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Histologic features of "acute" and "chronic" osteomyelitis exist in the same lesion. Hematoxylin and eosin-stained, paraffin-embedded, decalcified section of an infected metatarsal bone resected from a patient with a diabetic foot ulcer is shown, illustrating salient features of both acute and chronic osteomyelitis in the same bone. a Low power micrograph of the lesion in which most of the trabecular bone in this part of the metatarsus has been destroyed and replaced by an acute inflammatory reaction, consisting of neutrophils (*) and fibrovascular granulation tissue (black arrow) (scale bar = 1 mm). The inflammation extends to the bone beneath the articular cartilage (yellow arrow) and has destroyed much of the cortical bone (white arrow). Reactive new bone has formed in the lower part of the image, along with a chronic inflammatory and fibrovascular reaction. b A region of interest of acute inflammation (white box in a) is shown highlighting a fragment of dead cortical bone surround by neutrophils (black arrow), with an associated fibrinous exudate, which are hallmarks of acute osteomyelitis (scale bar = 25 mm). c A region of interest of chronic inflammation (black box in a) showing new bone formation (black arrow), and replacement of normal bone marrow with fibrovascular inflammatory tissue (boxed region) (scale bar = 50 mm). d This region of interest (boxed area in c) is presented at high power, showing blood vessels, osteoblasts rimming newly formed woven bone (bottom right), and collections of lymphocytes and plasma cells (arrows), which are characteristic of chronic osteomyelitis (scale bar = 25 mm)
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Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly high. Staphylococcus aureus is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persist...
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... a segment of infected bone is investigated histologically for hallmarks of acute and chronic inflammations (Fig. 4), it becomes clear that features of both acute and chronic osteomyelitis can be present in the same specimen. From a case of acute osteomyelitis in a tarsal bone under an infected ulcer in a diabetic patient, we can observe distinct characteristics of acute infection, as well as chronic inflammation within the same lesion (Fig. 4a). A ...
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... inflammations (Fig. 4), it becomes clear that features of both acute and chronic osteomyelitis can be present in the same specimen. From a case of acute osteomyelitis in a tarsal bone under an infected ulcer in a diabetic patient, we can observe distinct characteristics of acute infection, as well as chronic inflammation within the same lesion (Fig. 4a). A region of acute infection can be identified by the presence of predominantly newly activated neutrophils, as well as fibrovascular granulation tissue around foci of dead bone (Fig. 4b). However, adjacent to this lesion, we can identify hallmarks of chronic inflammation where normal bone marrow is replaced by fibrosis, reactive bone ...
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... an infected ulcer in a diabetic patient, we can observe distinct characteristics of acute infection, as well as chronic inflammation within the same lesion (Fig. 4a). A region of acute infection can be identified by the presence of predominantly newly activated neutrophils, as well as fibrovascular granulation tissue around foci of dead bone (Fig. 4b). However, adjacent to this lesion, we can identify hallmarks of chronic inflammation where normal bone marrow is replaced by fibrosis, reactive bone formation, blood vessels and collections of lymphocytes and plasma cells (Fig. 4c, d). This case highlights the significant amount of heterogeneity that can exist within a single ...
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... of predominantly newly activated neutrophils, as well as fibrovascular granulation tissue around foci of dead bone (Fig. 4b). However, adjacent to this lesion, we can identify hallmarks of chronic inflammation where normal bone marrow is replaced by fibrosis, reactive bone formation, blood vessels and collections of lymphocytes and plasma cells (Fig. 4c, d). This case highlights the significant amount of heterogeneity that can exist within a single osteomyelitis lesion and is typical of many infected foot ulcers with underlying osteomyelitis that has been treated conservatively before ...
Citations
... These microorganisms can be the source of an exacerbation of a PJI, especially in conditions of a depressed immune status of a human [41]. Persistent osteitis can be another explanation for these reinfections [42,43]. ...
