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Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila, a gut probiotic, ameliorates systemic inflammation by tightening the intestinal barrier. In this study, fractured mice intragastrically administrated with A. muciniphila were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muciniphila at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis, and can be stimulated by PDGF-BB. Moreover, A. muciniphila treatment significantly reduced gut permeability and inflammation at the early stage. Dextran sulfate sodium (DSS) was used to disrupt the gut barrier to determine its role in fracture healing and whether A. muciniphila still can stimulate bone fracture healing. As expected, A. muciniphila evidently improved gut barrier, reduced inflammation and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muciniphila reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB+ preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidence for the involvement of type H vessels in fracture healing and suggests the potential of A. muciniphila as a promising strategy for bone healing. This article has an associated First Person interview with the first author of the paper.

Objective To investigate the factors influencing the healing of open fractures in circumpolar latitude region seawater immersion conditions. Materials and methods A femoral fracture model was established in ninety 6-to-8-week-old male Sprague-Dawley rats, randomly assigned to five groups ( n  = 18 per group): (1) fracture only, (2) fracture with circumpolar seawater immersion, (3) fracture with low-temperature isotonic solution immersion, (4) fracture with aseptic circumpolar seawater immersion, and (5) fracture with low-temperature aseptic circumpolar seawater immersion. Fractures were confirmed postoperatively by radiographs on days 7, 21, and 42. Micro-CT and H&E staining were performed on day 42 to assess bone healing. Bacterial cultures from internal fixation devices were analyzed on day 3. Blood samples were collected on days 3, 7, and 14 to assess leukocyte and neutrophil counts, and serum ALP and VEGF levels were measured on days 7, 14, and 21. Pathogenic microorganisms in the seawater were identified by metagenomic analysis. Fracture healing and callus formation rates were compared using the Log-rank test. Results X-ray, micro-CT, and histological analyses revealed significantly impaired fracture healing in the group exposed to circumpolar seawater immersion compared to the fracture-only group ( P  < 0.05). Bacterial colony counts on internal fixation devices were highest in the circumpolar seawater group ( P  < 0.05). Leukocyte and neutrophil levels were significantly elevated in this group on days 3 and 7 ( P  < 0.05), with no significant differences observed on day 14 ( P  > 0.05). Serum ALP and VEGF levels were significantly reduced on days 7, 14, and 21 ( P  < 0.05), although ALP levels on day 21 showed no significant difference ( P  > 0.05). Log-rank analysis indicated that the bone union and callus maturation rates were significantly lower in the circumpolar seawater group compared to the other four groups. Metagenomic analysis identified Flavobacterium, Rhodobacter, and Bacteroides as the dominant pathogens in circumpolar seawater. Conclusions This study demonstrates that hyperosmolarity, low temperature, and exposure to opportunistic pathogens under circumpolar seawater conditions collectively delay open fracture healing. Among these factors, opportunistic pathogens exert the most significant impact, highlighting microbial contamination as the primary barrier to bone regeneration in such environments and providing direction for future therapeutic strategies. Clinical trial number not applicable.

Cerament (Bonesupport Holding, Lund, Sweden) is a bioresorbable synthetic bone substitute consisting of calcium sulfate and hydroxyapatite which is successfully used as a bone graft in bone defects or in delayed and non-unions after fractures. Besides, calcium sulfate/ hydroxyapatite (CAS/HA) could have, attributed to its composition and osteoinductive properties, have great importance in the treatment of bone infections with critical size defects (CSD). Aim of the study was to evaluate the effects of antibiotic infused CAS/HA on inflammation and bone healing in an implant-associated osteitis mice model. In a standardized murine model, the left femur of 72 BALB/c mice were osteotomized, generating a CSD (2,5 mm) with stabilization through a 6-hole titanium locking plate. Osteitis has been induced through inoculation of Staphylococcus aureus (SA) into the fracture gap. To analyze the effect of CAS/HA, following groups were generated with either CAS/HA, CAS/HA with gentamycin (CAS/ HA-G) or CAS/HA with vancomycin (CAS/HA-V) insets placed into the osteotomy. Debridément and lavages were progressed on day 7 and 42 to determine the local bacterial growth and the immune reaction. Fracture healing was quantified on day 7 and 42 by x-ray and bone healing markers from blood samples. Progression of infection was assessed by estimation of colony-forming units (CFU) and immune response was analyzed by determination of Interleukin (IL)- 6 and polymorphonuclear neutrophils (PMN) in lavage samples. Osteitis induced higher IL-6 and PMN-levels in the lavage samples on day 7. Both parameters showed a reduction in all groups on day 42. CAS/HA-V revealed a significant reduction of CFU and PMNs in lavage samples on day 42. A positive effect on bone healing could only be shown in non-infected mice. Whereas, application of mere CAS/HA in infected mice did show tendencies of bone destruction and lysis, independent of impregnation with antibiotics or not. Thus, application of CAS/HA in acute implant-associated infections is not recommended. In non-infectious environments or after infect-convalescence CAS/HA could albeit serve as a suggestive tool in trauma and orthopedic surgery.

