Evading the host response: Staphylococcus “hiding” in cortical bone canalicular system causes increased bacterial burden

AbstractExtremity reconstruction surgery is increasingly performed rather than amputation for patients with large-segment pathologic bone loss. Debate persists as to the optimal void filler for this “limb salvage” surgery, whether metal or allograft bone. Clinicians focus on optimizing important functional gains for patients, and the risk of devastating implant infection has been thought to be similar regardless of implant material. Recent insights into infection pathophysiology are challenging this equipoise, however, with both basic science data suggesting a novel mechanism of infection of Staphylococcus aureus (the most common infecting agent) into the host lacunar–canaliculi network, and also clinical data revealing a higher rate of infection of allograft over metal. The current translational study was therefore developed to bridge the gap between these insights in a longitudinal murine model of infection of allograft bone and metal. Real-time Staphylococci infection characteristics were quantified in cortical bone vs metal, and both microarchitecture of host implant and presence of host immune response were assessed. An orders-of-magnitude higher bacterial burden was established in cortical allograft bone over both metal and cancellous bone. The establishment of immune-evading microabscesses was confirmed in both cortical allograft haversian canal and the submicron canaliculi network in an additional model of mouse femur bone infection. These study results reveal a mechanism by which Staphylococci evasion of host immunity is possible, contributing to elevated risks of infection in cortical bone. The presence of this local infection reservoir imparts massive clinical implications that may alter the current paradigm of osteomyelitis and bulk allograft infection treatment.

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Mechanical Anisotropy of Individual Osteons in Bone Tissue at High Spatial Resolutions

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206586 ◽

2009 ◽

Author(s):

Davide Carnelli ◽

Haimin Yao ◽

Ming Dao ◽

Pasquale Vena ◽

Roberto Contro ◽

...

Keyword(s):

Mechanical Properties ◽

Cortical Bone ◽

Mechanical Anisotropy ◽

Haversian Canal ◽

Maximum Penetration ◽

Fundamental Units ◽

Anisotropy Of Mechanical Properties ◽

Penetration Depths ◽

Secondary Osteons ◽

Mineralized Collagen

Secondary osteons, the fundamental units of cortical bone, consist of cylindrical lamellar composites composed of mineralized collagen fibrils. Due to its lamellar structure, a multiscale knowledge of the mechanical properties of cortical bone is required to understand the biomechanical function of the tissue. In this light, nanoindentation tests were performed along the axial and transverse directions following a radial path from the Haversian canal to the osteonal edges. Different length scales are explored by means of indentations at different maximum penetration depths. Indentation moduli and hardness data were then interpreted in the context of the known microstructure. Results suggest that secondary osteons hierarchical structure is responsible for an observed length scale effect, homogenization phenomena and anisotropy of mechanical properties.

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Assessment of Extra-Cortical Bone Bridge Interface in Cemented Mega Endoprosthesis for Limb Salvage Surgery

Malaysian Orthopaedic Journal ◽

10.5704/moj.2103.014 ◽

2021 ◽

Vol 15 (1) ◽

pp. 93-99

Author(s):

Murugan K ◽

Faisham WI ◽

Zulmi W

Keyword(s):

Cortical Bone ◽

Limb Salvage ◽

Salvage Surgery ◽

Limb Salvage Surgery ◽

Bone Bridge

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Histomorphometric variance of haversian canal in cortical bone of Malaysian ethnic groups

Journal of Physics Conference Series ◽

10.1088/1742-6596/1019/1/012009 ◽

2018 ◽

Vol 1019 ◽

pp. 012009

Author(s):

Hadi Abdullah ◽

Muhammad Mahadi Abdul Jamil ◽

Faridah Mohd Nor

Keyword(s):

Cortical Bone ◽

Ethnic Groups ◽

Haversian Canal

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A phase I study of zoledronic acid and low dose cyclophosphamide in children with recurrent/refractory neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) study

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9572 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9572-9572

Author(s):

H. V. Russell ◽

S. Groshen ◽

T. Ara ◽

Y. DeClerck ◽

M. Malkovsky ◽

...

