Clinical characteristics and outcomes associated with culture-negative status in limb osteomyelitis patients.

Aims: This study aimed to investigate the clinical characteristics and outcomes associated with culture-negative limb osteomyelitis patients. Methods: A total of 1,047 limb osteomyelitis patients aged 18 years or older who underwent debridement and intraoperative culture at our clinic centre from 1 January 2011 to 31 December 2020 were included. Patient characteristics, infection eradication, and complications were analyzed between culture-negative and culture-positive cohorts. Results: Of these patients, 264 (25.2%) had negative cultures. Patients with a culture-negative compared with a culture-positive status were more likely to have the following characteristics: younger age (≤ 40 years) (113/264 (42.8%) vs 257/783 (32.8%); p = 0.004), a haematogenous aetiology (75/264 (28.4%) vs 150/783 (19.2%); p = 0.002), Cierny-Mader host A (79/264 (29.9%) vs 142/783 (18.1%); p < 0.001), antibiotic use before sampling (34/264 (12.9%) vs 41/783 (5.2%); p＜0.001), fewer taken samples (n＜3) (48/264 (18.2%) vs 60/783 (7.7%); p＜0.001), and less frequent presentation with a sinus (156/264 (59.1%) vs 665/783 (84.9%); p < 0.001). After initial treatments of first-debridement and antimicrobial, infection eradication was inferior in culture-positive osteomyelitis patients, with a 2.24-fold increase (odds ratio 2.24 (95% confidence interval 1.42 to 3.52)) in the redebridement rate following multivariate analysis. No statistically significant differences were found in long-term recurrence and complications within the two-year follow-up. Conclusion: We identified several factors being associated with the culture-negative result in osteomyelitis patients. In addition, the data also indicate that culture negativity is a positive prognostic factor in early infection eradication. These results constitute the basis of optimizing clinical management and patient consultations.

The induced membrane technique for the management of infected segmental bone defects.

Aims: The aim of the present study was to assess the outcomes of the induced membrane technique (IMT) for the management of infected segmental bone defects, and to analyze predictive factors associated with unfavourable outcomes. Methods: Between May 2012 and December 2020, 203 patients with infected segmental bone defects treated with the IMT were enrolled. The digital medical records of these patients were retrospectively analyzed. Factors associated with unfavourable outcomes were identified through logistic regression analysis. Results: Among the 203 enrolled patients, infection recurred in 27 patients (13.3%) after bone grafting. The union rate was 75.9% (154 patients) after second-stage surgery without additional procedures, and final union was achieved in 173 patients (85.2%) after second-stage surgery with or without additional procedures. The mean healing time was 9.3 months (3 to 37). Multivariate logistic regression analysis of 203 patients showed that the number (≥ two) of debridements (first stage) was an independent risk factor for infection recurrence and nonunion. Larger defect sizes were associated with higher odds of nonunion. After excluding 27 patients with infection recurrence, multivariate analysis of the remaining 176 patients suggested that intramedullary nail plus plate internal fixation, smoking, and an allograft-to-autograft ratio exceeding 1:3 adversely affected healing time. Conclusion: The IMT is an effective method to achieve infection eradication and union in the management of infected segmental bone defects. Our study identified several risk factors associated with unfavourable outcomes. Some of these factors are modifiable, and the risk of adverse outcomes can be reduced by adopting targeted interventions or strategies. Surgeons can fully inform patients with non-modifiable risk factors preoperatively, and may even use other methods for bone defect reconstruction.

Activated allograft combined with induced menbrane technique for the reconstruction of infected segmental bone defects.