Reconstruction of large bone defects can be complicated by the presence of both infection and local antibiotic administration. This can be addressed through a two-stage reconstructive approach, called the Masquelet technique, that involves the generation of an induced osteogenic membrane over a temporary poly(methyl methacrylate) (PMMA) space maintainer, followed by definitive reconstruction after the induced membrane is formed. Given that infection and antibiotic delivery each have independent effects on local tissue response, the objective of this study is to evaluate the interaction between local clindamycin release and bacterial contamination with regards to infection prevention and the restoration of pro-osteogenic gene expression in the induced membrane. Porous PMMA space maintainers with or without clindamycin were implanted in an 8 mm rat femoral defect model with or without Staphylococcus aureus inoculation for 28 days in a full-factorial study design (four groups, n  = 8/group). Culture results demonstrated that 8/8 animals in the inoculated/no antibiotic group were infected at 4 weeks, which was significantly reduced to 1/8 animals in the inoculated/antibiotic group. Quantitative polymerase chain reaction analysis demonstrated that clindamycin treatment restores inflammatory cytokine and growth factor expression to the same levels as the no inoculation/no antibiotic group, demonstrating that clindamycin can ameliorate the negative effects of bacterial inoculation and does not itself negatively impact the expression of important cytokines. Main effect analysis shows that bacterial inoculation and clindamycin treatment have independent and interacting effects on the gene expression profile of the induced membrane, further highlighting that antibiotics play an important role in the regeneration of infected defects apart from their antimicrobial properties.

S. epidermidis is responsible for biofilm-related nonunions. This study compares the response to S. epidermidis-infected fractures in rats systemically or locally injected with vancomycin or bone marrow mesenchymal stem cells (BMSCs) in preventing the nonunion establishment. The 50% of rats receiving BMSCs intravenously (s-rBMSCs) died after treatment. A higher cytokine trend was measured in BMSCs locally injected rats (l-rBMSCs) at day 3 and in vancomycin systemically injected rats (l-VANC) at day 7 compared to the other groups. At day 14, the highest cytokine values were measured in l-VANC and in l-rBMSCs for IL-10. µCT showed a good bony bridging in s-VANC and excellent both in l-VANC and in l-rBMSCs. The bacterial growth was lower in s-VANC and l-VANC than in l-rBMSCs. Histology demonstrated the presence of new woven bone in s-VANC and a more mature bony bridging was found in l-VANC. The l-rBMSCs showed a poor bony bridging of fibrovascular tissue. Our results could suggest the synergic use of systemic and local injection of vancomycin as an effective treatment to prevent septic nonunions. This study cannot sustain the systemic injection of BMSCs due to high risks, while a deeper insight into local BMSCs immunomodulatory effects is mandatory before developing cell therapies in clinics.

In this study, a novel oxygenated nanocomposite thin film, TaON-Ag, was investigated in vitro and in vivo to evaluate its biocompatibility and antibacterial ability. The antibacterial ability of TaON-Ag nanocomposite-coated titanium (Ti) was evaluated using the Kirby-Bauer disk diffusion susceptibility test. The effects of TaON-Ag nanocomposite-coated metal on osteogenesis were further evaluated in an in vitro osteogenic culture model with rat marrow-derived mesenchymal stem cells (rMSCs). Furthermore, titanium rods coated with TaON-Ag were implanted into a rat femur fracture model either with or without osteomyelitis to investigate the effects of TaON-Ag in osteogenesis. The TaON-Ag-coated Ti exhibited an effective antibacterial effect against , coagulase-negative , and the Gram-negative strains and . Using an osteogenic culture with rMSCs and a rat femoral fracture model, the TaON-Ag-coated Ti did not interfere with the ossification of rMSCs in vitro or during fracture healing in vivo. Field-emission scanning electron microscopy (FE-SEM) revealed that coating with TaON-Ag could inhibit pathogen adhesion and biofilm formation in both and Using the proposed novel oxygenation process, TaON-Ag nanocomposite-coated Ti yielded robust biocompatibility and antibacterial ability against common microorganisms in orthopedic infections, thereby demonstrating potential for use in clinical applications.

The osteoinductive capability of BMPs appears diminished in the setting of acute infection. We applied rhBMP-2 to a segmental defect in a rat femur and measured the expression of key bone formation genes in the presence of acute infection. Types I and II collagen, osteocalcin, and BMP Type II receptor mRNA expression were characterized in 72 Sprague-Dawley rats, which received either bovine collagen carrier with 200 μg rhBMP-2 plus Staphylococcus aureus, carrier with bacteria only, carrier with rhBMP-2 only, or carrier alone. Six animals from each group were euthanized at 1, 2, and 4 weeks. Total RNA was isolated and extracted, and mRNA was determined by real-time comparative quantitative PCR. Infected defects had little expression of collagen I and II and osteocalcin mRNAs, while BMP receptor II expression with infection was greater than carrier-only controls at Weeks 2 and 4. Notably, all four genes were upregulated in infected defects in the presence of rhBMP-2. Thus, in a clinical setting with a high risk of infection and nonunion, such as a compound fracture with bone loss, rhBMP-2 may increase the rate and extent of bone formation. Even if infection does occur, rhBMP-2 may allow a quicker overall recovery time.