Background: Two-stage septic revision is the prevailing method for addressing late periprosthetic infections. Using at least dual-antibiotic-impregnated bone cement leads to synergistic effects with a more efficient elution of individual antibiotics. Recent data on the success rates of multiantibiotic cement spacers in two-stage revisions are rare. Methods: We conducted a retrospective follow-up single-center study involving 250 patients with late periprosthetic hip infections and 95 patients with prosthetic knee infections who underwent septic two-stage prosthesis revision surgery between 2017 and 2021. In accordance with the antibiotic susceptibility profile of the microorganisms, a specific mixture of antibiotics within the cement spacer was used, complemented by systemic antibiotic treatment. All patients underwent preoperative assessments and subsequent evaluations at 3, 6, 9, 12, 18, and 24 months post operation and at the most recent follow-up. Results: During the observation period, the survival rate after two-step septic revision was 90.7%. Although survival rates tended to be slightly lower for difficult-to-treat (DTT) microorganism, there was no difference between the pathogen groups (easy-to-treat (ETT) pathogens, methicillin-resistant staphylococci (MRS), and difficult-to-treat (DTT) pathogens). Furthermore, there were no differences between monomicrobial and polymicrobial infections. No difference in the survival rate was observed between patients with dual-antibiotic-loaded bone cement without an additional admixture (Copal® G+C and Copal® G+V) and patients with an additional admixture of antibiotics to proprietary cement. Conclusion: Employing multiple antibiotics within spacer cement, tailored to pathogen susceptibility, appears to provide reproducibly favorable success rates, even in instances of infections with DTT pathogens and polymicrobial infections.
... Since the 1970s, infection rates for open fractures have continued to increase to 5%-33%, while infection rates for joint replacements have increased to 1%-4%. 3,4 Despite the use of the best medical care, osteomyelitis remains difficult to cure, with treatment failure rates ranging from 10% to 40%. 5,6 Common pathogens that cause osteomyelitis include Staphylococcus aureus (S. aureus), hemolytic streptococcus, pneumococcus, Escherichia coli (E. ...
... The primary mechanisms of S. aureus in bone infections include intracellular infection, OLCN invasion, biofilm and abscess formation. 3,24 Studies have shown that the persistence and recurrence of osteomyelitis are associated with the intracellular infection of bone cells by S. aureus. 25 S. aureus is capable of intracellular proliferation within a variety of cell types, including macrophages, keratinocytes, epithelial cells, endothelial cells, osteoclasts, osteoblasts, and osteocytes. ...
... 31,32 Currently, the three main mechanisms of S. aureus intracellular infection are believed to include survival within acidified phagosomes, formation of dormant SCVs to resist host defenses, and persistence within host autophagosomes. 3,24 However, the detailed processes and life cycle of this infection are not fully understood, making further research of significant value. ...
Osteomyelitis is a devastating disease caused by microbial infection in deep bone tissue. Its high recurrence rate and impaired restoration of bone deficiencies are major challenges in treatment. Microbes have evolved numerous mechanisms to effectively evade host intrinsic and adaptive immune attacks to persistently localize in the host, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants (SCVs). Moreover, microbial-mediated dysregulation of the bone immune microenvironment impedes the bone regeneration process, leading to impaired bone defect repair. Despite advances in surgical strategies and drug applications for the treatment of bone infections within the last decade, challenges remain in clinical management. The development and application of tissue engineering materials have provided new strategies for the treatment of bone infections, but a comprehensive review of their research progress is lacking. This review discusses the critical pathogenic mechanisms of microbes in the skeletal system and their immunomodulatory effects on bone regeneration, and highlights the prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections. It will inform the development and translation of antimicrobial and bone repair tissue engineering materials for the management of bone infections.
