Proliferating and differentiating effects of three different growth factors on pluripotent mesenchymal cells and osteoblast like cells

Growth factors are in clinical use to stimulate bone growth and regeneration. BMP-2 is used in long bone and spinal surgery, PDGFbb for the treatment of periodontal defects and children with growth hormone receptor deficiency are treated with IGF-I

A new animal model for delayed osseous union secondary to osteitis

Background: The treatment of infection-related delayed bone unions is still very challenging for the orthopedic surgeon. The prevalence of such infection-related types of osteitis is high in complex fractures, particularly in open fractures with extensive soft-tissue damage. The aim of this study was to develop a new animal model for delayed union due to osteitis. Methods. After randomization to infected or non-infected groups 20 Sprague–Dawley rats underwent a transverse fracture of the midshaft tibia. After intramedullary inoculation with staphylococcus aureus (103 CFU) fracture stabilization was done by intramedullary titanium K-wires. After 5 weeks all rats were euthanized and underwent biomechanical testing to evaluate bone consolidation or delayed union, respectively. Micro-CT scans were additionally used to quantitatively evaluate the callus formation by the score of Lane and Sandhu. Blood samples were taken to analyze infectious disease markers (day 1, 14 and 35). Results: Biomechanical testing showed a significant higher maximum torque in the non-infected group 5 weeks postoperatively compared with the infected group (p < 0.001). According to the Lane and Sandhu score a significantly higher callus formation was found in the non-infected group (p < 0.001). Similarly, the leucocyte count in the infected group was significantly higher than in the non-infected group (p < 0.05). Conclusions: Here we have established a new animal model for delayed osseous union secondary to osteitis. The animal model appears to be appropriate for future experimental studies to test new therapeutic strategies in these difficult to treat bone healing complications

Evaluation of the clinical effectiveness of bioactive glass (S53P4) in the treatment of non-unions of the tibia and femur: study protocol of a randomized controlled non-inferiority trial

Background: Treatment of non-union remains challenging and often necessitates augmentation of the resulting defect with an autologous bone graft (ABG). ABG is limited in quantity and its harvesting incurs an additional surgical intervention leaving the risk for associated complications and morbidities. Therefore, artificial bone graft substitutes that might replace autologous bone are needed. S53P4-type bioactive glass (BaG) is a promising material which might be used as bone graft substitute due to its osteostimulative, conductive and antimicrobial properties. In this study, we plan to examine the clinical effectiveness of BaG as a bone graft substitute in Masquelet therapy in comparison with present standard Masquelet therapy using an ABG with tricalciumphosphate to fill the bone defect. Methods/design: This randomized controlled, clinical non-inferiority trial will be carried out at the Department of Orthopedics and Traumatology at Heidelberg University. Patients who suffer from tibial or femoral non-unions with a segmental bone defect of 2–5 cm and who are receiving Masquelet treatment will be included in the study. The resulting bone defect will either be filled with autologous bone and tricalciumphosphate (control group, N = 25) or BaG (S53P4) (study group, N = 25). Subsequent to operative therapy, all patients will receive the same standardized follow-up procedures. The primary endpoint of the study is union achieved 1year after surgery. Discussion: The results from the current study will help evaluate the clinical effectiveness of this promising biomaterial in non-union therapy. In addition, this randomized trial will help to identify potential benefits and limitations regarding the use of BaG in Masquelet therapy. Data from the study will increase the knowledge about BaG as a bone graft substitute as well as identify patients possibly benefiting from Masquelet therapy using BaG and those who are more likely to fail, thereby improving the quality of non-union treatment. Trial registration: German Clinical Trials Register (DRKS), ID: DRKS00013882 . Registered on 22 January 2018

Characterization of a rat osteotomy model with impaired healing

<p>Abstract</p> <p>Background</p> <p>Delayed union or nonunion are frequent and feared complications in fracture treatment. Animal models of impaired bone healing are rare. Moreover, specific descriptions are limited although understanding of the biological course of pathogenesis of fracture nonunion is essential for therapeutic approaches.</p> <p>Methods</p> <p>A rat tibial osteotomy model with subsequent intramedullary stabilization was performed. The healing progress of the osteotomy model was compared to a previously described closed fracture model. Histological analyses, biomechanical testing and radiological screening were undertaken during the observation period of 84 days (d) to verify the status of the healing process. In this context, particular attention was paid to a comparison of bone slices by histological and immunohistological (IHC) methods at early points in time, <it>i.e</it>. at 5 and 10 d post bone defect.</p> <p>Results</p> <p>In contrast to the closed fracture technique osteotomy led to delayed union or nonunion until 84 d post intervention. The dimensions of whole reactive callus and the amounts of vessels in defined regions of the callus differed significantly between osteotomized and fractured animals at 10 d post surgery. A lower fraction of newly formed bone and cartilaginous tissue was obvious during this period in osteotomized animals and more inflammatory cells were observed in the callus. Newly formed bone tissue accumulated slowly on the anterior tibial side with both techniques. New formation of reparative cartilage was obviously inhibited on the anterior side, the surgical approach side, in osteotomized animals only.</p> <p>Conclusion</p> <p>Tibial osteotomy with intramedullary stabilisation in rats leads to pronounced delayed union and nonunion until 84 d post intervention. The early onset of this delay can already be detected histologically within 10 d post surgery. Moreover, the osteotomy technique is associated with cellular and vascular signs of persistent inflammation within the first 10 d after bone defect and may be a contributory factor to impaired healing. The model would be excellent to test agents to promote fracture healing.</p