This study was desinged to evaluate the efficacy and safety of activated allograft combined with the induced membrane technique for reconstruction of infected segment bone defects of lower limbs. A retrospective analysis was conducted on 19 patients from May 2015 to February 2017. After debridements, the bone defects were filled with antibiotic bone cement to form the induced membrane. Autologous mesenchymal stem cells were seeded onto allografts to construct activated allograft, which was implanted into the induced membrane after infection was controlled. The clinical efficacy and complications were observed. 19 patients with 20 infected segment bone defect were evaluated. The average deficit size was 11.08 (4-17) cm in length. After a mean follow-up of 71.84 (61-82) months, bone union was achieved in 16 patients (17 sites), resulting in a final union rate of 84.21% (16/19 patients). The average bone union time was 10.18 (5-28) months. There were 2 patients with recurrence of infection, 3 patients with graft absorption, and 1 patient with malunion due to implant breakage. There were no graft-related complications. This study provides clinical significance for the treatment of patients with insufficient autologous bone.

Induced membrane technique versus one-stage autografting in management of atrophic nonunion of long bone in the lower limb: clinical and health burden outcomes.

OBJECTIVE: In this study, we aimed to compare the outcomes of the two-stage induced membrane technique (IMT) and one-stage autografting in the treatment of aseptic atrophic nonunion in lower limb long bones. METHODS: From January 2014 to January 2022, we reviewed all surgically treated long bone nonunion patients, including patients aged 18 years or older with atrophic nonunion, who were either treated with the two-stage induced membrane technique (IMT) or one-stage autografting. Outcome parameters interns of clinical, quality of life and healthcare burden were recorded and retrospectively analysed between the two treatment populations. The follow-up time was at least 1 year. RESULTS: In total, 103 patients who met the criteria for aseptic atrophic nonunion were enrolled. Among them, 41 (39.8%) patients were treated with two-stage IMT, and 62 (60.2%) patients were treated with one-stage autologous bone grafting. The follow-up time was 12 to 68 months, with an average of 28.4 months. The bone healing rate was comparable in both groups (IMT: 92.7% vs. one-stage grafting: 91.9%, P = 0.089) at 12 months post-operation, and the bone healing Lane-Sandhu score was superior in the IMT group (mean: 8.68 vs. 7.81, P = 0.002). Meanwhile, the SF-12 scores of subjective physical component score (PCS) (mean: 21.36 vs. 49.64, P < 0.01) and mental health component score (MCS) (mean: 24.85 vs. 46.14, P < 0.01) significantly increased in the IMT group, as well as in the one-stage grafting group, and no statistically significant difference was found within groups. However, the total hospital stays (median: 8 days vs. 14 days, P < 0.01) and direct medical healthcare costs (median: ¥30,432 vs. ¥56,327, P < 0.05) were greater in the IMT group, while the complications (nonunion 8, infection 3, material failure 2, and donor site pain 6) were not significantly different between the two groups (17.1% vs. 19.4, P = 0.770). CONCLUSION: The data indicate that two-stage method of IMT serves as an alternative method in treating atrophic nonunion; however, it may not be a preferred option, in comprehensive considering patient clinical outcomes and healthcare burden. More evidence-based research is needed to further guide clinical decision-making.

Discovery of multipotent progenitor cells from human induced membrane: Equivalent to periosteum-derived stem cells in bone regeneration.

Background: The periosteum stem cells (PSCs) plays a critical role in bone regeneration and defect reconstruction. Insertion of polymethyl methacrylate (PMMA) bone cement can form an induced membrane(IM) and showed promising strategy for bone defect reconstruction, the underlying mechanism remains unclear. Our study sought to determine whether IM-derived cells(IMDCs) versus PSCs have similar characteristics in bone regeneration. Methods: IM and periosteum were harvested from ten bone defect patients treated with PMMA, the IMDCs and PSCs were isolated respectively. Morphological, functional and molecular evaluation was performed and matched for comparison. Results: Both progenitor-like IMDCs and PSCs were successfully isolated. In vitro, we found IMDCs were similar to PSCs in morphology, colony forming capacity and expression of surface marker(CD90+, CD73+, CD105+, CD34-/CD45-). Meanwhile, these IMSCs displayed multipotency with chondrogenic, adipogenic and osteogenic differentiation, but differed in some IMSCs(3/10) population showing relatively poor osteogenic differentiation. The molecular profiles suggests that cell cycle and DNA replication signaling pathways were associated with these varying osteogenic potential. In vivo, we established a cell-based tissue-engineered bone by seeding IMDSs/PSCs to demineralized bone matrix (DBM) scaffold and demonstrated both IMDSs and PSCs enhanced bone regeneration in SCID mice bone defect model compared with DBM alone. Conclusion: Our data demonstrated IM containing multipotent progenitor cells similar to that periosteum promoting bone regeneration, and indicated the existence of multiple subsets in osteogenic differentiation. Overall, the study provided a cellular and molecular insights in understanding the successful or failed outcome of bone defect healing.The translational potential of this article: This study confirmed IMDCs and PSCs share similar regeneration capacity and inform a translation potential of that cellular therapy applying IMDCs in bone defect repair.

