Influence of implant base material on secondary bone healing: an in silico study.

The implant material at the fracture site influences fracture healing not only from biological perspective but also from mechanical perspective. Biodegradable implants such as magnesium (Mg) based alloys have shown faster secondary bone healing properties as compared to bioinert implants such as titanium (Ti). The general reasoning behind this is the benefit of Mg from biocompatibility perspectives. We studied the effect of Ti and Mg as base materials for implants from mechanical perspectives, where we focused on the displacements at the fracture site of the tibia and their influence on the stimulus for bone healing. We found out that in comparison to Ti, Mg implants have minimal stress shielding problem, only which led to better mechanical stimulus at the fracture site.

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.

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.

The regulation of self-tolerance and the role of inflammasome molecules.

Inflammasome molecules make up a family of receptors that typically function to initiate a proinflammatory response upon infection by microbial pathogens. Dysregulation of inflammasome activity has been linked to unwanted chronic inflammation, which has also been implicated in certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and related animal models. Classical inflammasome activation-dependent events have intrinsic and extrinsic effects on both innate and adaptive immune effectors, as well as resident cells in the target tissue, which all can contribute to an autoimmune response. Recently, inflammasome molecules have also been found to regulate the differentiation and function of immune effector cells independent of classical inflammasome-activated inflammation. These alternative functions for inflammasome molecules shape the nature of the adaptive immune response, that in turn can either promote or suppress the progression of autoimmunity. In this review we will summarize the roles of inflammasome molecules in regulating self-tolerance and the development of autoimmunity.

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.

[Movement analysis and musculoskeletal simulation in non-union treatment-Experiences and first clinical results]. / Bewegungsanalyse und muskuloskeletale Simulation in der Pseudarthrosentherapie ­ Erfahrungen und erste klinische Ergebnisse.

BACKGROUND: The mechanical boundary conditions of the non-union and osteosynthetic construct are a key determinant of fracture healing after revision surgery. Aim of this study was to introduce a movement analysis and simulation workflow to determine the mechanical conditions during non-union healing in vivo. MATERIAL AND METHODS: On an individual case basis after non-union revision surgery we performed an accelerometry-based movement analysis. The results were then used as input for a musculoskeletal simulation of the non-union, osteosynthetic construct as well as adjacent joints mechanical boundary conditions. RESULTS: A total of 13 patients were analyzed with our new workflow. The introduced protocol allows an in vivo determination of the mechanical boundary conditions. On clinical follow-up all patients showed radiographic consolidation of the non-union. CONCLUSION: The introduced workflow allows a clinically applicable determination of the mechanical boundary conditions of fracture and non-union healing. Further studies can now determine the effect of the introduced technique for mechanically optimized postoperative aftercare regimes as well as biomechanically adapted surgical treatment.

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.

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.

A GPU-based caching strategy for multi-material linear elastic FEM on regular grids.

In this study, we present a novel strategy to the method of finite elements (FEM) of linear elastic problems of very high resolution on graphic processing units (GPU). The approach exploits regularities in the system matrix that occur in regular hexahedral grids to achieve cache-friendly matrix-free FEM. The node-by-node method lies in the class of block-iterative Gauss-Seidel multigrid solvers. Our method significantly improves convergence times in cases where an ordered distribution of distinct materials is present in the dataset. The method was evaluated on three real world datasets: An aluminum-silicon (AlSi) alloy and a dual phase steel material sample, both captured by scanning electron tomography, and a clinical computed tomography (CT) scan of a tibia. The caching scheme leads to a speed-up factor of ×2-×4 compared to the same code without the caching scheme. Additionally, it facilitates the computation of high-resolution problems that cannot be computed otherwise due to memory consumption.

The protective effect of betacellulin against acute pancreatitis is ERBB4 dependent.

