Impact of low bone mass and antiresorptive therapy on antibiotic efficacy in a rat model of orthopedic device-related infection.

A significant proportion of orthopedic devices are implanted in osteoporotic patients, but it is currently unclear how estrogen deficiency and/or exposure to antiresorptive bisphosphonates (BPs) influence orthopedic device-related infection (ODRI), or response to therapy. The aim of this study is to characterize the bone changes resulting from Staphylococcus epidermidis infection in a rodent ODRI model and to determine if ovariectomy (OVX) or BP treatment influences the infection or the success of antibiotic therapy. A sterile or S. epidermidis-contaminated screw was implanted into the proximal tibia of skeletally mature female Wistar rats (n = 6-9 per group). Bone changes were monitored over 28 days using in vivo micro-computed tomography scanning. OVX was performed 12 weeks before screw implantation. The BP zoledronic acid (ZOL) was administered 4 days before screw insertion. A combination antibiotic regimen (rifampin plus cefazolin) was administered from Days 7-21. In skeletally healthy animals, S. epidermidis induced marked changes in bone, with peak osteolysis occurring at Day 9 and woven bone deposition and periosteal mineralization from Day 14 onwards. Antibiotic therapy cleared the infection in the majority of animals (2/9 infected) but did not affect bone responses. OVX did not affect the pattern of infection-induced changes in bone, nor bacterial load, but reduced antibiotic efficacy (5/9 infected). ZOL treatment did not protect from osteolysis in OVX animals, or further affect antibiotic efficacy (5/9 infected) but did significantly increase the bacterial load. This study suggests that both BPs and OVX can influence host responses to bone infections involving S. epidermidis.

Longitudinal time-lapse in vivo micro-CT reveals differential patterns of peri-implant bone changes after subclinical bacterial infection in a rat model.

Subclinical infection associated with orthopedic devices can be challenging to diagnose. The goal of this study was to evaluate longitudinal, microcomputed tomography (microCT) imaging in a rat model of subclinical orthopedic device-related infection caused by Staphylococcus epidermidis and four different Cutibacterium (previously Propionibacterium) acnes strains, and compare outcomes with non-inoculated and historical S. aureus-inoculated controls. Sterile screws or screws colonized with bacteria were placed in the tibia of 38 adult Wistar rats [n = 6 sterile screws; n = 6 S. epidermidis-colonized screws; n = 26 C. acnes-colonized screws (covering all three main subspecies)]. Regular microCT scans were taken over 28 days and processed for quantitative time-lapse imaging with dynamic histomorphometry. At euthanasia, tissues were processed for semiquantitative histopathology or quantitative bacteriology. All rats receiving sterile screws were culture-negative at euthanasia and displayed progressive bony encapsulation of the screw. All rats inoculated with S. epidermidis-colonized screws were culture-positive and displayed minor changes in peri-implant bone, characteristic of subclinical infection. Five of the 17 rats in the C. acnes inoculated group were culture positive at euthanasia and displayed bone changes at the interface of the screw and bone, but not deeper in the peri-implant bone. Dynamic histomorphometry revealed significant differences in osseointegration, bone remodeling and periosteal reactions between groups that were not measurable by visual observation of still microCT images. Our study illustrates the added value of merging 3D microCT data from subsequent timepoints and producing inherently richer 4D data for the detection and characterization of subclinical orthopedic infections, whilst also reducing animal use.

Concentric and Eccentric Pedaling-Type Interval Exercise on a Soft Robot for Stable Coronary Artery Disease Patients: Toward a Personalized Protocol.

