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Infection related to osteosynthesis often has dramatic consequences for the patient. Prolonged hospitalization with systemic antibiotic therapy, several revision procedures, possible amputation, and even death may occur. To investigate the pathology of infection in orthopedic surgery, a new rat model of implant related osteomyelitis was developed. Three different concentrations (10(6), 10(3), and 10(2) colony-forming units (CFU)/10 microl) of Staphylococcus aureus were inoculated into the tibial medullary cavity with simultaneous insertion of a titanium Kirschner wire. Controls received phosphate-buffered saline (PBS). Each group consisted of 10 animals. Animals were followed for 4 weeks until sacrifice. X-rays of the tibiae were taken weekly, blood counts were analyzed, and body temperature and weight were determined. After sacrifice, infection was evaluated by histological and microbiological investigations. All animals inoculated with Staph. aureus in either concentration developed microbiological, histological, and radiological signs of osteomyelitis in correlation to the amount of inoculated bacteria. X-rays clearly revealed osseous destruction after 14 days with progression of osteomyelitis during the following weeks. CFU/g bone and bone weight after sacrifice showed dependence on the amount of inoculated CFU. The histological results confirmed the radiological findings. No significant changes in blood counts, body weight, and body temperature between the groups could be observed. The results demonstrate that it is possible to develop a model of implant-related osteomyelitis in rats with dependence on the amount of inoculated bacteria. No other promoters of infection besides intramedullary insertion of titanium Kirschner wires were used in this model.

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BackgroundThe TGF family plays a key role in bone homeostasis. Systemic or topic application of proteins of this family apparently positively affects bone healing in vivo. However, patients with chronic inflammation, having increased TGF-β1 serum-levels, often show reduced bone mineral content and disturbed bone healing. Therefore, we wanted to identify intracellular mechanisms induced by chronic presence of TGF-β1 and their possible role in bone homeostasis in primary human osteoblasts.Methodology/Principal FindingsOsteoblasts were isolated from femur heads of patients undergoing total hip replacement. Adenoviral reporter assays showed that in primary human osteoblasts TGF-β1 mediates its signal via Smad2/3 and not Smad1/5/8. It induces proliferation as an intermediate response but decreases AP-activity and inorganic matrix production as a late response. In addition, expression levels of osteoblastic markers were strongly regulated (AP↓; Osteocalcin↓; Osteopontin↑; MGP↓; BMP 2↓; BSP2↓; OSF2↓; Osteoprotegerin↓; RANKL↑) towards an osteoclast recruiting phenotype. All effects were blocked by inhibition of Smad2/3 signaling with the Alk5-Inhibitor (SB431542). Interestingly, a rescue experiment showed that reduced AP-activities did not recover to base line levels, even 8 days after stopping the TGF-β1 application.Conclusions/SignificanceIn spite of the initial positive effects on cell proliferation, it is questionable if continuous Smad2/3 phosphorylation is beneficial for bone healing, because decreased AP-activity and BMP2 levels indicate a loss of function of the osteoblasts. Thus, inhibition of Smad2/3 phosphorylation might positively influence functional activity of osteoblasts in patients with chronically elevated TGF-β1 levels and thus, could lead to an improved bone healing in vivo.

The use of DLS reduces the stiffness of the plate-screw interface and thus increases the interfragmentary motion at the near cortical side without altering the advantages of angular stability and the strength.

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tTF-NGR consists of the extracellular domain of tissue factor and the peptide GNGRAHA, a ligand of the surface protein aminopeptidase N and of integrin αvβ3. Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR shows antitumor activity in xenografts and inhibition of tumor blood flow in cancer patients. We performed random TMS(PEG)12 PEGylation of tTF-NGR to improve the antitumor profile of the molecule. PEGylation resulted in an approximately 2-log step decreased procoagulatory activity of the molecule. Pharmacokinetic studies in mice showed a more than 1-log step higher mean area under the curve. Comparison of the LD10 values for both compounds and their lowest effective antitumor dose against human tumor xenografts showed an improved therapeutic range (active/toxic dose in mg/kg body weight) of 1/5 mg/kg for tTF-NGR and 3/>160 mg/kg for TMS(PEG)12 tTF-NGR. Results demonstrate that PEGylation can significantly improve the therapeutic range of tTF-NGR.