Studies published between 1995 and 1st June 2020 in the Cochrane library, MEDLINE and Web of Science databases were included. Only clinical studies comparing titanium and stainless steel implants regarding the susceptibility to infections were selected for detailed review. RESULTS: Five studies out of 384 papers were identified and reviewed. From the studies meeting inclusion criteria one study was a systematic review, two studies were randomized controlled studies (RCT) and two studies were of retrospective comparative nature of level IV evidence. CONCLUSION: Our results show that currently, no proven advantage for titanium implants in respect to IAI can be seen in contemporary literature. Implants preserving periosteal blood-flow and minimising soft-tissue trauma show statistically significant benefits in reducing the incidence of IAI. Clinical studies providing reliable evidence regarding the influence of titanium implants on IAI and investigating the susceptibility of titanium to infection are necessary.

Potential Application of Protamine for Antimicrobial Biomaterials in Bone Tissue Engineering.

Bacterial infection of biomaterials is a serious problem in the field of medical devices. It is urgently necessary to develop new biomaterials with bactericidal activity. Antimicrobial peptides and proteins (AMPs), alternative antibacterial agents, are expected to overcome the bacterial resistance. The aim of this study was to develop a new intelligent material in bone tissue engineering based on protamine-loaded hydroxyapatite (protamine/HAp) that uses AMPs rather than antibiotics. It was found that the adsorption of protamine to HAp followed the Langmuir adsorption model and was due to electrostatic and/or hydrophobic interactions. In vitro bacterial adhesion and growth on protamine/HAp was inhibited in a protamine dose-dependent manner. Adherent bacteria exhibited an aberrant morphology for high dosages of protamine/HAp, resulting in the formation of large aggregates and disintegration of the membrane. The released protamine from protamine/HAp also prevented the growth of planktonic bacteria in vitro. However, a high dosage of protamine from powders at loading concentrations over 1000 µg·mL-1 induced a cytotoxic effect in vitro, although those exhibited no apparent cytotoxicity in vivo. These data revealed that protamine/HAp (less than 1000 µg·mL-1) had both antimicrobial activity and biocompatibility and can be applied for bone substitutes in orthopedic fields.

Bactericidal and Bioresorbable Calcium Phosphate Cements Fabricated by Silver-Containing Tricalcium Phosphate Microspheres.

Bacterial adhesion to the calcium phosphate surface is a serious problem in surgery. To prevent bacterial infection, the development of calcium-phosphate cements (CPCs) with bactericidal properties is indispensable. The aim of this study was to fabricate antibacterial CPCs and evaluate their biological properties. Silver-containing tricalcium phosphate (Ag-TCP) microspheres consisting of α/ß-TCP phases were synthesized by an ultrasonic spray-pyrolysis technique. The powders prepared were mixed with the setting liquid to fabricate the CPCs. The resulting cements consisting of ß-TCP and hydroxyapatite had a porous structure and wash-out resistance. Additionally, silver and calcium ions could be released into the culture medium from Ag-TCP cements for a long time accompanied by the dissolution of TCP. These data showed the bioresorbability of the Ag-TCP cement. In vitro antibacterial evaluation demonstrated that both released and immobilized silver suppressed the growth of bacteria and prevented bacterial adhesion to the surface of CPCs. Furthermore, histological evaluation by implantation of Ag-TCP cements into rabbit tibiae exhibited abundant bone apposition on the cement without inflammatory responses. These results showed that Ag-TCP cement has a good antibacterial property and good biocompatibility. The present Ag-TCP cements are promising for bone tissue engineering and may be used as antibacterial biomaterials.

Development and challenges in setting up an international bone infection registry.

INTRODUCTION: Osteomyelitis is an increasing burden on the society especially due to the emergence of multiple drug-resistant organisms. The lack of a central registry that prospectively collects data on patient risk factors, laboratory test results, treatment modalities, serological analysis results, and outcomes has hampered the research effort that could have improved and provided guidelines for treatments of bone infections. The current manuscript describes the lessons learned in setting up a multi-continent registry. MATERIALS AND METHODS: This multicenter, international registry was conducted to prospectively collect essential patient, clinical, and surgical data with a 1-year follow-up period. Patients 18 years or older with confirmed S. aureus long bone infection through fracture fixation or arthroplasty who consented to participate in the study were included. The outcomes using the Short Form 36 Health Survey Questionnaire (version 2), Parker Mobility Score, and Katz Index of Independence in Activities of Daily Living were assessed at baseline and at 1 month, 6 months, and 12 months. Serological samples were collected at follow-ups. RESULTS: Contract negotiation with a large number of study sites was difficult; obtaining ethics approvals were time-consuming but straightforward. The initial patient recruitment was slow, leading to a reduction of target patient number from 400 to 300 and extension of enrollment period. Finally, 292 eligible patients were recruited by 18 study sites (in 10 countries of 4 continents, Asia, North and South America, and Central Europe). Logistical and language barriers were overcome by employing courier service and local monitoring personnel. CONCLUSIONS: Multicenter registry is useful for collecting a large number of cases for analysis. A well-defined data collection practice is important for data quality but challenging to coordinate with the large number of study sites.

