Characteristic Changes of the Stance-Phase Plantar Pressure Curve When Walking Uphill and Downhill: Cross-Sectional Study.

BACKGROUND: Monitoring of gait patterns by insoles is popular to study behavior and activity in the daily life of people and throughout the rehabilitation process of patients. Live data analyses may improve personalized prevention and treatment regimens, as well as rehabilitation. The M-shaped plantar pressure curve during the stance phase is mainly defined by the loading and unloading slope, 2 maxima, 1 minimum, as well as the force during defined periods. When monitoring gait continuously, walking uphill or downhill could affect this curve in characteristic ways. OBJECTIVE: For walking on a slope, typical changes in the stance phase curve measured by insoles were hypothesized. METHODS: In total, 40 healthy participants of both sexes were fitted with individually calibrated insoles with 16 pressure sensors each and a recording frequency of 100 Hz. Participants walked on a treadmill at 4 km/h for 1 minute in each of the following slopes: -20%, -15%, -10%, -5%, 0%, 5%, 10%, 15%, and 20%. Raw data were exported for analyses. A custom-developed data platform was used for data processing and parameter calculation, including step detection, data transformation, and normalization for time by natural cubic spline interpolation and force (proportion of body weight). To identify the time-axis positions of the desired maxima and minimum among the available extremum candidates in each step, a Gaussian filter was applied (σ=3, kernel size 7). Inconclusive extremum candidates were further processed by screening for time plausibility, maximum or minimum pool filtering, and monotony. Several parameters that describe the curve trajectory were computed for each step. The normal distribution of data was tested by the Kolmogorov-Smirnov and Shapiro-Wilk tests. RESULTS: Data were normally distributed. An analysis of variance with the gait parameters as dependent and slope as independent variables revealed significant changes related to the slope for the following parameters of the stance phase curve: the mean force during loading and unloading, the 2 maxima and the minimum, as well as the loading and unloading slope (all P<.001). A simultaneous increase in the loading slope, the first maximum and the mean loading force combined with a decrease in the mean unloading force, the second maximum, and the unloading slope is characteristic for downhill walking. The opposite represents uphill walking. The minimum had its peak at horizontal walking and values dropped when walking uphill and downhill alike. It is therefore not a suitable parameter to distinguish between uphill and downhill walking. CONCLUSIONS: While patient-related factors, such as anthropometrics, injury, or disease shape the stance phase curve on a longer-term scale, walking on slopes leads to temporary and characteristic short-term changes in the curve trajectory.

Experimental and virtual testing of bone-implant systems equipped with the AO Fracture Monitor with regard to interfragmentary movement.

Introduction: The management of fractured bones is a key domain within orthopedic trauma surgery, with the prevention of delayed healing and non-unions forming a core challenge. This study evaluates the efficacy of the AO Fracture Monitor in conjunction with biomechanical simulations to better understand the local mechanics of fracture gaps, which is crucial for comprehending mechanotransduction, a key factor in bone healing. Through a series of experiments and corresponding simulations, the study tests four hypotheses to determine the relationship between physical measurements and the predictive power of biomechanical models. Methods: Employing the AO Fracture Monitor and Digital Image Correlation techniques, the study demonstrates a significant correlation between the surface strain of implants and interfragmentary movements. This provides a foundation for utilizing one-dimensional AO Fracture Monitor measurements to predict three-dimensional fracture behavior, thereby linking mechanical loading with fracture gap dynamics. Moreover, the research establishes that finite element simulations of bone-implant systems can be effectively validated using experimental data, underpinning the accuracy of simulations in replicating physical behaviors. Results and Discussion: The findings endorse the combined use of monitoring technologies and simulations to infer the local mechanical conditions at the fracture site, offering a potential leap in personalized therapy for bone healing. Clinically, this approach can enhance treatment outcomes by refining the assessment precision in trauma trials, fostering the early detection of healing disturbances, and guiding improvements in future implant design. Ultimately, this study paves the way for more sophisticated patient monitoring and tailored interventions, promising to elevate the standard of care in orthopedic trauma surgery.