BACKGROUND: Cardiovascular diseases are the leading causes of death worldwide, and coronary artery disease (CAD) is one of the most common causes of death in Europe. Leading cardiac societies recommend exercise as an integral part of cardiovascular rehabilitation because it reduces the morbidity and mortality of patients with CAD. Continuous low-intensity exercise using shortening muscle actions (concentric, CON) is a common training modality during cardiovascular rehabilitation. However, a growing clinical interest has been recently developed in high-intensity interval training (HIIT) for stable patients with CAD. Exercise performed with lengthening muscle actions (eccentric, ECC) could be tolerated better by patients with CAD as they can be performed with higher loads and lower metabolic cost than CON exercise. OBJECTIVE: We developed a clinical protocol on a soft robot to compare cardiovascular and muscle effects of repeated and work-matched CON versus ECC pedaling-type interval exercise between patients with CAD during cardiovascular rehabilitation. This study aims to ascertain whether the developed training protocols affect peak oxygen uptake (VO2peak), peak aerobic power output (Ppeak), and parameters of muscle oxygen saturation (SmO2) during exercise, and anaerobic muscle power. METHODS: We will randomize 20-30 subjects to either the CON or ECC group. Both groups will perform a ramp test to exhaustion before and after the training period to measure cardiovascular parameters and SmO2. Moreover, the aerobic skeletal muscle power (Ppeak) is measured weekly during the 8-week training period using a simulated squat jump and a counter movement jump on the soft robot and used to adjust the training load. The pedaling-type interval exercise on the soft robot is performed involving either CON or ECC muscle actions. The soft robotic device being used is a closed kinetic chain, force-controlled interactive training, and testing device for the lower extremities, which consists of two independent pedals and free footplates that are operated by pneumatic artificial muscles. RESULTS: The first patients with CAD, who completed the training, showed protocol-specific improvements, reflecting, in part, the lower aerobic training status of the patient completing the CON protocol. Rehabilitation under the CON protocol, more than under the ECC protocol, improved cardiovascular parameters, that is, VO2peak (+26% vs -6%), and Ppeak (+20% vs 0%), and exaggerated muscle deoxygenation during the ramp test (248% vs 49%). Conversely, markers of metabolic stress and recovery from the exhaustive ramp test improved more after the ECC than the CON protocol, that is, peak blood lactate (-9% vs +20%) and peak SmO2 (+7% vs -7%). Anaerobic muscle power only improved after the CON protocol (+18% vs -15%). CONCLUSIONS: This study indicates the potential of the implemented CON and ECC protocols of pedaling-type interval exercise to improve oxygen metabolism of exercised muscle groups while maintaining or even increasing the Ppeak. The ECC training protocol seemingly provided a lower cardiovascular stimulus in patients with CAD while specifically enhancing the reoxygenation and blood lactate clearance in recruited muscle groups during recovery from exercise. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845063; https://clinicaltrials.gov/ct2/show/NCT02845063.

Five Days Granulocyte Colony-Stimulating Factor Treatment Increases Bone Formation and Reduces Gap Size of a Rat Segmental Bone Defect: A Pilot Study.

Bone is an organ with high natural regenerative capacity and most fractures heal spontaneously when appropriate fracture fixation is provided. However, additional treatment is required for patients with large segmental defects exceeding the endogenous healing potential and for patients suffering from fracture non-unions. These cases are often associated with insufficient vascularization. Transplantation of CD34+ endothelial progenitor cells (EPCs) has been successfully applied to promote neovascularization of bone defects, however including extensive ex vivo manipulation of cells. Here, we hypothesized, that treatment with granulocyte colony-stimulating factor (G-CSF) may improve bone healing by mobilization of CD34+ progenitor cells into the circulation, which in turn may facilitate vascularization at the defect site. In this pilot study, we aimed to characterize the different cell populations mobilized by G-CSF and investigate the influence of cell mobilization on the healing of a critical size femoral defect in rats. Cell mobilization was investigated by flow cytometry at different time points after five consecutive daily G-CSF injections. In a pilot study, bone healing of a 4.5-mm critical femoral defect in F344 rats was compared between a saline-treated control group and a G-CSF treatment group. In vivo microcomputed tomography and histology were applied to compare bone formation in both treatment groups. Our data revealed that leukocyte counts show a peak increase at the first day after the last G-CSF injection. In addition, we found that CD34+ progenitor cells, including EPCs, were significantly enriched at day 1, and further increased at day 5 and day 11. Upregulation of monocytes, granulocytes and macrophages peaked at day 1. G-CSF treatment significantly increased bone volume and bone density in the defect, which was confirmed by histology. Our data show that different cell populations are mobilized by G-CSF treatment in cell specific patterns. Although in this pilot study no bridging of the critical defect was observed, significantly improved bone formation by G-CSF treatment was clearly shown.