Inhibition of biofilm formation on iodine-supported titanium implants.

PURPOSE: We have developed iodine-supported titanium implants that suppress microbial activities and conducted in vivo and in vitro studies to determine their antimicrobial properties. METHODS: The implants were Ti-6Al-4 V titanium implants either untreated (Ti), treated with oxide film on the Ti surface by anodization (Ti-O), or treated with an iodine coating on oxidation film (Ti-I). The strain of bacteria used in this study was Gram-positive Staphylococcus aureus strain ATCC 25923. We analyzed the antibacterial attachment effects in vivo by using rats. The attachment bacteria on the implant surface were evaluated using a spread-plate method assay. A biofilm study was performed in vitro. The biofilm formed after bacterial attachment was qualitatively studied with fluorescence microscopy (FM) and scanning electron microscopy (SEM). Also, the formed biofilm was quantitatively studied with a spread-plate method assay. RESULTS: In vivo analysis of antimicrobial attachment effects showed that the mean viable bacterial number was significantly lower on Ti-I than Ti or Ti-O surfaces. In the in vitro biofilm study, FM and SEM images showed thick and mature biofilm formation on Ti and Ti-O and thin, small biofilm formation on Ti-I. A quantitative biofilm analysis found a significant difference in the number of viable bacteria between Ti-I and Ti or Ti-O. CONCLUSIONS: This study showed that iodine-supported implants have a good antibacterial attachment effect and inhibit biofilm formation and growth. Iodine-supported implants may have great potential as innovative antibacterial implants that can prevent implant related infection in orthopaedic surgery.

[Susceptibility to infections and behavior of stainless steel : Comparison with titanium implants in traumatology]. / Infektanfälligkeit und Verhalten von Stahl : Vergleich mit Titanimplantaten in der Traumatologie.

BACKGROUND: Despite modern treatment options, implant-associated infections (IAI) remain a severe and challenging complication in the treatment of trauma patients. Almost 30 years after the introduction of implants made of titanium alloy into the treatment of trauma patients, there is still no uniform consensus regarding the clinical benefit of titanium alloy in the context of patients with IAI. OBJECTIVE: We sought to determine if implants made of titanium alloy have been proven to be less susceptible regarding IAI in contrast to implants made of stainless steel. MATERIAL AND METHODS: A review of the current literature on IAI in association with the utilized implant material was conducted. Relevant articles from the years 1995 to 2016 were searched in the PubMed database. A total of 183 articles were identified and all abstracts were reviewed for relevance. A total of 14 articles met the inclusion criteria and were stratified according to the level of evidence and furthermore evaluated regarding the influence of the implant material on IAI. RESULTS AND DISCUSSION: Considerable debate remains concerning the influence of the implant material on the susceptibility to IAI; however, the available literature shows that despite slight tendencies, there is no proof of titanium alloy being favorable in the susceptibility to IAI. Furthermore, the literature shows that the design of plates for osteosynthesis might influence IAI. In particular, plates that cause less soft tissue damage and preserve perfusion of the periosteum proved to be beneficial regarding IAI.

The clinical presentation of prosthetic joint infection.

Prosthetic joint infection (PJI) complicates ∼1% of arthroplasties but accounts for considerable morbidity. Both the timing and features of PJI can vary widely. Patients may present with early (≤3 months post-operatively), delayed (3-24 months) or late disease (>24 months). They may be acutely unwell with systemic signs of sepsis or describe only a chronically painful joint with or without sinus formation. Diagnostic criteria as proposed by the Infectious Diseases Society of America and the Musculoskeletal Infection Society highlight the importance of joint sampling to obtain histological and robust microbiological evidence. Staphylococcus aureus and coagulase-negative staphylococci account for >50% of infections. Early infections are likely to have been acquired intra- or peri-operatively, whereas late infection is usually haematogenous in origin. Acute joint inflammation suggests the presence of intra-articular free-living bacteria, whereas chronic infections are associated with the formation of biofilm at the bone-cement or bone-prosthesis interface. The most significant risk factors predisposing to PJI are previous operation on the index joint, previous arthroplasty at a different site, American Society of Anesthesiologists' grade 2, 3 or 4, body mass index >25, malignancy and procedure duration <2 or >4 h.