Long-term continuous instrumented insole-based gait analyses in daily life have advantages over longitudinal gait analyses in the lab to monitor healing of tibial fractures.

Introduction: Monitoring changes in gait during rehabilitation allows early detection of complications. Laboratory-based gait analyses proved valuable for longitudinal monitoring of lower leg fracture healing. However, continuous gait data recorded in the daily life may be superior due to a higher temporal resolution and differences in behavior. In this study, ground reaction force-based gait data of instrumented insoles from longitudinal intermittent laboratory assessments were compared to monitoring in daily life. Methods: Straight walking data of patients were collected during clinical visits and in between those visits the instrumented insoles recorded all stepping activities of the patients during daily life. Results: Out of 16 patients, due to technical and compliance issues, only six delivered sufficient datasets of about 12 weeks. Stance duration was longer (p = 0.004) and gait was more asymmetric during daily life (asymmetry of maximal force p < 0.001, loading slope p = 0.001, unloading slope p < 0.001, stance duration p < 0.001). Discussion: The differences between the laboratory assessments and the daily-life monitoring could be caused by a different and more diverse behavior during daily life. The daily life gait parameters significantly improved over time with union. One of the patients developed an infected non-union and showed worsening of force-related gait parameters, which was earlier detectable in the continuous daily life gait data compared to the lab data. Therefore, continuous gait monitoring in the daily life has potential to detect healing problems early on. Continuous monitoring with instrumented insoles has advantages once technical and compliance problems are solved.

Reappraisal of clinical trauma trials: the critical impact of anthropometric parameters on fracture gap micro-mechanics-observations from a simulation-based study.

The evidence base of surgical fracture care is extremely sparse with only few sound RCTs available. It is hypothesized that anthropometric factors relevantly influence mechanical conditions in the fracture gap, thereby interfering with the mechanoinduction of fracture healing. Development of a finite element model of a tibia fracture, which is the basis of an in silico population (n = 300) by systematic variation of anthropometric parameters. Simulations of the stance phase and correlation between anthropometric parameters and the mechanical stimulus in the fracture gap. Analysis of the influence of anthropometric parameters on statistical dispersion between in silico trial cohorts with respect to the probability to generate two, with respect to anthropometric parameters statistically different trial cohorts, given the same power assumptions. The mechanical impact in the fracture gap correlates with anthropometric parameters; confirming the hypothesis that anthropometric factors are a relevant entity. On a cohort level simulation of a fracture trial showed that given an adequate power the principle of randomization successfully levels out the impact of anthropometric factors. From a clinical perspective these group sizes are difficult to achieve, especially when considering that the trials takes advantage of a "laboratory approach ", i.e. the fracture type has not been varied, such that in real world trials the cohort size have to be even larger to level out the different configurations of fractures gaps. Anthropometric parameters have a significant impact on the fracture gap mechanics. The cohort sizes necessary to level out this effect are difficult or unrealistic to achieve in RCTs, which is the reason for sparse evidence in orthotrauma. New approaches to clinical trials taking advantage of modelling and simulation techniques need to be developed and explored.

"Fall Risk Scoring" in Outpatient Gait Analysis: Validation of a New Fall Risk Assessment for Nursing Home Residents. / "Fall Risk Scoring" in der ambulanten Ganganalyse: Validierung eines neuen Sturzrisikoassessments bei Heimbewohnern.

Falls in senior home residents are common. Individual preventive training can lower the fall risk. To detect the need for training, a systematic assessment of the individual fall risk is needed. The aim of this study was thus to assess whether a fall risk score based on free field insole measurements can distinguish between an at-risk group of senior home residents and a healthy young control group. A published fall risk score was used in senior home residents over the age of 75 and a young (< 40 years) control group to determine the individual fall risk. In addition, the fall events over 12 months were assessed. Statistical analysis including ROC analysis was performed to determine the ability of the score to detect participants at heightened fall risk. In total, 18 nursing home residents and 9 young control participants were included. Of the nursing home residents, 15 had at least one fall, with a total of 37 falls recorded over 12 months. In the control group, no falls were recorded. The fall risk score was significantly different between nursing home residents and the control group (9.2 + 3.2 vs. 5.7 ± 2.2). Furthermore, the score significantly differentiated fallers from non-fallers (10.3 ± 1.8 vs. 5.2 ± 2.5), with a cut-off > 7.5 (AUC: 0.95) and a sensitivity of 86.7% (specificity 83.3%). The fall risk score is able to detect the difference between senior nursing home residents and young, healthy controls, as well as between fallers and non-fallers. Its main proof of concept is demonstrated, as based on movement data outside special gait labs, and it can simplify the risk of fall determination in geriatric nursing home residents and can now be used in further, prospective studies.