... Conventional osteomyelitis management includes long-term antibiotic therapy, surgical debridement, and management of the dead space (Panteli & Giannoudis, 2016). Despite treatment strategies, S. aureus infections recur over time (Masters et al., 2019). Moreover, long-term antibiotic treatment increases adverse events, costs, and antimicrobial resistance ( of the antibiotic regimen is complicated due to antibiotic resistance. ...
Bone infections caused by Staphylococcus aureus may lead to an inflammatory condition called osteomyelitis, which results in progressive bone loss. Biofilm formation, intracellular survival, and the ability of S. aureus to evade the immune response result in recurrent and persistent infections that present significant challenges in treating osteomyelitis. Moreover, people with diabetes are prone to osteomyelitis due to their compromised immune system, and in life-threatening cases, this may lead to amputation of the affected limbs. In most cases, bone infections are localized; thus, early detection and targeted therapy may prove fruitful in treating S. aureus-related bone infections and preventing the spread of the infection. Specific S. aureus components or overexpressed tissue biomarkers in bone infections could be targeted to deliver active therapeutics, thereby reducing drug dosage and systemic toxicity. This review paper presents information about the targeting strategies and agents for the therapy and diagnostic imaging of S. aureus bone infections.
... Distraction osteogenesis is effective but inefficient due to the very long treatment durations required and the high risk of infection at the pin sites for the distraction mechanism [2]. Although effective to varying degrees, none of these techniques address all the requirements for managing critical-sized bone defects effectively while minimizing surgical morbidity for patients and there remains a risk of infection at the reconstruction site and surgical wound [6,7]. ...
Limitations of bone defect reconstruction include poor bone healing and osteointegration with acrylic cements, lack of strength with bone putty/paste, and poor osteointegration. Tissue engineering aims to bridge these gaps through the use of bioactive implants. However, there is often a risk of infection and biofilm formation associated with orthopedic implants, which may develop anti-microbial resistance. To promote bone repair while also locally delivering therapeutics, 3D-printed implants serve as a suitable alternative. Soft, nanoporous 3D-printed filaments made from a thermoplastic polyurethane and polyvinyl alcohol blend, LAY-FOMM and LAY-FELT, have shown promise for drug delivery and orthopedic applications. Here, we compare 3D printability and sustained antibiotic release kinetics from two types of commercial 3D-printed porous filaments suitable for bone tissue engineering applications. We found that both LAY-FOMM and LAY-FELT could be consistently printed into scaffolds for drug delivery. Further, the materials could sustainably release Tetracycline over 3 days, independent of material type and infill geometry. The drug-loaded materials did not show any cytotoxicity when cultured with primary human fibroblasts. We conclude that both LAY-FOMM and LAY-FELT 3D-printed scaffolds are suitable devices for local antibiotic delivery applications, and they may have potential applications to prophylactically reduce infections in orthopedic reconstruction surgery.
... Nevertheless, understanding them can also help to enlighten neutrophil-biofilm interactions, as it is likely that some evasion mechanisms occur in biofilms as well or could concur to biofilm formation by hiding from the sight of neutrophils; those planktonic bacteria will subsequently organize themselves in a biofilm community. In 2019, Masters et al. [9] described three pathogenically distinct reservoirs of biofilm bacteria in osteomyelitis: glycocalyx on the implant, colonization of osteocyte lacuno-canalicular network, and staphylococcal abscess communities (SACs). ...
In the presence of orthopedic implants, opportunistic pathogens can easily colonize the biomaterial surfaces, forming protective biofilms. Life in biofilm is a central pathogenetic mechanism enabling bacteria to elude the host immune response and survive conventional medical treatments. The formation of mature biofilms is universally recognized as the main cause of septic prosthetic failures. Neutrophils are the first leukocytes to be recruited at the site of infection. They are highly efficient in detecting and killing planktonic bacteria. However, the interactions of these fundamental effector cells of the immune system with the biofilm matrix, which is the true interface of a biofilm with the host cells, have only recently started to be unveiled and are still to be fully understood. Biofilm matrix macromolecules consist of exopolysaccharides, proteins, lipids, teichoic acids, and the most recently described extracellular DNA. The latter can also be stolen from neutrophil extracellular traps (NETs) by bacteria, who use it to strengthen their biofilms. This paper aims to review the specific interactions that neutrophils develop when they physically encounter the matrix of a biofilm and come to interact with its polymeric molecular components.