Scabies infestation might predispose surgical site infection: Case report.

INTRODUCTION AND CLINICAL IMPORTANCE: Human scabies is a contagious skin condition caused by the Sarcoptes scabiei mite, leading to skin damage and subsequent mechanical irritation from scratching. This impaired skin integrity predisposes individuals to skin infections. While the association between scabies and skin infections caused by Staphylococcus aureus and Streptococcus pyogenes is well-documented, there is limited literature on the risk of surgical site infections in such cases. CASE PRESENTATION: This case report aims to explore this risk by presenting a case of surgical site infection caused by Streptococcus pyogenes following surgery for a complex elbow injury in a patient with scabies infestation. DISCUSSION: Scabies infestation leads to direct spread of bacteria and contributes to bacterial infection. Furthermore, complement inhibition and dysbiosis induced by the scabies may facilitate the occurrence of these bacterial infections. CONCLUSION: Skin infections are frequently encountered in scabies infestations. Preferred incision should be evaluated meticulously before surgery. Further studies are needed to reach a definitive conclusion on this subject.

Orthopedic Challenges in Avascular Necrosis Management: A Case Report of Surgical Complications and Multidisciplinary Care.

A 52-year-old woman, with a multifaceted medical background encompassing spinal cord injury, pneumonia, and recurrent hospitalizations, presents with enduring left hip and leg discomfort ultimately diagnosed as avascular necrosis (AVN). She previously underwent intraosseous direct anterior arthroplasty (DAA) of the left hip during the removal of orthopedic artifacts. Despite enduring hypertension, severe trochanter dislocation, and prosthesis fracture, she recovered and required additional surgery to address the dislocation and fracture. This case underscores the challenges in diagnosing and treating AVN, emphasizing the importance of meticulous postoperative care and a multidisciplinary approach. Challenges highlighted by AVN include delayed diagnosis, intricate surgical procedures, and the potential need for further interventions due to hardware complications and infection as seen in this patient.

Utility of Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry in Periprosthetic Joint Infection Diagnosis.

One of the most feared complications of arthroplasty surgery is septic loosening. Periprosthetic joint infection (PJI) requires an accurate and fast diagnosis, and identification of pathogen microorganisms is essential for successful treatment. While standard bacteriological cultures can identify bacteria in seven to 14 days with sensitivity ranging from 35% to 70% that could further be increased by sonication of the explanted prosthesis, we would like to review a more novel and faster method of PJI detection and bacterial identification. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS) is a technique that identifies bacteria based on peptides and protein ions from the cell surface, comparing the obtained results within a database. While MALDI-TOF/MS is not a novel method, being already successfully used in microbiology, its role in PJI is still being researched. With this paper, we would like to reveal the current state of development in implementing MALDI-TOF/MS as an alternative or auxiliary test to classic bacterial cultures in orthopedic implant infectious pathology to increase the accuracy of detecting and identifying bacteria.

Positron Emission Tomography-Computed Tomography and Magnetic Resonance Imaging Assessments in a Mouse Model of Implant-Related Bone and Joint Staphylococcus aureus Infection.

Osteomyelitis is an infection of the bone, associated with an inflammatory process. Imaging plays an important role in establishing the diagnosis and the most appropriate patient management. However, data are lacking regarding the use of preclinical molecular imaging techniques to assess osteomyelitis progression in experimental models. This study aimed to compare structural and molecular imaging to assess disease progression in a mouse model of implant-related bone and joint infections caused by Staphylococcus aureus. In SWISS mice, the right femur was implanted with a resorbable filament impregnated with S. aureus (infected group, n = 10) or sterile culture medium (uninfected group, n = 6). Eight animals (5 infected, 3 uninfected) were analyzed with magnetic resonance imaging (MRI) at 1, 2, and 3 weeks postintervention, and 8 mice were analyzed with [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) at 48 h and at 1, 2, and 3 weeks postintervention. In infected animals, CT showed bone lesion progression, mainly in the distal epiphysis, although some uninfected animals presented evident bone sequestra at 3 weeks. MRI showed a lesion in the articular area that persisted for 3 weeks in infected animals. This lesion was smaller and less evident in the uninfected group. At 48 h postintervention, FDG-PET showed higher joint uptake in the infected group than in the uninfected group (P = 0.025). Over time, the difference between groups increased. These results indicate that FDG-PET imaging was much more sensitive than MRI and CT for differentiating between infection and inflammation at early stages. FDG-PET clearly distinguished between infection and postsurgical bone healing (in uninfected animals) from 48 h to 3 weeks after implantation. IMPORTANCE Our results encourage future investigations on the utility of the model for testing different therapeutic procedures for osteomyelitis.