A novel minimally invasive and press-fit method for symphysiodesis - a biomechanical analysis.

PURPOSE: Does the cylindrical shaped bone block allow a stable construct for the arthrodesis of the pubic symphysis compared to a rectangular shaped bone block. The cylindrical shaped bone block stabilized by a 3.5 symphyseal plate is inferior to the stabilization with an internal fixator. METHODS: This study analyzed the arthrodesis of the pubic symphysis on 24 synthetic pelvises, using a rectangular shaped bone block (control group) or a cylindrical shaped bone block, stabilized with a symphysis locking plate (n = 8) as the standard clinical procedure. Additionally we analyzed the stability using an internal fixator. RESULTS: This study showed that utilizing a cylindrical shaped synthetic bone graft results in a significant higher contact area and compression force compared to the classical rectangular shaped graft. Furthermore, the stabilization with an internal fixator had the tendency for increases of compression force and contact area, yet without a statistical significance, when compared to the plate fixation. CONCLUSION: The novel method of cylindrical symphysis resection and cylindrical bone block implantation allowed an increased biomechanical stability compared to using a classical rectangular bone graft, also resulting in higher contact area. Moreover, this technique would also allow a minimally invasive approach for this purpose, which in turn could preserve perisymphyseal ligaments, thereby improving healing in a clinical context.

Effects of age, body height, body weight, body mass index and handgrip strength on the trajectory of the plantar pressure stance-phase curve of the gait cycle.

The analysis of gait patterns and plantar pressure distributions via insoles is increasingly used to monitor patients and treatment progress, such as recovery after surgeries. Despite the popularity of pedography, also known as baropodography, characteristic effects of anthropometric and other individual parameters on the trajectory of the stance phase curve of the gait cycle have not been previously reported. We hypothesized characteristic changes of age, body height, body weight, body mass index and handgrip strength on the plantar pressure curve trajectory during gait in healthy participants. Thirty-seven healthy women and men with an average age of 43.65 ± 17.59 years were fitted with Moticon OpenGO insoles equipped with 16 pressure sensors each. Data were recorded at a frequency of 100 Hz during walking at 4 km/h on a level treadmill for 1 minute. Data were processed via a custom-made step detection algorithm. The loading and unloading slopes as well as force extrema-based parameters were computed and characteristic correlations with the targeted parameters were identified via multiple linear regression analysis. Age showed a negative correlation with the mean loading slope. Body height correlated with Fmeanload and the loading slope. Body weight and the body mass index correlated with all analyzed parameters, except the loading slope. In addition, handgrip strength correlated with changes in the second half of the stance phase and did not affect the first half, which is likely due to stronger kick-off. However, only up to 46% of the variability can be explained by age, body weight, height, body mass index and hand grip strength. Thus, further factors must affect the trajectory of the gait cycle curve that were not considered in the present analysis. In conclusion, all analyzed measures affect the trajectory of the stance phase curve. When analyzing insole data, it might be useful to correct for the factors that were identified by using the regression coefficients presented in this paper.

Simulation-based prediction of bone healing and treatment recommendations for lower leg fractures: Effects of motion, weight-bearing and fibular mechanics.