Keyword(s):

Zoledronic Acid ◽

Phase I ◽

Bone Metastases ◽

Cortical Bone ◽

Low Dose ◽

Recommended Dose ◽

Bone Lesions ◽

Study Results ◽

Grade 3 ◽

Dose Levels

9572 Background: Zoledronic acid (ZA), is a new generation, highly potent bisphosphonate that delays progression of bone metastases in adult malignancies. Bone metastases occur in 60% of children with advanced neuroblastoma. Pre-clinical studies demonstrated ZA with low dose chemotherapy delayed progression of osteolytic neuroblastoma lesions in a xenograft mouse model, prompting a phase I trial of ZA in neuroblastoma. Methods: Three dose levels of intravenous ZA (2, 3 or 4 mg/m2) administered every 28 days were evaluated in combination with continuous daily oral cyclophosphamide (CTX) (25 mg/m2/day) in patients with recurrent/refractory neuroblastoma and cortical bone lesions. The primary objective was to determine a recommended dose of ZA for future trials. Serial blood and urine samples were collected for pharmacokinetics, markers of osteoclast activity, and immunologic assays. Results: 14 patients (9 male), median age 7.9 years (0.8 - 26.6 years), were enrolled at ZA dose levels 2 mg/m2 (n=4), 3 mg/m2 (n=3), and 4 mg/m2 (n=7). To date, 13 patients are evaluable for toxicity. Thirty-nine cycles were administered with a median of 1 cycle per patient (range 1 - 12). Treatment was well tolerated; one DLT (Grade 3 hypophosphatemia) occurred at 4 mg/m2 ZA. Other grade 3 or 4 toxicities attributable to the combination included hypocalcemia (n=2), elevated transaminases (n=2), neutropenia (n=2), anemia (n=1), lymphopenia (n=1), and hypokalemia (n=1). Hypocalcemia occurred in 69% of first cycles and 8% of subsequent cycles. There were no renal toxicities or dental complications. There have been 2 partial responses by MIBG (central review pending), 4 stable disease, and 7 progressive disease; one patient is too early for response. Pharmacokinetic and correlative biology study results are pending. Conclusions: ZA is well tolerated and had evidence of responses when given with low dose CTX to children with recurrent/refractory neuroblastoma. The recommended dose of ZA for subsequent study is 4 mg/m2. Future studies incorporating ZA into the regimen for children with NB and cortical bone lesions are planned. No significant financial relationships to disclose.

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Orientation and size-dependent mechanical modulation within individual secondary osteons in cortical bone tissue

Journal of The Royal Society Interface ◽

10.1098/rsif.2012.0953 ◽

2013 ◽

Vol 10 (81) ◽

pp. 20120953 ◽

Cited By ~ 21

Author(s):

Davide Carnelli ◽

Pasquale Vena ◽

Ming Dao ◽

Christine Ortiz ◽

Roberto Contro

Keyword(s):

Mechanical Properties ◽

Cortical Bone ◽

Mechanical Behaviour ◽

Long Bone ◽

Periodic Pattern ◽

Haversian Canal ◽

Length Scale ◽

Lamellar Bone ◽

Mechanical Modulation ◽

Secondary Osteons

Anisotropy is one of the most peculiar aspects of cortical bone mechanics; however, its anisotropic mechanical behaviour should be treated only with strict relationship to the length scale of investigation. In this study, we focus on quantifying the orientation and size dependence of the spatial mechanical modulation in individual secondary osteons of bovine cortical bone using nanoindentation. Tests were performed on the same osteonal structure in the axial (along the long bone axis) and transverse (normal to the long bone axis) directions along arrays going radially out from the Haversian canal at four different maximum depths on three secondary osteons. Results clearly show a periodic pattern of stiffness with spatial distance across the osteon. The effect of length scale on lamellar bone anisotropy and the critical length at which homogenization of the mechanical properties occurs were determined. Further, a laminate-composite-based analytical model was applied to the stiffness trends obtained at the highest spatial resolution to evaluate the elastic constants for a sub-layer of mineralized collagen fibrils within an osteonal lamella on the basis of the spatial arrangement of the fibrils. The hierarchical arrangement of lamellar bone is found to be a major determinant for modulation of mechanical properties and anisotropic mechanical behaviour of the tissue.

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A phase II study of pazopanib in recurrent or persistent ovarian (EOC), peritoneal (PPC), or Fallopian tube cancer (FTC): A Spanish Ovarian Cancer Group (GEICO) study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.5068 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 5068-5068 ◽

Cited By ~ 7

Author(s):

Ana Oaknin ◽

Antonio Gonzalez-Martin ◽

Yolanda García ◽

Silvia Catot ◽

Cristina Caballero ◽

...