Incidence and risk factors of recurrence in limb osteomyelitis patients after antibiotic-loaded cement spacer for definitive bone defect treatment.

Aims: This study was designed to characterize the recurrence incidence and risk factors of antibiotic-loaded cement spacer (ALCS) for definitive bone defect treatment in limb osteomyelitis. Methods: We included adult patients with limb osteomyelitis who received debridement and ALCS insertion into the bone defect as definitive management between 2013 and 2020 in our clinical centre. The follow-up time was at least two years. Data on patients' demographics, clinical characteristics, and infection recurrence were retrospectively collected and analyzed. Results: In total, 314 patients with a mean age of 52.1 years (SD 12.1) were enrolled. After a mean of 50 months' (24 to 96) follow-up, 53 (16.9%) patients had infection recurrence including 32 tibiae, ten femora, ten calcanea, and one humerus. Of all patients with recurrence, 30 (9.6%) occurred within one year and 39 (12.4%) within two years. Among them, 41 patients needed reoperation, five received antibiotics treatment only, and seven ultimately required amputations. Following multivariable analysis, we found that patients infected with Gram-negative bacilli were more likely to have a recurrence (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.20 to 6.94; p = 0.046) compared to Staphylococcus aureus; segmental bone defects (OR 5.25, 95% CI 1.80 to 15.26; p = 0.002) and smoking (OR 3.00, 95% CI 1.39 to 6.50; p = 0.005) were also independent risk factors for recurrence after treatment. Conclusion: Permanent ALCS might be an alternative strategy for definitive bone defect management in selected osteomyelitis cases. However, the overall high recurrence found suggests that it should be cautiously treated. Additionally, segmental defects, Gram-negative infections, and smoking were associated with an increased risk of infection recurrence.

rFSAV promotes Staphylococcus aureus-infected bone defect healing via IL-13- mediated M2 macrophage polarization.

Staphylococcus aureus (S. aureus) contamination commonly occurs in orthopedic internal fixation operations, leading to a delayed healing of the defected bone tissue. However, antibiotic treatments are ineffective in dealing with S. aureus bone infections due to the rise in multiple antimicrobial resistances. Here, we reported the protective effects of a recombinant five-antigen S. aureus vaccine (rFSAV) in an S. aureus infected bone defect model. In this study, we found the number of M2 macrophages markedly increased in the defect site and played a critical role in the healing of defected bone mediated by rFSAV. Mechanistically, rFSAV mediated increased level of IL-13 in bone defect site predominant M2 macrophage polarization. In summary, our study reveals a key role of M2 macrophage polarization in the bone regeneration process in S. aureus infection induced bone defect, which provide a promising application of rFSAV for the treatment of bone infection for orthopedic applications.

The impact of methicillin resistance on clinical outcome among patients with Staphylococcus aureus osteomyelitis: a retrospective cohort study of 482 cases.