Despite recent experimental and clinical progress in the treatment of tibial and fibular fractures, in clinical practice rates of delayed bone healing and non-union remain high. The aim of this study was to simulate and compare different mechanical conditions after lower leg fractures to assess the effects of postoperative motion, weight-bearing restrictions and fibular mechanics on the strain distribution and the clinical course. Based on the computed tomography (CT) data set of a real clinical case with a distal diaphyseal tibial fracture, a proximal and a distal fibular fracture, finite element simulations were run. Early postoperative motion data, recorded via an inertial measuring unit system and pressure insoles were recorded and processed to study strain. The simulations were used to compute interfragmentary strain and the von Mises stress distribution of the intramedullary nail for different treatments of the fibula, as well as several walking velocities (1.0 km/h; 1.5 km/h; 2.0 km/h) and levels of weight-bearing restriction. The simulation of the real treatment was compared to the clinical course. The results show that a high postoperative walking speed was associated with higher loads in the fracture zone. In addition, a larger number of areas in the fracture gap with forces that exceeded beneficial mechanical properties longer was observed. Moreover, the simulations showed that surgical treatment of the distal fibular fracture had an impact on the healing course, whereas the proximal fibular fracture barely mattered. Weight-bearing restrictions were beneficial in reducing excessive mechanical conditions, while it is known that it is difficult for patients to adhere to partial weight-bearing recommendations. In conclusion, it is likely that motion, weight bearing and fibular mechanics influence the biomechanical milieu in the fracture gap. Simulations may improve decisions on the choice and location of surgical implants, as well as give recommendations for loading in the postoperative course of the individual patient.

Gait Analysis to Monitor Fracture Healing of the Lower Leg.

Fracture healing is typically monitored by infrequent radiographs. Radiographs come at the cost of radiation exposure and reflect fracture healing with a time lag due to delayed fracture mineralization following increases in stiffness. Since union problems frequently occur after fractures, better and timelier methods to monitor the healing process are required. In this review, we provide an overview of the changes in gait parameters following lower leg fractures to investigate whether gait analysis can be used to monitor fracture healing. Studies assessing gait after lower leg fractures that were treated either surgically or conservatively were included. Spatiotemporal gait parameters, kinematics, kinetics, and pedography showed improvements in the gait pattern throughout the healing process of lower leg fractures. Especially gait speed and asymmetry measures have a high potential to monitor fracture healing. Pedographic measurements showed differences in gait between patients with and without union. No literature was available for other gait measures, but it is expected that further parameters reflect progress in bone healing. In conclusion, gait analysis seems to be a valuable tool for monitoring the healing process and predicting the occurrence of non-union of lower leg fractures.

Experiences in the Use of Motorized Intramedullary Nails after Complex Injuries to the Extremities. / Erfahrungen bei der Anwendung motorisierter Marknägel nach komplexen Extremitätenverletzungen.

The treatment of complex injuries of the extremities after comminuted fractures or non-unions is a challenging area in the field of trauma surgery. Internal, motorized implants nowadays enable a patient-oriented and progressive treatment of these cases. The present article aims to present modern treatment strategies of complex injuries of the extremities, support the use of novel, motorized intramedullary nails and provide experiences for the handling with lengthening nails or transport nails. For this purpose, the preoperative planning including selection of patients, presentation of internal lengthening and transport systems and the most important factors during preparation of the surgery are described. Moreover, critical steps during the implantation of motorized nails and also during potential follow-up interventions are highlighted and the postoperative protocol including precise recommendations for the transport und consolidation phase are provided. Finally, the experiences are illustrated by presentation of the four different cases. The use of internal, motorized implants represents the latest step in the treatment of complex injuries of the extremities. These implants improve the quality of life and the authors recommend its use. However, these implants require a high expertise and adaption of established treatment protocols in these challenging trauma cases. Follow-up analyses with a considerably large number of cases are necessary and the research on implants to solve persisting problems in the area of complex injuries of the extremities has to be pursued intensively.

Concepts and clinical aspects of active implants for the treatment of bone fractures.