Keyword(s):

Kinase Inhibitor ◽

Complete Response ◽

Statistical Hypothesis ◽

Ca 125 ◽

Fallopian Tube Cancer ◽

Significance Level ◽

Translational Study ◽

Cancer Group ◽

Platinum Resistant ◽

Study Results

5068 Background: Pazopanib (P) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that inhibits angiogenesis. Signaling blockade of these pathways is associated with anti-tumor and anti- angiogenesis activity. Methods: Eligible patients (pts) had persistent or recurrent EOC/PPC /FTC up to 2 prior cytotoxic regimens. They had to have received at least a platinum–based line and fulfill platinum resistant criteria. Treatment consisted of P 800 mg orally QD until disease progression or prohibitive toxicity. The primary endpoint was Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial Response (PR) plus Stable Disease (SD) ≥ 8 weeks by RECIST v1.1.An optimal two-stage Simon design was utilized with H1and H0set at 60%and 40% respectively; Power =90% significance level of 5% (Stage 1: = 25pts; total=66). Correlative studies to identify angiogenic biomarkers to predict response to P were performed. Results: From 12/10 to 7/11, 25 pts were enrolled, 21 pts had EOC, 2PPT, and 2FTC. Median age: 64 years (range 43-81), ECOG 0/1/2:12/11/2 pts. Prior chemotherapy regimens 1/2:10/15 pts. Median weeks on treatment: 8 (range 4-25). Most frequent adverse events (AEs) were asthenia (56%), hypertension (36%) and diarrhea, nausea and anorexia (20% each).Grade 3 toxicities: Hypertension (6pts), ALT/AST elevations (3 pts), asthenia (2 pts), DVT (1pt), Fistula (1 pt), Anemia (1 pt). Six pts required dose reduction to 600 mg due to toxicity.Reasons for stopping study treatment: PD (18pts), AEs (3pts) and investigator decision (2pts). First stage analysis showed: PR:1/25, SD: 9/25, CBR:10/25; 40% (95% CI 21.1%-61.3%).No correlation between GCIG CA-125 response and RECIST criteria was established, 8 versus 1 response respectively. Median PFS was 1.83 months (95% CI 1.67-2). Conclusions: The CBR observed at the first stage did not reach the planned statistical hypothesis (CBR:12 pts). Therefore, the lack of activity of P in platinum resistant EOC/PPT/FT led to discontinuation of the study. Translational study results will be presented in an additional abstract.

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Snorkelers' In-Water Observations Can Alter Salmonid Behavior

Journal of Fish and Wildlife Management ◽

10.3996/052010-jfwm-012 ◽

2011 ◽

Vol 2 (1) ◽

pp. 90-98 ◽

Cited By ~ 4

Author(s):

William R. Brignon ◽

M. Brian Davis ◽

Douglas E. Olson ◽

Howard A. Schaller ◽

Carl B. Schreck

Keyword(s):

Species Abundance ◽

Fish Behavior ◽

Microhabitat Use ◽

Science Data ◽

Fisheries Science ◽

Study Results ◽

Total Movement ◽

Collection Methods ◽

Model Fish ◽

Downstream Movement

Abstract Direct underwater observation techniques (e.g., snorkel surveys) are widely used in fisheries science. Data collected from these surveys are used to estimate species abundance, detect presence and absence, and construct statistical models that predict microhabitat use and nonuse. To produce an unbiased estimate or model, fish should ideally behave as if there were no observer present. We conducted a study using underwater video to test whether snorkeling can elicit a change in fish behavior. Four behavioral metrics were measured: upstream movement, downstream movement, total movement, and number of fish in the field-of-view. Significant differences were detected in upstream, downstream, and total movements as a function of the in-water observer. These results suggest that an in-water observer can disturb fish, resulting in altered behavior, which in turn may bias study results. We suggest researchers use caution in making inferences to an entire population when data-collection methods have potential to bias fish behavior.

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Transversely Isotropic Model of Osteonal Cortical Bone: Contribution of Haversian and Resorptive Porosity

10.1115/imece1999-0438 ◽

1999 ◽

Author(s):

X. Neil Dong ◽

Y. Young Huang ◽

X. Edward Guo

Keyword(s):

Cortical Bone ◽

Transversely Isotropic ◽

The Elderly ◽

Haversian Canal ◽

Isotropic Model ◽

Elderly Men ◽

Men And Women ◽

Age Related ◽

Osteoclastic Resorption ◽

Old Men

Abstract Age related changes in porosity of cortical bone have been previously reported. The cortical porosity increases with age in both men and women, from 4.6% in men and 4% in women at age 40 to 10% and more at age 80 (Laval-Jeantet et al., 1983). The porosity is defined as the percentage of cortical bone occupied by vascular and resorption cavities. There are a few quantitative data regarding the influences of Haversian canal and resorption space on porosity. Age related increases in Haversian canal size and Haversian canal number contribute to the increasing porosity of cortical bone for the elderly men and women (Thompson, 1980; Nyssen-behets et al., 1997). The number of osteoclastic resorption space is also greater in the old men than in the young men (Nyssen-Behets et al., 1997).

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