This study was designed to evaluate the impact of methicillin resistance on the outcomes among patients with S. aureus osteomyelitis. We reviewed all extremity osteomyelitis patients treated in our clinic center between 2013 and 2020. All adult patients with S. aureus pathogen infection were included. Clinical outcome in terms of infection control, length of hospital stay, and complications were observed at the end of a 24-month follow-up and retrospectively analyzed between populations with/without methicillin resistance. In total, 482 osteomyelitis patients due to S. aureus were enrolled. The proportion of methicillin-resistant S. aureus (MRSA) was 17% (82) and 83% (400) of patients had Methicillin-sensitive S. aureus (MSSA). Of 482 patients, 13.7% (66) presented with infection persistence after initial debridement and antibiotic treatment (6 weeks), needed repeated debridement, 8.5% (41) had recurrence after all treatment end and a period infection cure, complications were observed in 17 (3.5%) patients (pathologic fracture; 4, nonunion; 5, amputation; 8) at final follow-up. Following multivariate analysis, we found patients with S. aureus osteomyelitis due to MRSA are more likely to develop a persistent infection (OR: 2.26; 95% CI 1.24-4.13) compared to patients with MSSA. Patients infected with MRSA also suffered more complications (8.5% vs. 2.5%, p = 0.015) and longer hospital stays (median: 32 vs. 23 days, p < 0.001). No statistically significant differences were found in recurrence. The data indicated Methicillin resistance had adverse clinical implication for infection persistence among patients with S. aureus osteomyelitis. These results will help for patients counsel and preparation for treatment.

Investigation of biofilm production and its association with genetic and phenotypic characteristics of OM (osteomyelitis) and non-OM orthopedic Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is a primary pathogen of orthopedic infections. By mediating antimicrobial resistance, S. aureus biofilm plays an important role in the recalcitrance of orthopedic infections, especially for the intractable osteomyelitis (OM). This study investigated the relationship between biofilm production and various genetic or phenotypic characteristics among orthopedic S. aureus strains. METHODS: A total of 137 orthopedic S. aureus isolates were enrolled and divided into OM and non-OM groups. Biofilm production was evaluated using the crystal violet assay. Genetic and phenotypic characteristics including MRSA identification, MLST and spa typing, carriage of virulence genes, drug resistance, and patients' inflammatory responses indicators were characterized. The relationship between biofilm production and above-mentioned features was respectively analyzed among all isolates and compared between OM and non-OM isolates. RESULTS: Biofilm production presented no significant difference between OM (including 9 MRSA isolates) and non-OM (including 21 MRSA isolates) strains. We found that ST88, t377 and ST630-MSSA-t377 strains produced very strong biofilms, while MLST types of ST15, ST25, ST398, ST5, ST59 and spa types of t002, t2325, t437 tended to produce weaker biofilms. Strains with the following profiles produced stronger biofilms: fib(+)-hlgv(+)-lukED(+)-sei(-)-sem(-)-seo(-) for all isolates, sei(-)-sem(-)-seo(-) for OM isolates, and cna (+)-fib (+)-hlgv (+)-lukED (+)-seb(-)-sed(-) for non-OM isolates. In addition, not any single drug resistance was found to be related to biofilm production. We also observed that, among OM patients, strains with stronger biofilms caused weaker inflammatory responses. CONCLUSION: Some genetic or phenotypic characteristics of orthopedic strains were associated with biofilm production, and this association could be different among OM and non-OM strains. The results are of great significance for better understanding, evaluating and managing different kinds of biofilm-associated orthopedic infections, and provide potential targets for biofilm clearance.

An antibiotic cement-coated locking plate as a temporary fixation for treatment of infected bone defects: a new method of stabilization.