Nonunion is a complication of long bone fractures that leads to disability, morbidity and high costs. Early detection is difficult and treatment through external stimulation and revision surgery is often a lengthy process. Therefore, alternative diagnostic and therapeutic options are currently being explored, including the use of external and internal sensors. Apart from monitoring fracture stiffness and displacement directly at the fracture site, it would be desirable if an implant could also vary its stiffness and apply an intervention to promote healing, if needed. This could be achieved either by a predetermined protocol, by remote control, or even by processing data and triggering the intervention itself (self-regulated 'intelligent' or 'smart' implant). So-called active or smart materials like shape memory alloys (SMA) have opened up opportunities to build active implants. For example, implants could stimulate fracture healing by active shortening and lengthening via SMA actuator wires; by emitting pulses, waves, or electromagnetic fields. However, it remains undefined which modes of application, forces, frequencies, force directions, time durations and periods, or other stimuli such implants should ideally deliver for the best result. The present paper reviews the literature on active implants and interventions for nonunion, discusses possible mechanisms of active implants and points out where further research and development are needed to build an active implant that applies the most ideal intervention. STATEMENT OF SIGNIFICANCE: Early detection of delays during fracture healing and timely intervention are difficult due to limitations of the current diagnostic strategies. New diagnostic options are under evaluation, including the use of external and internal sensors. In addition, it would be desirable if an implant could actively facilitate healing ('Intelligent' or 'smart' implant). Implants could stimulate fracture healing via active shortening and lengthening; by emitting pulses, waves, or electromagnetic fields. No such implants exist to date, but new composite materials and alloys have opened up opportunities to build such active implants, and several groups across the globe are currently working on their development. The present paper is the first review on this topic to date.

COVID-19: a catalyst for the digitization of surgical teaching at a German University Hospital.

BACKGROUND: The summer semester 2020, had to be restructured due to the SARS-CoV-2 pandemic and the associated contact restrictions. Here, for the first time, the established lectures in lecture halls and small group seminars could not be conducted in presence as usual. A possible tool for the implementation of medical teaching, offers the use of eLearning, online webinars and learning platforms. At present it is unclear how the SARS-CoV-2 pandemic will affect surgical teaching, how digitization will be accepted by students, and how virtual teaching can be expanded in the future. METHODS: The teaching, which was previously delivered purely through face-to-face lectures, was completely converted to digital media. For this purpose, all lectures were recorded and were available to students on demand. The seminars were held as a twice a week occurring online webinar. The block internship was also conducted as a daily online webinar and concluded with an online exam at the end. At the end of the semester, a survey of the students was carried out, which was answered by n = 192 students with an anonymized questionnaire. The questionnaire inquires about the previous and current experience with eLearning, as well as the possibility of a further development towards a purely digital university. RESULTS: There were n = 192 students in the study population. For 88%, the conversion of classes to web-based lectures represented their first eLearning experience. For 77% of all students, the digitization of teaching led to a change in the way they prepare for class. 73% of the participating students are of the opinion that eLearning lectures should continue to be offered. 54% of the students felt that eLearning lectures made more sense than face-to-face lectures. A purely virtual university could be imagined by 41% of the students. CONCLUSION: The conversion of teaching represented the first contact with eLearning for most students. Overall, the eLearning offering was experienced as positive. Due to the new teaching structure, the way of learning had already changed during the semester. Based on the new eLearning content, the already existing formats can be further expanded in the future. Nevertheless, it turned out that the practical-surgical contents and skills cannot be adequately represented by purely online offers; for this, the development of hybrid practice-oriented teaching concepts is necessary.

[Case-based learning can improve the teaching quality in trauma surgery education : A survey analysis among medical students]. / Fallbasiertes Lernen kann die Lehrqualität im unfallchirurgischen Unterricht verbessern : Eine Umfrageanalyse unter Medizinstudierenden.

BACKGROUND: Medical education has always been challenging for students and teachers. Of growing importance is the promotion of knowledge of correlations and knowledge transfer from theoretical aspects into clinical practice. In order to achieve this aim, student-centered teaching concepts are increasingly being employed in the literature. OBJECTIVE: Can a trauma surgery practical seminar be improved by a case-based teaching concept? MATERIAL AND METHODS: For this purpose, standardized case studies and corresponding teaching materials, such as classification aids and treatment strategies, were made available to the students and lecturers. Using a two-staged evaluation the effects of the modified teaching design could be recorded and statistically analyzed. RESULTS: The seminar was considered to be relevant for the examinations. The teaching by the lecturers was found to be more competent and appeared more motivated. Overall, the seminar was rated better by the students. CONCLUSION: A case-based teaching concept can significantly improve the education in trauma surgery, when correctly and specifically implemented.