... 1 These clinical failures are largely due to recalcitrant biofilm bacteria, which are now known to exist in four distinct forms: 1) intracellular bacteria, 2) bacteria within glycocalyx on the implant and necrotic tissue, 3) Staphylococcus abscess communities (SACs) and 4) bacteria within the osteocyte-lacuno-canalicular network (OLCN) of cortical bone. [2][3][4] While SOC debridement, irrigation, and conventional antibiotic therapy are effective against planktonic bacteria and some forms of biofilm, animal model studies demonstrated that this intervention has no efficacy against SACs and bacteria within the OLCN. 5,6 It has also been demonstrated that the combination of high dose local and systemic antibiotic therapy fails to achieve the minimum biofilm eradication concentration (MBEC) within the OLCN compartment, likely due to unfavorable pharmacokinetics, resulting in persistent infection of susceptible bacterial strains. ...
Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.
... Furthermore, specific dental treatments utilize Wolff's law to enhance the alignment of teeth within the dental arches (Cornelis et al. 2021). Bone remodeling in the vicinity of osteomyelitis (Masters et al. 2019) affected bone could also be influenced by the changed local loading environment both during disease development and after surgical treatment (Lamm et al. 2015). ...
We propose a variational approach that employs a generalized principle of virtual work to estimate both the mechanical response and the changes in living bone tissue during the remodeling process. This approach provides an explanation for the adaptive regulation of the bone substructure in the context of orthotropic material symmetry. We specifically focus upon the crucial gradual adjustment of bone tissue as a structural material that adapts its mechanical features, such as materials stiffnesses and microstructure, in response to the evolving loading conditions. We postulate that the evolution process relies on a feedback mechanism involving multiple stimulus signals. The mechanical and remodeling behavior of bone tissue is clearly a complex process that is difficult to describe within the framework of classical continuum theories. For this reason, a generalized continuum elastic theory is employed as a proper mathematical context for an adequate description of the examined phenomenon. To simplify the investigation, we considered a two-dimensional problem. Numerical simulations have been performed to illustrate bone evolution in a few significant cases: the bending of a rectangular cantilever plate and a three-point flexure test. The results are encouraging because they can replicate the optimization process observed in bone remodeling. The proposed model provides a likely distribution of stiffnesses and accurately represents the arrangement of trabeculae macroscopically described by the orthotropic symmetry directions, as supported by experimental evidence from the trajectorial theory.
... Recently, huge efforts have been made to develop new materials able to address the treatment of bone defects [2,12,15,18]. Moreover, bone loss is frequently associated with bacterial contamination and subsequent infection [10], therefore it appears fundamental to enrich the treatment options with new materials which also exert an antibacterial activity [7,9,11]. Rabbit models appear to be a feasible option to study both innovative materials and implantation techniques [17]. ...
Purpose:
The aims of this study were to assess the complications associated with the use of an external fixator-assisted plate osteosynthesis technique to stabilize a femoral bone defect in a rabbit model and to evaluate if this technique could avoid the mispositioning and the displacement of the femoral fragments during the surgical procedure.
Methods:
A preliminary cadaveric animal study was conducted to develop a new technique of external fixator-assisted plating. Thirty rabbits underwent a surgical procedure consisting in the creation of a femoral bone defect and, subsequently an implantation of a bone substitute through the assistance of a temporary external fixator. The fixator's ability to maintain length and alignment during surgery was documented. All intraoperative complications were prospectively collected.
Results:
No complications related to the use of the temporary external fixator were reported. The technique successfully prevented mispositioning and dislocation during plating in all the rabbits.