Infected Tibial Plateau Open Reduction Internal Fixation Treated Using External Fixation and a Gastrocnemius Flap: A Case Report.

Here, we describe the case of an 80-year-old female patient with type II insulin-dependent diabetes mellitus with a left proximal tibia fracture. Open reduction internal fixation was performed using a locking plate. After the surgical site infection, the plate was removed and negative-pressure wound therapy was applied. The bone was covered with a vastus medialis muscle flap, and a split-thickness skin graft and external fixation using an Ilizarov device was performed as the definitive treatment.

On-Demand Release of Anti-Infective Silver from a Novel Implant Coating Using High-Energy Focused Shock Waves.

Implant-related infections are a significant concern in orthopedic surgery. A novel anti-infective implant coating made of bioresorbable polymer with silver nitrate was developed. A controlled release of silver ions into the vicinity of the prosthesis can be triggered on-demand by extracorporeal shock waves to effectively combat all clinically relevant microorganisms. Microscopy techniques were used to examine the effects of shock wave application on coated titanium discs. Cytotoxicity was measured using a fibroblast proliferation assay. The anti-infective effect was assessed by monitoring the growth curves of three bacterial strains and by conventional culture. Microscopic analysis confirmed surface disruption of the coatings, with a complete release of silver in the focus area after shock wave application. Spectrometry detected an increase in silver concentration in the surrounding of the discs that surpassed the minimum inhibitory concentration (MIC) for both S. epidermidis RP62A and E. coli ATCC 25922. The released silver demonstrated an anti-infective effect, significantly inhibiting bacterial growth, especially at 6% and 8% silver concentrations. Cytotoxicity testing showed decreasing fibroblast viability with increasing silver concentration in the coating, with 6% silver maintaining viability above 25%. Compared to a commonly used electroplated silver coating on the market, the new coating demonstrated superior antimicrobial efficacy and lower cytotoxicity.

A Rare Case of Staphylococcus caprae-Caused Periprosthetic Joint Infection Following Total Hip Arthroplasty: A Literature Review and Antibiotic Treatment Algorithm Suggestion.

In this study, we discuss a case of a 59-year-old male who developed a periprosthetic joint infection (PJI) three months after a total hip arthroplasty (THA). The patient complained of groin and buttock pain, swelling, and high temperature. A palpable fluid collection, discomfort, edema, and elevated local temperature were present in the clinical examination. Laboratory analysis revealed elevated white blood cells, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The preoperative joint aspiration came up positive for Staphylococcus caprae (S. caprae) infection. Diagnosis and pathogen identification were confirmed by histological examination of six tissue samples obtained during surgery. We initially performed early debridement, antibiotics, and implant retention (DAIR) followed by antibiotic therapy suggested by an infectious disease specialist. DAIR failed two months later, and we proceeded to a two-stage revision. Following surgery, the patient was treated with intravenous antibiotic combination therapy for three weeks and thereafter with oral antibiotics for three months. Four months down the line, the patient is free of symptoms, and the inflammatory markers are normal. Finally, we will proceed with the second stage of revision. This study highlights a very rare case of PJI infection by S. caprae, reviews the limited literature, and provides the available evidence for surgical and antibiotic management.

Shock Wave-Activated Silver-Loaded Biopolymer Implant Coating Eliminates Staphylococcus epidermidis on the Surface and in the Surrounding of Implants.

Bacterial biofilms on foreign surfaces are considered a primary cause of implant-related infections, which are challenging to treat. A new implant coating was developed, containing anti-infective silver within a biocompatible polymer carrier substance. In addition to its passive effect on the implant surface, highly concentrated anti-infective silver can be released as needed via the application of high-energy shock waves. This intervention could be applied transcutaneously in a clinical setting without the need for additional surgery. We investigated the inhibition of biofilm formation and the effectiveness of eradication after activation of the coating via shock waves in an in vitro biofilm model using Staphylococcus epidermidis RP62A. This was performed via scanning electron microscopy and quantitative microbiology. Additionally, we examined the cytotoxicity of the new coating on normal human fibroblasts and Saos-2 osteoblast-like cells, depending on the silver concentration. All studies were compared to uncoated titanium surfaces Ti6Al4V and a conventional electroplated silver coating. Cytotoxicity toward normal human fibroblasts and Saos-2 osteoblast-like cells increased with higher silver content but remained tolerable at 6%. Compared to uncoated Ti6Al4V and the electroplated silver coating, the new coating with a silver content of 4% and 6% exhibited a significant reduction in adherent bacteria by a factor of approximately 1000. This was also evident via microscopic examination of the surface morphology of the biofilms. Furthermore, following shock wave activation, no bacteria were detectable on either the implant or in the surrounding fluid after a 24 h period.