The goal of this study was to use a segmental defect model in the rat femur to determine if osteogenic protein-1 (OP-1) is capable of inducing bone formation in the presence of bacterial contamination. A 6 mm segmental defect was surgically created and stabilized with a polyacetyl plate and Kirschner wires in one femur in each of 126 Sprague–Dawley rats. The animals were divided into eight groups in which the defect was either left untreated, or subjected to various combinations of OP-1 (11 or 50 μg), lyophilized bovine type I collagen (carrier for the OP-1), and 10 5 colony-forming units of Staphylococcus aureus. The animals were euthanized at either 2, 4, or 9 weeks. Quantitative radiographic and histologic analyses were performed on the harvested tissue. The initial contamination progressed to infection in all animals receiving bacteria, as determined by qualitative bacteriology. There was very little, if any, bone formation in the untreated defects, and in the contaminated defects with or without collagen carrier. Bone formation was significantly greater in contaminated defects with either dose of OP-1, compared with contaminated defects without OP-1. The 50 μg dose of OP-1 induced significantly more bone formation than the 11 μg dose, both with and without bacteria. This investigation has demonstrated that OP-1 maintains its osteoinductive capability in a contaminated segmental defect. OP-1 may potentially be used in the clinical management of contaminated fractures.

In the treatment of nonunions of the distal femur, infection should be excluded. However, it is difficult to determine whether the nonunion is infected or not with negative history and signs of infection. The purpose of this study was to investigate indolent infection as a cause of presumptive aseptic distal femur nonunion. All presumptive aseptic distal femur nonunions treated from 1998 to 2008 were retrospectively reviewed. Any patient with suspected of having an infection clinically was excluded. Multiple tissue cultures were performed at the nonunion site. The main outcomes were to analyze the rate of positive cultures in presumptive aseptic distal femur nonunion and to compare the rate of secondary surgery in positive and negative culture groups. Of the 22 patients, 3 (13.6 %) had positive culture results. The organisms cultured were Staphylococcus aureus , Staphylococcus epidermidis , and Enterobacter cloacae . The overall rate of infection was 9.1 % (2/22), and one patient underwent a secondary procedure. In the open fracture group, 2 of 10 patients (20 %) had positive cultures; all developed infection. In the closed fracture group, 1 of 12 patients (8.3 %) had positive culture results, but Infection did not occur in the patient with a 3-week intravenous antibiotic treatment. The postoperative infection rate was 67 % (2/3) in patients with positive intraoperative cultures, while 0 % (0/18) in the group with negative intraoperative cultures ( p  < 0.001). The presence of indolent infection can be verified in patients with presumptive aseptic nonunion of distal femoral fractures by obtaining intraoperative biopsy tissue cultures. Positive intraoperative culture results were related with postoperative infection.

Background It is important to predict the occurrence of deep infection in open fractures when treating such fractures. We tried to develop a new scoring system for predicting the occurrence of deep infection in open upper and lower extremity fractures on the basis of the Hannover Fracture Scale’98 (HFS-98). Methods A total of 394 open upper and lower extremity fractures (351 patients) were retrospectively reviewed in the initial analysis. The relationship between Gustilo’s grade and the eight items on HFS-98 in the open extremity fractures was first investigated by multivariate analysis. By this analysis, we selected significant items that correlated with Gustilo’s grade. Among these cases, 318 patients with 352 open extremity fractures (humerus = 27, forearm = 62, femur = 76, tibia = 187) were used for the following infection analyses. The relationships between the incidence of deep infection and sex (male or female), age (<30, 30–50, <50 years), grade of polytrauma (ISS < 18, 18 ≤ ISS ≤ 30, ISS > 30), site of fracture (humerus, forearm, femur, tibia), existence of fracture line around joint (+ or −) or some significant items in the above initial analysis were further analyzed by multivariate analysis after univariate analysis. We devised a new scoring system of open extremity fractures based on P values in the above analysis. The discrimination of the newly devised scoring system was evaluated with receiver operating characteristic (ROC) curves. Results The following factors: muscle injury (MI, P  = 0.0001); wound contamination (WC, P  = 0.0001); and local circulation (LC, P  = 0.0001) were significant factors affecting the occurrence of deep infection on multivariate analysis. We devised a new scoring system for open extremity fractures (MI: 0–20 points, WC: 0–20 points, and LC: 0–20 points). The cut-off point for occurrence of deep infection in these fractures was 35 by ROC analysis. Conclusions This new scoring system was thought to be useful for predicting the occurrence of deep infection in open extremity fractures. However, further prospective study or multicenter study would be needed to clarify the validity of this scale.