Conclusion:
In a rabbit animal model, the use of an external fixator-assisted plate osteosynthesis technique appears to be feasible and effective in avoiding misposition and rotation of femoral fragments when performing osteotomy and plating to create a mid-diaphyseal femoral defect.
... Staphylococcus aureus (S. aureus) is the most common bacterium causing osteomyelitis [8,12,13]. It was found to use various strategies, such as the formation of a biofilm and abscesses in soft tissue or bone marrow, colonization of the osteocyte-lacuno canalicular networks, intracellular persistence, and the formation of small colony variants with reduced metabolism [14]. ...
Osteomyelitis is an infection of the bone that is often difficult to treat and causes a significant
healthcare burden. Staphylococcus aureus is the most common pathogen causing osteomyelitis.
Osteomyelitis mouse models have been established to gain further insights into the pathogenesis and
host response. Here, we use an established S. aureus hematogenous osteomyelitis mouse model to
investigate morphological tissue changes and bacterial localization in chronic osteomyelitis with a
focus on the pelvis. X-ray imaging was performed to follow the disease progression. Six weeks post
infection, when osteomyelitis had manifested itself with a macroscopically visible bone deformation
in the pelvis, we used two orthogonal methods, namely fluorescence imaging and label-free Raman
spectroscopy, to characterise tissue changes on a microscopic scale and to localise bacteria in different
tissue regions. Hematoxylin and eosin as well as Gram staining were performed as a reference
method. We could detect all signs of a chronically florid tissue infection with osseous and soft tissue
changes as well as with different inflammatory infiltrate patterns. Large lesions dominated in the
investigated tissue samples. Bacteria were found to form abscesses and were distributed in high
numbers in the lesion, where they could occasionally also be detected intracellularly. In addition,
bacteria were found in lower numbers in surrounding muscle tissue and even in lower numbers in
trabecular bone tissue. The Raman spectroscopic imaging revealed a metabolic state of the bacteria
with reduced activity in agreement with small cell variants found in other studies. In conclusion, we
present novel optical methods to characterise bone infections, including inflammatory host tissue
reactions and bacterial adaptation.
... However, it should be underlined that LS is able to mark active infectious processes, but it is not clear if it also adequately traces the presence of mature biofilms that are highly tolerant to host immune defenses [34,35]. Therefore, its negativity does not exclude the presence of a viable biofilm potentially able to reactivate/exacerbate a local infectious process. ...
Prosthetic joint infection (PJI) and fracture-related infection (FRI) are difficult-to-treat conditions in patients with severe comorbidity or significant surgical risk. In cases not eligible for standard strategy, debridement procedures with the retention of prosthesis or internal fixation device, combined with long-term antibiotic treatment and subsequent indefinite chronic oral antimicrobial suppression (COAS), can be the only reasonable choice. The aim of this study was to investigate the role of COAS and its follow-up in the management of these cases. We retrospectively analyzed a cohort of 16 patients with a follow-up of at least 6 months (mean age 75 yo, 9F, 7M, 11 PJI, 5 FRI). All microbiological isolates were tetracycline-susceptible staphylococci and for this reason a minocycline-based COAS was adopted after debridement and 3 months of antibiogram-guided antibiotic treatment. Patient monitoring was carried out on a clinical basis, with bimonthly execution of the inflammation indices and serial radiolabeled leukocyte scintigraphy (LS). The overall median time of COAS follow-up was 15 months (min 6–max 30). Moreover, 62.5% of patients were still taking COAS with no relapse after cure at the last evaluation available. Clinical failure with a relapse of the infection was observed in 37.5% of patients; interestingly, 50% of them had previously stopped COAS due to side effects of the antibiotic used. In the COAS follow-up, a combination of clinical, laboratory and LS evaluation seems to monitor the infection properly. COAS can be considered as an interesting approach in patients not suitable for standard treatments of PJI or FRI but it requires careful monitoring.