BACKGROUND: The induced membrane technique has achieved good clinical results in the treatment of infected bone defects, and external fixation is the main method, but it causes inconvenience and complications in patients. In this study, our objective was to investigate the outcomes of using an antibiotic cement-coated locking plate as a temporary internal fixation in the first stage of the surgical induced membrane technique for treating extremities with infected bone defects. METHODS: We retrospectively analysed patients with lower extremity infected bone defects in our department between January 2013 and December 2017. All patients were treated with the induced membrane technique. In the first stage, the defects were stabilized with an antibiotic cement-coated locking plate as a temporary fixation after debridement, and polymethyl methacrylate cement was implanted to induce the formation of a membrane. In the second stage, bone grafting rebuilt the bone defects after infection control, and the temporary fixation was changed to a stronger fixation. RESULTS: A total of 183 patients were enrolled, with an average follow-up duration of 32.0 (12-66) months. There were 154 males and 29 females with an average age of 42.8 (10-68) years. The infection sites included 81 femurs, 100 tibias and 2 fibulas. After the first stage of treatment (infection control), 16 (8.7%) patients had recurrence of infection. In terms of the incidence of complications, 4 patients had poor wound healing, 2 patients had fixation failure and 1 patient had femoral fracture due to a fall. After the second stage of treatment (bone reconstruction), there were 24 (13.1%) recurrences of infection, with a mean time of 9.9 months (range 0.5 to 36). Among them, 18 patients underwent bone grafting after re-debridement, 6 received permanent placement of antibiotic bone cement after debridement and 2 patients refused further treatment and chose amputation. Bone healing was achieved in 175 (95.9%) patients at the last follow-up, and the average time to bone union was 5.4 (4-12) months. CONCLUSIONS: Antibiotic cement-coated locking plates have good clinical effects in the control of bone infection, but attention must be paid to the possible difficulty of skin coverage when applied in calves.

Investigating clinical characteristics and prognostic factors in patients with chronic osteomyelitis of humerus.

BACKGROUND: Chronic osteomyelitis in the humerus, which has complex neuroanatomy and a good soft tissue envelope, represents a unique clinical challenge. However, there are relatively few related studies in the literature. This article retrospectively reviewed a large case series with the aims of sharing our management experiences and further determining factors associated with the outcomes. METHODS: Twenty-eight consecutive adult patients with a mean age of 36 years were identified by reviewing the osteomyelitis database of our clinic centre. The database was used to prospectively identify all osteomyelitis cases between 2013 and 2017, and all data then was retrospectively analysed. RESULTS: The mean follow-up period was 35 months (range 24-60). The aetiology was trauma in 43% (12) of the patients and haematogenous in 57% (16) of the patients, and Staphylococcus aureus was a solitary agent in 50% (14) of the patients. Host-type (Cierny's classification) was IA in 8, IIIB in 11 and IVB in 9 patients. All patients required debridement followed by the placement of a temporary antibiotic-impregnated cement spacer (rod). Seventeen patients received a cement-coated plate for internal fixation after debridement, and 13 patients needed bone grafts when the spacer was staged removed. All patients attained an infection-free bone healing state at the final follow-up. The final average DASH (disabilities of the arm, shoulder and hand) score was 18.14 ± 5.39, while 6 patients (two developed traumatic olecranarthritis, four developed radial nerve injuries) showed the lowest levels of limb function (p = 0.000) and were unemployed. Three patients (type I; significant difference between type I versus type III and type IV patients, p < 0.05) experienced recurrence after debridement and underwent a second revision, which was not related to the bone graft (p = 0.226) or plate fixation (p = 0.050). CONCLUSIONS: Humeral chronic osteomyelitis can be treated with general surgery and anti-infective therapy; medullary (type I) infection presents a challenge, and the antibiotic-coated cement plate provides favourable fixation without increasing recurrence of infections. Clinicians should be aware of potential iatrogenic nerve injuries when treating these patients with complicated cases, and an experienced surgeon may improve the outcome.

Induced membrane technique: Advances in the management of bone defects.

Management of bone defects caused by trauma, osteomyelitis, and tumors is challenging, with many controversies over the optimal reconstruction method. Masquelet discovered induced membrane in management of large diaphyseal defects accidentally, and developed this technique with a concept of induced membrane. Induced membrane technique holds great potential for the reconstruction of bone defects, alternatively to manage this clinical challenge quiet easily. Induced membrane has unique structural characteristics and biological properties, which render this technique has an advantage of the time to bone healing is relatively independent of the length of bone defect. Herein, we reviewed the latest advances made in induced membrane technique and highlighted the concept of induced membrane in the management of bone defects.