BACKGROUND: The EGFR ligand betacellulin (BTC) has been previously shown to protect mice against experimentally induced acute pancreatitis (AP). BTC binds both autonomous ERBB receptors EGFR and ERBB4. In this study, we evaluated the mechanism underlying the protection from AP-associated inflammation in detail. METHODS: AP was induced with cerulein or L-arginine and investigated in a pancreas-specific ERBB4 knockout and in an EGFR knockdown mouse model (EgfrWa5/+). Pancreatitis was evaluated by scoring inflammation, necrosis, and edema, while microarrays were performed to analyze alterations in the transcriptome between mice with AP and animals which were protected against AP. The intracellular domain (ICD) of ERBB4 was analyzed in different cell compartments. RESULTS: While the pancreas of BTC transgenic mice in the background of EgfrWa5/+ is still protected against AP, the BTC-mediated protection is no longer present in the absence of ERBB4. We further demonstrate that BTC activates the ICD of ERBB4, and increases the expression of the extracellular matrix (ECM) proteins periostin and matrix gla protein as well as the ECM modulators matrix metalloproteinases 2 and 3, but only in the presence of ERBB4. Notably, the increased expression of these proteins is not accompanied by an increased ECM amount. CONCLUSIONS: These findings suggest that BTC derivates, as a drug, or the ERBB4 receptor, as a druggable target protein, could play an important role in modulating the course of AP and even prevent AP in humans.

RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis.

Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.

Validation and reliability testing of a new, fully integrated gait analysis insole.

BACKGROUND: A new tool (OpenGo, Moticon GmbH) was introduced to continuously measure kinetic and temporospatial gait parameters independently through an insole over up to 4 weeks. The goal of this study was to investigate the validity and reliability of this new insole system in a group of healthy individuals. METHODS: Gait data were collected from 12 healthy individuals on a treadmill at two different speeds. In total, six trials of three minutes each were performed by every participant. Validation was performed with the FDM-S System (Zebris). Complete sensor data were used for a within test reliability analysis of over 10000 steps. Intraclass correlation was calculated for different gait parameters and analysis of variance performed. RESULTS: Intraclass correlation for the validation was >0.796 for temporospatial and kinetic gait parameters. No statistical difference was seen between the insole and force plate measurements (difference between means: 36.3 ± 27.19 N; p = 0.19 and 0.027 ± 0.028 s; p = 0.36). Intraclass correlation for the reliability was >0.994 for all parameters measured. CONCLUSION: The system is feasible for clinical trials that require step by step as well as grouped analysis of gait over a long period of time. Comparable validity and reliability to a stationary analysis tool has been shown.

Less than full circumferential fusion of a tibial nonunion is sufficient to achieve mechanically valid fusion--proof of concept using a finite element modeling approach.

BACKGROUND: Although minimally invasive approaches are widely used in many areas of orthopedic surgery nonunion therapy remains a domain of open surgery. Some attempts have been made to introduce minimally invasive procedures into nonunion therapy. However, these proof of concept studies showed fusion rates comparable to open approaches never gaining wider acceptance in the clinical community. We hypothesize that knowledge of mechanically relevant regions of a nonunion might reduce the complexity of percutaneous procedures, especially in complex fracture patterns, and further reduce the amount of cancellous bone that needs to be transplanted. The aim of this investigation is to provide a proof of concept concerning the hypothesis that mechanically stable fusion of a nonunion can be achieved with less than full circumferential fusion. METHODS: CT data of an artificial tibia with a complex fracture pattern and anatomical LCP are converted into a finite element mesh. The nonunion area is segmented. The finite element mesh is assigned mechanical properties according to data from the literature. An optimization algorithm is developed that reduces the number of voxels in the non union area until the scaled von Mises stress in the implant reaches 20% of the maximum stress in the implant/bone system that occurs with no fusion in the nonunion area at all. RESULTS: After six iterations of the optimization algorithm the number of voxels in the nonunion area is reduced by 96.4%, i.e. only 3.6% of voxels in the non union area are relevant for load transfer such that the von Mises stress in the implant/bone system does not exceed 20% of the maximal scaled von Mises stress occurring in the system with no fusion in the non union area at all. CONCLUSIONS: The hypothesis that less than full circumferential fusion is necessary for mechanical stability of a nonunion is confirmed. As the model provides only qualitative information the observed reduction of fusion area may not be taken literally but needs to be calibrated in future experiments. However this proof of concept provides the mechanical foundation for further development of minimally invasive approaches to delayed union and nonunion therapy.

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis.

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic Kras(G12D)-dependent transformation of the pancreas.