Bioactivity and antibacterial activity of iodine-containing calcium titanate against implant-associated infection.

Developing antimicrobial biomaterials is a major challenge in the fields of orthopaedic and dental implants. In this study, we evaluated the bone-bonding ability and antibacterial activity of a novel biomaterial for preventing implant-associated infections. We have previously reported that NaOH heat treatment improved the bone-bonding ability of titanium, which was later modified to release target ions from the calcium titanate surface. Iodine, an essential nutrient, exhibits broad-spectrum antimicrobial activity; hence, we designed a calcium titanate that releases iodine ions (Ca-I-Ti). The material was prepared from a simple solution using heat treatments as well as inexpensive devices and chemical agents. MC3T3-E1 cells seeded on Ca-I-Ti displayed high degrees of bioactivity and viability, and Ca-I-Ti exhibited antibacterial activity against methicillin-susceptible Staphylococcus aureus. In vivo biomechanical and histological experiments showed that Ca-I-Ti had excellent bone-bonding ability at 8 weeks after implantation. In a subcutaneous infection model in rats, methicillin-susceptible Staphylococcus aureus on the implant was reduced by approximately 95% compared to that on commercially pure titanium, indicating that Ca-I-Ti has antibacterial effects in vivo. In addition, no local or systemic complications were observed, and active infection in the surrounding tissues was histologically inhibited. Thus, iodine-containing calcium titanate is a safe biomaterial with excellent bioactivity and antibacterial properties, indicating its potential in preventing implant-associated infections.

Black-Phosphorus-Nanosheet-Reinforced Coating of Implants for Sequential Biofilm Ablation and Bone Fracture Healing Acceleration.

Incurable implant-related infection may cause catastrophic consequences due to the existence of a biofilm that resists the infiltration of host immune cells and antibiotics. Innovative approaches inspired by nanomedicine, e.g., engineering innovative multifunctional bionic coating systems on the surface of implants, are becoming increasingly attractive. Herein, 2D black phosphorus nanosheets (BPs) were loaded onto a hydroxyapatite (HA)-coated metal implant to construct a BPs@HA composite coating. With its photothermal conversion effect and in situ biomineralization, the BPs@HA coating shows excellent performances in ablating the bacterial biofilm and accelerating fracture healing, which were verified through both in vitro and in vivo studies. Moreover, differentially expressed genes of bone formation and bone mesenchymal stem cells (BMSCs) regulated by the BPs@HA coating were identified using absolute quantitative transcriptome sequencing followed by the screening of gene differential expressions. A functional enrichment analysis reveals that the expression of core markers related to BMSC differentiation and bone formation could be effectively regulated by BPs through a metabolism-related pathway. This work not only illustrates the great potential in clinical application of the BPs@HA composite coating to eliminate bacteria and accelerate bone fracture healing but also contributes to an understanding of the underlying molecular mechanism of osteogenesis physiological function regulation based on an analysis of absolute quantitative transcriptome sequencing.

Development and Characterization of a Subcutaneous Implant-Related Infection Model in Mice to Test Novel Antimicrobial Treatment Strategies.

Orthopedic-device-related infection is one of the most severe complications in orthopedic surgery. To reduce the associated morbidity and healthcare costs, new prevention and treatment modalities are continuously under development. Preclinical in vivo models serve as a control point prior to clinical implementation. This study presents a mouse model of subcutaneously implanted titanium discs, infected with Staphylococcus aureus, to fill a gap in the early-stage testing of antimicrobial biomaterials. Firstly, three different inocula were administered either pre-adhered to the implant or pipetted on top of it following implantation to test their ability to reliably create an infection. Secondly, the efficacy of low-dose (25 mg/kg) and high-dose (250 mg/kg) cefazolin administered systemically in infection prevention was assessed. Lastly, titanium implants were replaced by antibiotic-loaded bone cement (ALBC) discs to investigate the efficacy of local antibiotics in infection prevention. The efficacy in infection prevention of the low-dose perioperative antibiotic prophylaxis (PAP) depended on both the inoculum and inoculation method. Bacterial counts were significantly lower in animals receiving the high dose of PAP. ALBC discs with or without the additional PAP proved highly effective in infection prevention and provide a suitable positive control to test other prevention strategies.