Two stage management of Cierny-Mader type IV chronic osteomyelitis of the long bones.

INTRODUCTION: Cierny-Mader (C-M) type IV chronic osteomyelitis represents a complex clinical challenge with permeation of extensive bone and soft tissue involvement. Aggressive debridement through viable tissue margin includes en bloc resection improves the odds of eradication of infection, which creates large bone and soft tissue loss in treating this type of osteomyelitis. The potentially large defects increase reconstruction problems with traditional reconstruction technique. The newly staged induced membrane technique presents length-independent, potential as an alternative reconstruction method for segmental bone defects due to type IV chronic osteomyelitis. The purpose of this study was to assess the result and related factors of C-M type IV chronic osteomyelitis treated with staged methods of aggressive debridement and induced membrane technique. METHODS: From January 2012 to January 2014, 36 consecutive adult patients of C-M type IV chronic osteomyelitis were treated by this staged method in our clinical center with a minimum of 2-years follow-up. The clinical and imaging results were retrospectively analyzed. RESULTS: Five patients had a second debridement and eight needed a local flap transfer to cover the wound in the first stage. Patients formed a mean of 5.5cm (range: 2-10.9) segmental bone defect; Sixteen patients had autograft and twenty had autograft mixed allograft in the second stage. The mean follow-up time was 29.5 months (range: 24-45). No patients required amputation. Bone union was achieved in all patients. Clinical eradication of osteomyelitis was achieved in 35 (97%) patients, 35 (97%) patients were able to walk independently, and 31patients (86%) returned to work. Patients returned to a mean of 82% (46.3%-100%) lower extremity function. Bone union time was not dependent on the length of bone defect, but associated with the infection site (p=0.005) and age (p=0.005). CONCLUSIONS: Staged methods of aggressive debridement and induced membrane technique seems to be a simple, reliable and effective for the treatment of C-M type IV chronic osteomyelitis. Advanced age and poor soft tissue envelope may have adverse affects and are relative contraindications. The combined assessment and management of such patients with a plastic surgeon are advocated.

Antibiotic cement-coated locking plate as a temporary internal fixator for femoral osteomyelitis defects.

PURPOSE: Recently we modified the Masquelet technique by using an antibiotic cement-coated locking plate as a temporary internal fixator when treating septic bone defects. This modification is in order to prevent the complications related to external fixator use and provides the involved limb with a greater stability to undergo earlier and more vigorous physical therapy for recovery of joint function. The purpose of this study was to assess the outcomes of large femoral osteomyelitis defects managed by Masquelet technique combined with the antibiotic cement-coated locking plate used as a temporary internal fixator. METHODS: Between November 2013 to November 2014, 13 cases of large femoral osteomyelitis defects were treated by Masquelet technique and the antibiotic cement-coated locking plate was used as a temporary internal fixator in the first stage surgery. All the patients' clinical and imaging results were retrospectively analyzed. RESULTS: After debridement, there was a femoral bone defect with a mean of 9.8 cm (range, 5-16 cm). The mean follow-up was 17.8 months (range 12 to 24 months). One patient developed infection in nine months after second stage surgery. Radiographic bony union was achieved within a mean 20.3 weeks (range, 18-30 weeks) in all patients. The mean time period to full weight bearing after the second step procedure was 5.8 months (range, 5-8.5 months). The mean knee range of motion for the patients at the last follow up was 122° (range 100-135°). CONCLUSION: Based on our experience, we believe that antibiotic cement-coated locking plate is a viable fixation method in the first stage of Masquelet technique for the management of large femoral osteomyelitis defects. It may offer a better chance of infection eradication as well as improved recovery of joint function without increasing the infection recurrence rate and without compromising bone graft union.