Macrophage-activating lipoprotein (MALP)-2 impairs the healing of partial tendon injuries in mice.

Tendon injuries are accounted for up to 50% of musculoskeletal injuries and often result in poor outcomes. Inflammation is a major hallmark of tendon regeneration. Therefore, we analyzed in this study whether the topical application of the pro-inflammatory mediator macrophage-activating lipoprotein (MALP)-2 improves the healing of partial tendon injuries. C57BL/6 mice underwent a partial tenotomy of the flexor digitorum longus tendon of the left hind limb, which was treated with a solution containing either 0.5 µg MALP-2 or vehicle (control). Repetitive gait analyses were performed prior to the surgical intervention as well as postoperatively on days 1, 3, 7, 14 and 36. The structural stability of the tendons was biomechanically tested on day 7 and 36. In addition, Western blot analyses were performed on isolated tendons that were treated in vitro with MALP-2 or vehicle. In both groups, partial tenotomy resulted in a pathological gait pattern during the initial postoperative phase. On day 7, the gait pattern normalized in vehicle-treated animals, but not in MALP-2-treated mice. Moreover, the tendons of MALP-2-treated mice exhibited a significantly reduced biomechanical stiffness after 7 and 36 days when compared to controls. Western blot analyses revealed a significantly higher expression of heme oxygenase (HO)-1 and lower expression of cyclin D in MALP-2-treated tendons. These findings indicate that MALP-2 delays the healing of injured tendons most likely due to increased intracellular stress and suppressed cell proliferation in this naturally bradytrophic tissue. Hence, the application of MALP-2 cannot be recommended for the treatment of tendon injuries.

Individualized Determination of the Mechanical Fracture Environment After Tibial Exchange Nailing-A Simulation-Based Feasibility Study.

Non-union rate after tibial fractures remains high. Apart from largely uncontrollable biologic, injury, and patient-specific factors, the mechanical fracture environment is a key determinant of healing. Our aim was to establish a patient-specific simulation workflow to determine the mechanical fracture environment and allow for an estimation of its healing potential. In a referred patient with failed nail-osteosynthesis after tibial-shaft fracture exchange nailing was performed. Post-operative CT-scans were used to construct a three-dimensional model of the treatment situation in an image processing and computer-aided design system. Resulting forces, computed in a simulation-driven workflow based on patient monitoring and motion capturing were used to simulate the mechanical fracture environment before and after exchange nailing. Implant stresses for the initial and revision situation, as well as interfragmentary movement, resulting hydrostatic, and octahedral shear strain were calculated and compared to the clinical course. The simulation model was able to adequately predict hardware stresses in the initial situation where mechanical implant failure occurred. Furthermore, hydrostatic and octahedral shear strain of the revision situation were calculated to be within published healing boundaries-accordingly the fracture healed uneventfully. Our workflow is able to determine the mechanical environment of a fracture fixation, calculate implant stresses, interfragmentary movement, and the resulting strain. Critical mechanical boundary conditions for fracture healing can be determined in relation to individual loading parameters. Based on this individualized treatment recommendations during the early post-operative phase in lower leg fractures are possible in order to prevent implant failure and non-union development.

Development of a dynamic fall risk profile in elderly nursing home residents: A free field gait analysis based study.

Falls in nursing home residents are associated with a significant individual and socioeconomic burden of disease. To trigger and tailor individual intervention programs, solid early detection measures of residents at risk are needed. Aim of this study was thus to test the capability of a free field gait analysis insole to determine its usefulness in determining fall risk. In an observational study gait data of 22 nursing home residents over the age of 75 years was collected over one week with a measuring insole. Clinical scores were performed at baseline (POMA; DGI, TUG). For 6 months before and after the insole measurement, the fall events per resident were recorded. Correlation analysis as well as receiver operating characteristic curve analysis were performed. The average resident age was 88.2 years (range 78-99), 15 had at least one fall event. There was no significant correlation between clinical assessment and fall risk. Moderate correlations between different temporospatial parameters and fall risk were seen. Pressure distribution during gait was markedly changed in fallers. Differences between fallers and non-fallers as well as cut off values for increased fall risk in the ROC analysis could be determined. The introduced measurement protocol suggests that patients at risk for falling can be detected without any additional office visits. Based on the introduced protocol in a limited patient setting, further large scale studies should now determine the effect of prevention measures triggered by gait analysis, the specific risk reduction and the associated personal and socioeconomic advantages.