Chemokine analysis as a novel diagnostic modality in the early prediction of the outcome of non-union therapy: a matched pair analysis

Background: Despite the regenerative capability of skeletal tissue fracture, non-union is common. Treatment of non-unions remains challenging, and early determination of the outcome is impossible. Chemokines play an important role in promoting the formation of new bone and remodeling existing bone. Despite their importance regarding the regulation of bone biology, the potential of chemokines as biological markers reflecting osseous regeneration is unknown. The purpose of this study was to determine (1) if serum chemokine expression levels correlate with the outcome of non-union surgery and (2) if chemokine expression analysis can be used to identify patients at risk for treatment failure. Methods: Non-union patients receiving surgical therapy in our institution between March 2012 and March 2014 were prospectively enrolled in a clinical observer study. Regular clinical and radiological follow-up was conducted for 12 months including collection of blood during the first 12 weeks. Based on the outcome, patients were declared as responders or non-responders to the therapy. To minimize biases, patients were matched (age, sex, body mass index (BMI)) and two groups of patients could be formed: responders (R, n = 10) and non-responders (NR, n = 10). Serum chemokine expression (CCL-2, CCL-3, CCL-4, CXCL-10, CCL-11, and interferon gamma (IFN-γ)) was analyzed using Luminex assays. Data was compared and correlated to the outcome. Results: CCL-3 expression in NR was significantly higher during the course of the study compared to R (p = 0.002), and the expression pattern of CCL-4 correlated with CCL-3 in both groups (NR: p &lt; 0.001 and r = 0.63). IFN-γ expression in NR was continuously higher than in R (p &lt; 0.001), and utilization of CCL-3 and IFN-γ serum expression levels 2 weeks after the treatment resulted in a predictive model that had an AUC of 0.92 (CI 0.74–1.00). Conclusion: Serum chemokine expression analysis over time is a valid and promising diagnostic tool. The chemokine expression pattern correlates with the outcome of the Masquelet therapy of lower limb non-unions. Utilization of the serum analysis of CCL-3 and IFN-γ 2 weeks after the treatment resulted in an early predictive value regarding the differentiation between patients that are likely to heal and those that are prone to high risk of treatment failure

Development and validation of an objective assessment scale for chest tube insertion under ‘direct’ and ‘indirect’ rating

Background: There is an increasing need for objective and validated educational concepts. This holds especially true for surgical procedures like chest tube insertion (CTI). Thus, we developed an instrument for objectification of learning successes: the assessment scale based on Objective Structured Assessment of Technical Skill (OSATS) for chest tube insertion, which is evaluated in this study. Primary endpoint was the evaluation of intermethod reliability (IM). Secondary endpoints are ‘indirect’ interrater reliability (IR) and construct validity of the scale (CV). Methods: Every participant (N = 59) performed a CTI on a porcine thorax. Participants received three ratings (one ‘direct’ on site, two ‘indirect’ via video rating). IM compares ‘direct’ with ‘indirect’ ratings. IR was assessed between ‘indirect’ ratings. CV was investigated by subgroup analysis based on prior experience in CTI for ‘direct’ and ‘indirect’ rating. Results: We included 59 medical students to our study. IM showed moderate conformity (‘direct’ vs. ‘indirect 1’ ICC = 0.735, 95% CI: 0.554–0.843; ‘direct’ vs. ‘indirect 2’ ICC = 0.722, 95% CI 0.533–0.835) and good conformity between ‘direct’ vs. ‘average indirect’ rating (ICC = 0.764, 95% CI: 0.6–0.86). IR showed good conformity (ICC = 0.84, 95% CI: 0.707–0.91). CV was proven between subgroups in ‘direct’ (p = 0.037) and ‘indirect’ rating (p = 0.013). Conclusion: Results for IM suggest equivalence for ‘direct’ and ‘indirect’ ratings, while both IR and CV was demonstrated in both rating methods. Thus, the assessment scale seems a reliable method for rating trainees’ performances ‘directly’ as well as ‘indirectly’. It may help to objectify and facilitate the assessment of training of chest tube insertion. - - - - - - - - - CORRECTION Published online 20.02.2019 in BMC Medical Education 19 (2019), Nr. 62; DOI: https://doi.org/10.1186/s12909-019-1491-4. Following publication of the original article, the author reported that the given name and family name of all authors were swapped. The original article has been corrected

A Trans-Atlantic Perspective on Stagnation in Clinical Translation of Antimicrobial Strategies for the Control of Biomaterial-Implant-Associated Infection

Current regulatory requirements impede clinical translation and market introduction of many new antimicrobial combination implants and devices, causing unnecessary patient suffering, doctor frustration, and costs to healthcare payers. Regulatory requirements of antimicrobial combination implants and devices should be thoroughly revisited and their approval allowed based on enrichment of benefit demonstrations from high-risk patient groups and populations or device components to facilitate their clinical translation. Biomaterial implant and devices equipped with antimicrobial strategies and approved based on enrichment claims should be mandatorily enrolled in global registry studies supervised by regulatory agencies for a minimum five-year period or until statistically validated evidence for noninferiority or superiority of claims is demonstrated. With these recommendations, this trans-Atlantic consortium of academicians and clinicians takes its responsibility to actively seek to relieve the factors that stagnate downward clinical translation and availability of antimicrobial combination implants and devices. Improved dialogue between the various key players involved in the current translational blockade, which include patients, academicians and doctors, policymakers, regulatory agencies, manufacturers, and healthcare payers, is urgently needed.</p