In Vivo MicroCT Monitoring of Osteomyelitis in a Rat Model.

Infection associated with orthopedic implants often results in bone loss and requires surgical removal of the implant. The aim of this study was to evaluate morphological changes of bone adjacent to a bacteria-colonized implant, with the aim of identifying temporal patterns that are characteristic of infection. In an in vivo study with rats, bone changes were assessed using in vivo microCT at 7 time points during a one-month postoperative period. The rats received either a sterile or Staphylococcus aureus-colonized polyetheretherketone screw in the tibia. Bone-implant contact, bone fraction, and bone changes (quiescent, resorbed, and new bone) were calculated from consecutive scans and validated against histomorphometry. The screw pullout strength was estimated from FE models and the results were validated against mechanical testing. In the sterile group, bone-implant contact, bone fraction, and mechanical fixation increased steadily until day 14 and then plateaued. In the infected group, they decreased rapidly. Bone formation was reduced while resorption was increased, with maximum effects observed within 6 days. In summary, the model presented is capable of evaluating the patterns of bone changes due to implant-related infections. The combined use of longitudinal in vivo microCT imaging and image-based finite element analysis provides characteristic signs of infection within 6 days.

Osseointegration of machined, injection moulded and oxygen plasma modified PEEK implants in a sheep model.

Machined and injection moulded polyetheretherketone (PEEK) implants with and without an oxygen plasma modification were prepared and implanted in sheep cancellous and cortical bone. After 4, 12 and 26 weeks, osseointegration was evaluated through mechanical push-out tests and histomorphometry. In the cancellous bone, push-out force increased with time, a trend toward higher force was observed for machined compared to moulded, and oxygen plasma modified compared to unmodified. On-going remodelling of the bone was detected in the periphery of the implants at 4 weeks. Minimal or no inflammation was observed with all the implants at all locations and time-points. Bone-implant contact (BIC) was quantified at all-time points and locations for all the four PEEK implant surfaces. The BIC values ranged from 15 to 75% with an average of 29 ± 13% in the cancellous bone and 25-65% with an average of 50 ± 12% in the cortical bone. In the cortical bone the BIC increased significantly from 4 to 26 weeks. This in vivo study has identified that surface topography of PEEK implants influences osseointegration. In addition, oxygen plasma has the potential to increase bone-implant interface stability. This study provides a unique reference for further modifications and in vivo assessment of PEEK implants.

Stride rate recommendations for moderate-intensity walking.

UNLABELLED: Current physical activity guidelines recommend physical activity of at least moderate intensity to gain health benefits. Previous studies have recommended a moderate-intensity walking cadence of 100 steps per minute for adults, but the influence of height or stride length has not been investigated. PURPOSE: the purpose of the current study was to determine the role of height and stride length in moderate-intensity walking cadence in adults. METHODS: seventy-five adults completed three treadmill walking trials and three overground walking trials at slow, medium, and fast walking speeds while V˙O2 was measured using indirect calorimetry. Five stride length-related variables were also measured. RESULTS: mixed model regression analysis demonstrated that height explained as much variability in walking intensity at a given cadence as did two different measures of leg length and two different stride length tests. CONCLUSIONS: the previous general recommendations of 100 steps per minute were supported for use where a simple public health message is needed. Depending on height, moderate-intensity walking cadence can vary by more than 20 steps per minute, from 90 to 113 steps per minute for adults 198 to 152 cm tall, respectively. Height should therefore be taken into consideration for more precise evaluation or prescription of walking cadence in adults to provide health benefits.