Vascularization Strategies in the Prevention of Nonunion Formation.

Delayed healing and nonunion formation are major challenges in orthopedic surgery, which require the development of novel treatment strategies. Vascularization is considered one of the major prerequisites for successful bone healing, providing an adequate nutrient supply and allowing the infiltration of progenitor cells to the fracture site. Hence, during the last decade, a considerable number of studies have focused on the evaluation of vascularization strategies to prevent or to treat nonunion formation. These involve (1) biophysical applications, (2) systemic pharmacological interventions, and (3) tissue engineering, including sophisticated scaffold materials, local growth factor delivery systems, cell-based techniques, and surgical vascularization approaches. Accumulating evidence indicates that in nonunions, these strategies are indeed capable of improving the process of bone healing. The major challenge for the future will now be the translation of these strategies into clinical practice to make them accessible for the majority of patients. If this succeeds, these vascularization strategies may markedly reduce the incidence of nonunion formation. Impact statement Delayed healing and nonunion formation are a major clinical problem in orthopedic surgery. This review provides an overview of vascularization strategies for the prevention and treatment of nonunions. The successful translation of these strategies in clinical practice is of major importance to achieve adequate bone healing.

Pantoprazole impairs fracture healing in aged mice.

Proton pump inhibitors (PPIs) belong to the most common medication in geriatric medicine. They are known to reduce osteoclast activity and to delay fracture healing in young adult mice. Because differentiation and proliferation in fracture healing as well as pharmacologic actions of drugs markedly differ in the elderly compared to the young, we herein studied the effect of the PPI pantoprazole on bone healing in aged mice using a murine fracture model. Bone healing was analyzed by biomechanical, histomorphometric, radiological and protein biochemical analyses. The biomechanical analysis revealed a significantly reduced bending stiffness in pantoprazole-treated animals when compared to controls. This was associated with a decreased amount of bone tissue within the callus, a reduced trabecular thickness and a higher amount of fibrous tissue. Furthermore, the number of osteoclasts in pantoprazole-treated animals was significantly increased at 2 weeks and decreased at 5 weeks after fracture, indicating an acceleration of bone turnover. Western blot analysis showed a lower expression of the bone morphogenetic protein-4 (BMP-4), whereas the expression of the pro-angiogenic parameters was higher when compared to controls. Thus, pantoprazole impairs fracture healing in aged mice by affecting angiogenic and osteogenic growth factor expression, osteoclast activity and bone formation.

Profiling microRNA expression in murine bone healing and non-union formation: Role of miR-140 during the early stage of bone healing.

Although cellular and molecular mechanisms during the course of bone healing have been thoroughly investigated, the regulation of gene expression by microRNA during bone regeneration is still poorly understood. We hypothesized that nonunion formation is associated with different microRNA expression patterns and that target proteins of these microRNAs are differently expressed in callus tissue of nonunions compared to physiologically healing bones. In a well-established femoral osteotomy model in CD-1 mice osteotomies were induced which result either in healing or in nonunion formation. MicroRNA and target protein expression was evaluated by microarray, quantitative real-time polymerase chain reaction (qrt-PCR) and Western blot. Microarray analyses demonstrated 44 microRNAs to be relevant for nonunion formation compared to physiological bone healing. In nonunions qrt-PCR could validate a higher expression of microRNA-140-3p and microRNA-140-5p. This was associated with a reduced expression of Dnpep and stromal cell-derived factor (SDF)-1α, which are both known to be target proteins of microRNA-140 and also to be involved in the process of bone healing. These data suggest that an increased expression of microRNA-140-3p and microRNA-140-5p markedly contributes to the development of nonunions, most probably by affecting bone morphogenetic protein (BMP)-2 function during the early stage of healing due to a reduced SDF-1α expression.